NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.

Kruger L, Light AR, editors. Translational Pain Research: From Mouse to Man. Boca Raton, FL: CRC Press/Taylor & Francis; 2010.

Cover of Translational Pain Research

Translational Pain Research: From Mouse to Man.

Show details

Chapter 2Neurotrophic Factors and Nociceptor Sensitization

and .

Chronic pain affects the lives of millions of people, and its treatment remains one of the most challenging problems faced by clinicians who can offer their patients few if any effective means of relief devoid of serious side effects. Chronic pain commonly arises following injury to the peripheral nervous system, and this is termed neuropathic pain. A major problem in developing effective treatments for chronic neuropathic pain lies in the translation of basic science research using animal models to the clinic. The consensus arising from both clinical and preclinical data is that peripheral neuropathic pain reflects aberrant activity in subsets of primary afferent neurons. However, there is little agreement on which subpopulations are responsible for each and/or all aspects of neuropathic pain, which afferents are necessary for the initiation of neuropathic pain, and whether the same afferents continue to play the same role over time. The unraveling of neuropathic pain requires the development of new approaches that allow investigators to selectively identify and modulate activity in specific subsets of sensory neurons believed to be involved in this process. Here we will discuss recent developments in our understanding of possible molecular mechanisms involved in modulation of primary sensory neuron function and new experimental methods for investigating unique subsets. In addition, we will discuss similarities in sensory neurons across species and the parallel changes in function observed in animal models and human pain disorders.

Primary afferent neurons have their cell bodies housed in the dorsal root ganglia (DRG) or trigeminal ganglia (TG) and convey somatosensory information from the periphery to the central nervous system (CNS). Specific subpopulations of afferents convey various modalities of sensory information such as mechanical, thermal, and chemical sensation. In general, afferents can be divided into cell body diameter and axon caliber, which correlates with myelin thickness (or absence of myelination) and conduction velocity. The large diameter and fastest conducting Aα- and Aβ-fibers, which immunocytochemically label for neurofilaments (e.g., NF150 and NF200), mostly respond to relatively innocuous stimuli, although there are some Aβ fibers that respond to noxious stimulation (rev. in Todd and Koerber). Examples of these fibers include rapidly and slowly adapting low-threshold mechanoreceptors. Medium diameter, mid-range conducting Aδ-fibers, some of which are immunoreactive for neurofilaments, can respond to both innocuous and noxious stimulation. Aδ-fibers respond to high- or low threshold mechanical stimulation and in some cases respond to thermal stimuli. Small-diameter, neurofilament-negative, slowly conducting C-fibers detect both noxious and innocuous stimuli and comprise additional subpopulations, with the greatest complexity within each category found in fibers that encode noxious stimulus intensities, generally referred to as nociceptors. The majority of nociceptive afferents respond to multiple types of stimuli (i.e., polymodal nociceptors), while others only respond to a single stimulus modality (Figure 2.1). In addition to subdivision by modality, nociceptors can be further differentiated based on target of innervation (cutaneous, muscle, viscera, etc.) and histological and biochemical properties. For example, some unmyelinated C-fiber nociceptors contain peptides, such as Substance P (SP) and calcitonin gene-related peptide (CGRP), while others are non-peptidergic but bind isolectin B4 (IB4; Bennett et al. 1996; Molliver et al. 1997). Myelinated nociceptors can also be divided into groups based on presence or lack of peptides. However, depending on the species, specific labeling patterns can vary. For example, in rats, there is a large overlap between the IB4 population and those that label for heat-transducing channel transient receptor vanilloid type 1 (TRPV1); however, in mouse, there is relatively little overlap between these markers.

FIGURE 2.1. Response properties of cutaneous A- and C-fibers in mouse.

FIGURE 2.1

Response properties of cutaneous A- and C-fibers in mouse. Both A- and C-fibers in mouse can be polymodal or responsive to a single stimulus modality. A-fibers are mostly mechanically sensitive (AM) with some of these being responsive to both mechanical (more...)

Recent studies have made progress on the relationship between function and neurochemical phenotype (Figure 2.1). Using an ex vivo skin-nerve-DRG-spinal cord preparation, single DRG neurons have been recorded intracellularly and peripheral response characteristics determined. After characterization of a sensory neuron’s peripheral response properties, the DRG cell body was filled with neurobiotin and subsequently processed immunocytochemically to determine its neurochemical identity. The results of these studies have provided new information on the relationship between functional and neurochemical phenotype. In uninjured (naïve) mice, polymodal C-fibers (CPMs) are mostly IB4+ and occasionally CGRP+, but lack TRPV1, which is known to overlap extensively with the peptidergic population of DRG neurons (Funakoshi et al. 2006; Price and Flores 2007). Mechanically insensitive C-fibers that respond to heating of the skin (CH) are consistently IB4 negative and TRPV1 positive (Woodbury et al. 2004; Lawson et al. 2008). A-fiber nociceptors do not fit into either of these categories exclusively, but most were positive for putative mechano-sensing channel, acid sensing ion channel 3 (ASIC3; McIlwrath et al. 2007).

During development, all sensory neurons are initially dependent on neurotrophic factor signaling from the periphery for survival. After migration from the neural crest, almost all neurons express the tyrosine kinase receptors trkB and trkC and are dependent on their ligands, neurotrophic factors brainderived neurotrophic factor (BDNF) and/or neurotrophin-3 (NT-3). In subsequent days, DRG neurons undergo extensive proliferation and some become trkA positive, the receptor for another neurotrophic factor, nerve growth factor (NGF). Following this period of proliferation is a phase of rapid cell death, and only cells that have access to sufficient amounts of a particular neurotrophic factor survive into adulthood.

Neurotrophic factor signaling from the periphery to DRG neurons is also thought to play a role in the maintenance of phenotype (Diamond et al. 1992), but under conditions of inflammation or nerve injury, neurotrophic factors play a role in sensory neuron sensitization and cause pain. The discussion below details the changes in neurotrophic factor expression and how they modify primary afferent response properties leading to conditions of acute and/or chronic pain.

2.1. NEUROTROPHIC FACTORS CAN SENSITIZE SPECIFIC POPULATIONS OF SENSORY NEURONS

2.1.1. Nerve Growth Factor (NGF)

NGF is the most commonly studied growth factor in relation to nociceptor sensitization and serves to promote the survival of DRG neurons during development that express its receptor, trkA (Averill et al. 1995; Huang et al. 2001; Patapoutian and Reichardt 2001). These neurons are generally part of the small and medium diameter DRG population, but some larger cells also express trkA (Wright and Snider 1995; Patapoutian and Reichardt 2001). In addition to its role in development and neuronal survival, it promotes sprouting and regulates innervation density of NGF-responsive neurons in peripheral targets in early post-natal and adult life. For example, it has been shown that ligation of a peripheral nerve induces NGF expression in its target area and these elevated levels are associated with sprouting of adjacent, non-injured afferents into the denervated region (Pertens et al. 1999). Other studies analyzing constitutive overexpression of NGF in the skin (NGF-OEs) report enhanced innervation of the epidermis by both sensory and sympathetic neurons (Albers et al. 1994; Davis et al. 1994, 1996; Goodness et al. 1997).

Although NGF appears to be necessary and beneficial for development and maintenance of the peripheral sensory neuron system (Diamond et al. 1992), it has also been shown to participate in the development of thermal and mechanical hyperalgesia (i.e., increased pain in response to normally painful stimuli; Malin et al. 2006; Pertens et al. 1999; Andreev et al. 1995; Lewin et al. 1993) and pain in disorders such as bone cancer and interstitial cystitis (Lowe et al. 1997; Sevcik et al. 2005). Rats chronically treated with NGF are hypersensitive to both mechanical and radiant heat stimulation (Lewin et al. 1993; Andreev et al. 1995; Pertens et al. 1999) in a dose-dependent fashion, and injection of NGF directly into the paw of mice induces a decrease in the paw withdrawal latency to radiant heat (Malin et al. 2006). This NGF sensitization is partially dependent on sympathetic neurons, as sympathectomy partly reduces the effect of NGF in causing hyperalgesia (Andreev et al. 1995). NGF also acts indirectly by activating mast cells and neutrophils, which in turn release additional inflammatory mediators causing hypersensitivity (Lewin et al. 1994; Andreev et al. 1995; Amann et al. 1996; Woolf et al. 1996; Bennett et al. 1998; Bennett 2001). Regardless, it is clear that NGF levels in the target tissue participate in sensitization of nociceptors. For example, NGF-OEs display increases in afferent responses to thermal and mechanical stimulation in a skin-nerve preparation. Stucky and Lewin (1999) found that large diameter Aβ non-nociceptive afferents (typically trkA negative) were unaffected by NGF overexpression, but thermal responsiveness was significantly increased in nociceptive afferents as a result of enhanced cutaneous NGF levels.

NGF-sensitive, trkA positive neurons co-label with a variety of other molecules thought to be involved in pain processing. trkA overlaps with neurons containing peptides CGRP and SP (Averill et al. 1995; Molliver and Snider 1997), known mediators of pain behaviors (Koltzenburg et al. 1999; Reeh and Kress 2001; Li et al. 2008) shown to induce hyperalgesia (Oku et al. 1987; Nakamura-Craig and Gill 1991; McMahon, 1996; Sann and Pierau 1998). This population also co-labels with TRPV1, crucial for the development of heat hyperalgesia (Caterina et al. 2000).

NGF-induced hyperalgesia may also be mediated by sodium channel, Nav1.8. In mice lacking this channel, NGF does not induce heat hyperalgesia (Kerr et al. 2001), although Nav1.8 knockout mice display indistinguishable thermal thresholds under normal conditions compared to wildtypes (WTs). Since many NGF-responsive neurons contain TRPV1, this channel is suspected of a role in NGF-mediated hypersensitivity (Caterina et al. 1997; Tominaga et al. 1998; Michael and Priestley 1999). Cultured DRG neurons treated with NGF display enhanced inward current in response to application of the TRPV1 agonist capsaicin (Shu and Mendell 1999; Caterina et al. 2000; Zhu et al. 2004). NGF can increase TRPV1 expression (Donnerer et al. 2005; Xue et al. 2007) and promote TRPV1 insertion into the plasma membrane (Zhang et al. 2005). Furthermore, anti-NGF antibodies injected into the hindpaw after peripheral inflammation decrease levels of TRPV1 in DRGs and reduce inflammation-induced hyperalgesia (Ji et al. 2002; Cheng and Ji 2008).

Given a clear role for NGF in sensory neuron sensitization and hyperalgesia, anti-NGF treatments may constitute an effective means of treating pain in humans (Anand et al. 1997; Lowe et al. 1997; Saldanha et al. 1999; Sena et al. 2006; Jimenez-Andrade et al. 2007). These hypotheses, however, have not been extensively studied (Abdiche et al. 2008) or verified. Perhaps NGF may only affect a small proportion of nociceptors in the DRG, and other molecules and neurotrophic factors most certainly are involved in hyperalgesia and overall sensory neuron sensitization.

2.1.2. Neurotrophin-3 (NT-3)

NT-3 has long been studied in association with survival and sprouting of neurons that express its receptor, trkC. trkC is mainly localized to large diameter DRG neurons although also found in some small and medium cells (Wright and Snider 1995; Molliver et al. 2005b). NT-3 plays a role in sympathetic neurons survival (Elshamy and Ernfors 1996), and increased levels of NT-3 may foster sympathetic neuron sprouting into the DRG (Zhou et al. 1999; Deng et al. 2000). Intrathecal NT-3 elicits selective regeneration of injured axons of NF200 positive DRG neurons through the dorsal root entry zone (DREZ) of the spinal cord (Ramer et al. 2000). This selective regeneration of NF200 neurons also was correlated with selective functional recovery of large myelinated A-fibers, suggesting that NT-3, like NGF, may play a dual role in regulating processes in both sympathetic and sensory neurons.

NT-3 may also play an anti-nociceptive role in neuropathic pain processing (White 2000; Park et al. 2003; Wilson-Gerwing et al. 2005; Wilson-Gerwing and Verge 2006). Delivery of NT-3 to nerve-injured rats in a rat model of neuropathic pain caused a decreased paw withdrawal threshold after thermal, but not mechanical, stimulation (Wilson-Gerwing et al. 2005). This correlates with other studies showing that under conditions of neuropathic pain, NT-3 reduces injury-induced expression of putative pain-related channels localized to small diameter nociceptors such as Nav1.8, Nav1.9 (Wilson-Gerwing et al. 2008) and TRPV1 (Wilson-Gerwing et al. 2005), although the mechanism of this action is unclear since the majority of small diameter nociceptors lack trkC. However, it has also been shown that NT-3 has low-affinity trkA binding (Kullander and Ebendal 1994; Ryden and Ibanez 1996); thus it is possible that under conditions of inflammation and nerve injury, NT-3 may have a greater affect on these cells compared to naïve conditions.

Although NT-3 may be anti-nociceptive, NT-3 may also play a pro-nociceptive role in conditions such as spondyloarthritis synovitus (Rihl et al. 2005) and colitis (Flamig et al. 2001). In support of this, another recent study has shown that cutaneous overexpression of NT-3 enhances the mechanical response properties of larger diameter non-nociceptive and nociceptive A-fibers (McIlwrath et al. 2007). Slowly adapting type 1 (SA1) and Aδ-nociceptors display significantly higher firing rates to mechanical stimulation in an ex vivo skin-nerve-DRG-spinal cord preparation compared to WTs (Woodbury et al. 2004; McIlwrath et al. 2007). These A-fibers are immunopositive for trkC and ASIC3, and the overexpression of NT-3 is correlated with increased ASIC1 and ASIC3 mRNA expression in DRGs. Although ASIC3 is co-expressed in both trkA and trkC neurons and overlaps with some peptidergic sensory neurons in the DRGs (Molliver et al. 2005b), these new results suggest an additional role for NT-3 in pain processing and sensory neuron sensitization that may not be anti-nociceptive and involves the myelinated DRG population.

2.1.3. Glial Cell Line-Derived Neurotrophic Factor

Another family of growth factors that may play a role in sensory neuron sensitivity is the glial cell line-derived neurotrophic factor (GDNF) family which includes GDNF, neurturin, and artemin. GDNF family ligands signal through a different tyrosine kinase receptor (ret), but neurotrophic factor specificity is conferred by a co-receptor. GDNF binds mainly to GDNF Family Receptor α1 (GFRα1; Treanor et al. 1996; Baloh et al. 1997; Klein et al. 1997; Enokido et al. 1998; Milbrandt et al. 1998; Trupp et al. 1998) and to a degree to GFRα2 (Sanicola et al. 1997) to promote the survival of this neurotrophic factor responsive population of sensory neurons. Neurturin has the highest affinity for GFRα2, although it binds GFRα1 to a lesser extent (Jing et al. 1997). GFRα3 is highly selective for the GDNF family member artemin, which does not bind to either GFRα1 or GFRα2 (Baloh et al. 1998; Orozco et al. 2001).

One of the main roles of GDNF family neurotrophic factors is in neuronal survival and maturation in early postnatal life. During the first week of postnatal development (P0–7), a subset of small sensory neurons downregulate trkA (Molliver and Snider 1997) and become dependent on GDNF for survival (Molliver et al. 1997). During this period, ret-positive cells begin to co-label extensively with IB4, which is not colocalized with trkA. For some sensory neurons, this is maintained throughout life. In rodents, the trkA and ret-positive sensory neurons develop into separate populations (Molliver et al. 1997). For example, the NGF- and GDNF-responsive populations of sensory neurons also terminate in slightly different regions of the skin and spinal cord (Coimbra et al. 1974; Silverman and Kruger 1990; Zylka et al. 2003, 2005; Lindfors et al. 2006; Liu et al. 2008). In addition, constitutive overexpression of GDNF (GDNF-OE) in the skin causes selective survival of the IB4 population of sensory neurons and an increase in the innervation density of the epidermis and lamina II of the dorsal horn (Zwick et al. 2002), a result suggesting possible fundamental differences between the functional properties of the GDNF-responsive population of sensory neurons from other neurotrophic factor responsive populations.

There are many studies that support this possibility. For example, IB4-positive neurons appear to have smaller noxious heat-activated currents compared to IB4-negative neurons (Stucky and Lewin 1999). Furthermore, in vitro treatment of primary DRG neurons with GDNF does not cause an increase in the percentage of neurons that respond to heat in the same manner as NGF (Stucky and Lewin 1999). It has thus been hypothesized that these two populations of nociceptors are involved in different aspects of pain (Snider and McMahon 1998).

Acute exogenous GDNF can lead to the prevention of injury-induced pain behaviors (Boucher et al. 2000); however, other studies suggest a possible pro-nociceptive role for GDNF. Studies using GDNF-OEs in which constitutive GDNF is expressed in the skin did not alter heat or mechanical withdrawal responses (Zwick et al. 2002). In addition, GDNF-OEs also had higher levels of mRNA in the DRGs for kappa opioid receptor 1 (KOR1), metabotropic glutamate receptor R1 (mGluR1), and TRPV2; and a decrease in delta opioid receptor 1 (DOR1) compared to WTs (Zwick et al. 2003). After peripheral inflammation, GDNF-OEs express less TRPV1 and NMDA receptor subunit NR1 but higher levels of μ opioid receptor (MOR) and κopioid receptor (KOR) in the DRGs compared to WTs (Molliver et al. 2005a).

These data make understanding the role of GDNF on nociceptor sensitization difficult, but a recent study analyzing single DRG neurons has provided some insight (Albers et al. 2006). Mice with enhanced levels of GDNF in the skin show that mechanically sensitive C-fibers have significantly lower mechanical thresholds compared to WTs. These mice also reveal a significant increase in the percentage of C-fibers that responded to heat (Albers et al. 2006). Neurochemical identification of individually characterized sensory neurons showed that only non-peptidergic, IB4 positive C-polymodal fibers were affected by the excess cutaneous GDNF. Other fiber types were unaffected, such as the high-threshold, mechanically sensitive, IB4-and CGRP+ afferents and low-threshold mechanically sensitive afferents that were neither IB4 nor CGRP positive (Albers et al. 2006). The mechanism of this sensitization in this population of CPM fibers is unclear, although GDNF-OEs did have increased levels of putative mechanosensitive ion channels, ASIC2a and ASIC2b, predominantly localized to the IB4 positive population.

These data caution that behavioral analysis studying the function of a single growth factor may fail to display its true purpose since single fiber analysis revealed a functional effect of chronic GDNF exposure. However, it should be noted that acute injection of GDNF into the hindpaw has been found to induce heat hyperalgesia in mice (Malin et al. 2006). Thus while GDNF may have a role in a sensory neuron sensitization, its role in pain processing is still unclear.

2.1.4. Artemin

The most recently characterized neurotrophic factor related to sensory neuron sensitization is artemin, another member of the GDNF family. Unlike GDNF and neurturin, which are slightly more promiscuous in binding GFRα receptors in the DRGs (Baloh et al. 1997; Klein et al. 1997; Enokido et al. 1998; Milbrandt et al. 1998; Trupp et al. 1998), artemin is highly selective in binding its receptor GFRct3 (Baloh et al. 1998; Orozco et al. 2001). GFRα3 co-localizes extensively with the TRPV1+, peptidergic population of sensory neurons, and rarely co-localizes with IB4 (Orozco et al. 2001; Elitt et al. 2006; Lawson et al. 2008).

Constitutive overexpression of artemin in the skin did not cause a selective survival of sensory neurons as seen in other transgenic mice overexpressing NGF (Albers et al. 1994) or GDNF (Zwick et al. 2002). Developmentally, overexpression of artemin was not found to increase the percentage of GFRα3+ cells in the DRG, but it did cause hypertrophy of the GFRα3+ population. Overproduction of artemin did result in an increase in the innervation density of GFRα3+ fibers in the skin, but did not alter the peptidergic or IB4 staining patterns in the spinal cord dorsal horn (Elitt et al. 2006). This result suggests that artemin may selectively alter the response properties of certain sensory neurons in the DRGs, but may not be involved in neuronal survival and growth to the same degree as NGF, NT-3, GDNF, and other neurotrophic factors.

As with GDNF, artemin signaling may have both pro- and antinociceptive effects. In the spinal nerve ligation (SNL) model of nerve injury in which one spinal nerve that contributes axons to the sciatic nerve is ligated and the other spinal nerves remain intact, Gardell and colleagues 2003 found that systemic delivery of artemin reduces the injury-induced decrease in paw withdrawal threshold to both mechanical and thermal stimulation. They also found that artemin reduced the capsaicin-induced release of CGRP and dynorphin, and it prevented the decrease in IB4 binding, and substance P (SP) and P2X3 immunoreactivity in DRGs. This group suggested, based on these findings, that artemin may be therapeutically useful for patients with nerve injury-induced chronic pain. However, in a study of pancreatic cancer, Ceyhan and colleagues (2007) found that artemin was enhanced in human cancer cells and hypertrophic afferents of the pancreas and actually promoted cancer cell invasion in pancreatic ductal adenocarcinoma, but these changes in artemin did not correlate with pain. Additional future studies involving delivery of artemin in humans would facilitate the determination of the benefits of artemin in relieving chronic pain.

Although these studies may suggest that artemin could be antinociceptive, other studies also show that enhanced cutaneous artemin could also sensitize nociceptors. Polymodal C-fibers (CPM) in artemin overexpressors (ART-OEs) possess lower heat thresholds and higher firing rates per degree, and dissociated DRG neurons from these mice reveal significantly larger responses to capsaicin application, which correlated with the observed increase in TRPV1 expression in the DRGs in these animals (Elitt et al. 2006). These results conflict with data reported from naive mice (Woodbury et al. 2004; Lawson et al. 2008) in which the vast majority of cutaneous CPM neurons were found to be IB4+ and TRPV1-. Recent data however have shown that several CPMs in ART-OEs contained TRPV1 (Albers K.M. and Koerber H.R. unpublished), suggesting that enhanced levels of artemin may induce a neurochemical switch in some neurons. One hypothesis is that the GFRα3+/ TRPV1+ CH neurons gain mechanical sensitivity in the presence of excess artemin. In any case, artemin is likely to have a significant role in nociceptive processing under normal conditions as well as after peripheral injury.

2.2. PERIPHERAL INJURY CAUSES SENSITIZATION OF NOCICEPTORS

The typical features of nociceptor sensitization include increased prevalence of cells with ongoing activity, an increase in the level of ongoing activity, changes in stimulus–response properties, and changes in the expression of transmitters and receptors in the sensory ganglia (Koltzenburg et al. 1999). These changes in afferent properties depend on a number of factors including the type and site of injury and the time after injury. Recently, it has also been determined that there are significant changes in various molecules at the site of tissue injury and in the targets of injured afferents that may lead to the changes observed in the sensory neurons. These include, but are not limited to, changes in inflammatory mediators, signaling molecules, CGRP, bradykinin, prostaglandins, serotonin, histamine, H+, ATP, and neurotrophic factors (Reeh and Kress 2001; Koltzenberg et al. 1999; Malin et al. 2006; Li et al. 2008; Jankowski et al. 2009a). Combinations of these changes probably underlie various aspects of thermal and mechanical pain, including ongoing pain, hyperalgesia, and the perception of pain in response to normally innocuous stimuli (allodynia).

These features seem to be common among many types of injury in animal models of persistent pain including plantar incision (Pogatzki et al. 2002; Woo et al. 2004; Banik and Brennan 2004, 2009; Mujenda et al. 2007), SNL (Wu et al. 2001; Shim et al. 2005), chronic constriction injury (Aley and Levine 2002; Milligan et al. 2004; Wilson-Gerwing et al. 2008; Zhang et al. 2008), and axotomy and regeneration (Michalski et al. 2008; Jankowski et al. 2009a). In these neuropathic pain models two distinct patterns of change emerge. One set of changes occurs in the injured afferents, which includes the emergence of spontaneous activity and alterations in the pattern of transmitter expression (see above) that appears to reflect, at least in part, the loss of access to neurotrophic factors supplied by the target of innervation. The second set of changes occurs in the “uninjured” neighboring afferents. These fibers are exposed to aforementioned inflammatory mediators released during the process of Wallerian degeneration of the injured axons and alterations in neurotrophic factors (among other molecules) present in the denervated or partially denervated target tissue and/or the injury site that serve to promote regeneration of the injured fibers. The changes in the uninjured afferents are similar to those described in the presence of inflammation (Koltzenburg et al. 1999; Djouhri et al. 2006). There is also evidence of time-dependent changes in both injured and uninjured afferents, suggesting that the relative contribution of each to various aspects of pain may change with time following injury.

Although there are several molecular mechanisms that could be involved in nociceptor sensitization after injury, enhanced neurotrophic factor signaling from the periphery may be vital regardless of whether an afferent is injured or uninjured. After all of these injuries, neurotrophic factor levels are changed in the DRGs, injury site, and/or peripheral innervation field (e.g., Malin et al. 2006; Jankowski et al. 2009a; above). For example, NGF has been shown by many groups to be upregulated in the peripheral target tissue after inflammation and nerve injury (Weskamp and Otten 1987; Woolf et al. 1994; Braun et al. 1998; Malin et al. 2006; Nicol and Vasko 2007; Paterson et al. 2008; Jankowski et al. 2009a), which could play a role in the sensitization of some of the peptidergic, trkA+ neurons. Nerve lesion has also been shown to induce NT-3 upregulation in the nerve at the site of afferent injury (Lee et al. 2001; Campana et al. 2006; Hoke et al. 2006) and in the target regions (Jankowski et al. 2009a). This increase could play a role in the sensitization of trkC+/ ASIC3+ myelinated nociceptors (McIlwrath et al. 2007). GDNF has been shown to be upregulated in the cutaneous tissue after axotomy (Jankowski et al. 2009a) and after peripheral inflammation (Malin et al. 2006), and mechanically sensitive neurons in GDNF-OEs are sensitized to mechanical stimulation (Albers et al. 2006) and acute injection of GDNF into the skin of mice induces some pain behaviors (Malin et al. 2006). These actions may rely on sensitization of the IB4+ subset of sensory neurons (Albers et al. 2006). Artemin has also been found to be upregulated in the skin after inflammation (Malin et al. 2006) and nerve injury (Jankowski et al. 2009a) and may alter the GFRα3+/ TRPV1+ CH neurons by causing some of these cells to gain mechanical sensitivity (Elitt et al. 2006; Albers K.M. and Koerber H.R. unpublished). This phenotypic switch suggests that artemin may play a crucial role in nociceptor sensitization and development of pain. From these results, it is clear that altered levels of several neurotrophic factors can cause sensory neuron sensitization after nerve injury, which may lead to conditions of chronic pain.

Although it is apparent that altered nociceptor properties are critical for both the initiation and maintenance of pain, the relative contribution of specific subpopulations is unknown. Recent data from a mouse model of nociceptor sensitization after injury reveals that two specific populations of C-fibers are affected differently by nerve injury. GDNF-sensitive, IB4+/ TRPV1- CPM neurons (Albers et al. 2006) exhibit lower heat thresholds after axotomy and regeneration. On the other hand, artemin-sensitive GFRα3+/TRPV1+/IB4- CH fibers (Elitt et al. 2006; Lawson et al. 2008) were not sensitized but increased in number compared to the naive condition, apparently recruited from a silent population. Interestingly, some CPM neurons also stained positive for TRPV1 after injury. Immunolabeling also showed that there was an increase in the overlap between IB4 and TRPV1 after regeneration. However, this was found to be due to an increase in the number of cells binding IB4, not an increase in the number of TRPV1-positive cells (Jankowski et al. 2009a). Taken together these results suggest that in addition to CH fiber recruitment, some of the artemin-responsive CH fibers may be gaining mechanical sensitivity after injury similar to what has been shown in the ART-OEs (Elitt et al. 2006).

2.3. CLINICAL RELEVANCE

Clinical data on the role of atypical afferent activity in pain states comes from the use of regional nerve blocks (Hsieh et al. 1995), surgical interventions and analyses of excised nerves (Hilz 2002; Brisby 2006), and microneurography (Orstavik et al. 2006). For example, microneurographic recordings suggest that a specific subpopulation of C-fiber nociceptors, referred to as mechanically insensitive afferents (MIAs) in healthy control subjects, play a major role in the maintenance of chronic neuropathic pain. Fibers that have the biophysical properties of MIAs in patients with erythromyalgia acquire mechanical responsiveness (Orstavik et al. 2003); and in patients with diabetic neuropathy, mechanically insensitive, heat-sensitive afferents increase in prevalence compared to normal control subjects (Orstavik et al. 2006). The MIAs found in humans (Schmidt et al. 1995) have several characteristics in common with the TRPV1+ CH neurons characterized in mouse (Lawson et al. 2008; Jankowski et al. 2009a) and non-human primates (Baumann et al. 1991). In addition to the lack of mechanical sensitivity, these fibers are among the slowest-conducting cutaneous fibers in the DRGs. Although murine CH fibers are the only cutaneous fibers to contain TRPV1 (Lawson et al. 2008), MIA fibers found in humans and CH fibers in non-human primates are the only cells to respond to TRPV1 agonist capsaicin in a way that correlates with pain assessments following capsaicin injection (Baumann et al. 1991; Schmelz et al. 2000; Ringkamp et al. 2001; Jankowski et al. 2009a). In addition, following nerve injury and regeneration in mice, some CH fibers apparently are recruited from a silent population of DRG neurons, and some gain mechanical sensitivity (Jankowski et al. 2009a) similar to that reported for MIA fibers in microneurographic recordings from chronic pain patients (Orstavik et al. 2003, 2006). These results suggest that the CH/MIA fibers may play the largest role in the development of chronic neuropathic pain.

2.4. FUTURE TREATMENTS FOR NEUROTROPHIC FACTOR-INDUCED NOCICEPTOR SENSITIZATION

These data suggest that different populations of sensory neurons may actually be involved in different aspects of tactile and thermal detection. The changes in the artemin/NGF-responsive, peptidergic, TRPV1+/ GFRα3+/ IB4-, mechanically insensitive, heat-sensitive afferents (CHs) may play a dominant role in thermal hyperalgesia; and the GDNF responsive, IB4+/TRPV1- polymodal nociceptors (CPMs) may be more important in mechanical and/or other aspects of nociceptive processing. A recent publication supports this hypothesis in which they have shown that ablation of the TRPV1+ (CH) population of sensory neurons only resulted in changes in thermal, not mechanical, sensitivity. Conversely, elimination of the IB4+ (CPMs) cells only caused a deficit in mechanical sensitivity (Cavanaugh et al. 2009). Further support for this hypothesis comes from studies using TRPV1 knockout mice that have normal heat sensitivity but do not develop heat hyperalgesia after inflammation (Caterina et al. 2000; Woodbury et al. 2004).

It is unclear why the GDNF-sensitive IB4+ CPM neurons (Albers et al. 2006) are sensitized to heat after injury and inflammation (Jankowski et al. 2008, 2009a) if they may not be involved in heat hyperalgesia. Injection of GDNF was found to induce heat hyperalgesia in mice, which should affect these neurons specifically (Malin et al. 2006). One possible explanation is that these fibers engage central networks that are more involved in processing mechanical, rather than thermal, information. Nevertheless, these data do suggest that modality-specific aspects of pain syndrome development may be determined by which subpopulation of nociceptors is most affected.

The difficulty in developing effective treatments for chronic pain syndromes has come in translating work performed in the laboratory to the clinic. The inability to selectively silence specific subpopulations of afferents has seemingly proven to be a major barrier to the development of effective therapeutic interventions devoid of side effects. Outside of conventional pharmacological treatments, which are not adequate at treating all pain conditions, recent developments have begun to test the validity of utilizing genetically engineered viruses to deliver various molecules involved in pain processing to sensory neurons in order to treat pain states. There are obvious limitations and potentially dangerous side effects from the use of these methodologies since viruses require host cell invasion and, in certain cases, manipulation of the cell’s genome.

One way to develop appropriate treatments for chronic pain using animal models derives from recent studies using experimental manipulation of the endogenous RNA interference (RNAi) pathway. RNAi targets the transcriptional output of the cell rather than the genome itself. Short (19–21) base-pair RNA duplexes that have perfect complementarity to a particular mRNA induce degradation of the mRNA so that it cannot be translated into protein. Since there are a variety of changes in gene expression in DRG neurons under conditions of inflammation and nerve injury, targeted RNA degradation may be a better way to selectively alter the function of specific subsets of sensory neurons. A new study using injection of modified small interfering RNAs (siRNAs) into specific nerves in vivo has proven to be effective in inducing functional changes in identified nerves (Jankowski et al. 2008, 2009b). Another recent study using this technology has also shown that targeted inhibition of the inflammation-induced increase in purinergic receptor expression (P2Y1) had the effect of completely blocking the inflammation-induced decrease in CPM thermal threshold (Jankowski et al. 2008). Only IB4+ CPM neurons are thought to contain P2Y1 (Dussor et al. 2008), and P2Y1-negative sensory neurons did not appear to be affected by injection of P2Y1 targeting siRNAs. Moreover, the injection of modified siRNAs did not cause the levels of P2Y1 mRNA to drop below baseline and did not induce a hyposensitive state in CPM neurons. Thus this new strategy for specifically targeting particular molecules in identified afferents without inducing sub-baseline neuronal activity after inflammation and/or nerve injury may provide a new way to develop suitable therapeutic agents for neuropathic pain conditions. In addition, clinical use of RNAi may even offer a safe and effective means of treating conditions of chronic pain in the future.

REFERENCES

  • Abdiche YN, Malashock DS, Pons J. Probing the binding mechanism and affinity of tanezumab, a recombinant humanized anti-NGF monoclonal antibody, using a repertoire of biosensors. Protein Sci. 2008;17:1326–1335. [PMC free article: PMC2492818] [PubMed: 18505735]
  • Albers KM, Wright DE, Davis BM. Overexpression of nerve growth factor in epidermis of transgenic mice causes hypertrophy of the peripheral nervous system. J Neurosci. 1994;14:1422–1432. [PubMed: 8126547]
  • Albers KM, Woodbury CJ, Ritter AM, Davis BM, Koerber HR. Glial cell-line-derived neurotrophic factor expression in skin alters the mechanical sensitivity of cutaneous nociceptors. J Neurosci. 2006;26:2981–2990. [PubMed: 16540576]
  • Aley KO, Levine JD. Different peripheral mechanisms mediate enhanced nociception in metabolic/toxic and traumatic painful peripheral neuropathies in the rat. Neuroscience. 2002;111:389–397. [PubMed: 11983324]
  • Amann R, Schuligoi R, Lanz I, Peskar BA. Effect of a 5-lipoxygenase inhibitor on nerve growth factor-induced thermal hyperalgesia in the rat. Eur J Pharmacol. 1996;306:89–91. [PubMed: 8813619]
  • Anand P, Terenghi G, Birch R, Wellmer A, Cedarbaum JM, Lindsay RM, Williams-Chestnut RE, Sinicropi DV. Endogenous NGF and CNTF levels in human peripheral nerve injury. Neuroreport. 1997;8:1935–1938. [PubMed: 9223080]
  • Andreev N, Dimitrieva N, Koltzenburg M, McMahon SB. Peripheral administration of nerve growth factor in the adult rat produces a thermal hyperalgesia that requires the presence of sympathetic post-ganglionic neurones. Pain. 1995;63:109–115. [PubMed: 8577480]
  • Averill S, McMahon SB, Clary DO, Reichardt LF, Priestley JV. Immunocytochemical localization of trkA receptors in chemically identified subgroups of adult rat sensory neurons. Eur J Neurosci. 1995;7:1484–1494. [PMC free article: PMC2758238] [PubMed: 7551174]
  • Baloh RH, Gorodinsky A, Golden JP, Tansey MG, Keck CL, Popescu NC, Johnson EM Jr., Milbrandt J. GFRαlpha3 is an orphan member of the GDNF/neurturin/persephin receptor family. Proc Natl Acad Sci USA. 1998;95:5801–5806. [PMC free article: PMC20460] [PubMed: 9576965]
  • Baloh RH, Tansey MG, Golden JP, Creedon DJ, Heuckeroth RO, Keck CL, Zimonjic DB, Popescu NC, Johnson EM Jr., Milbrandt J. TrnR2, a novel receptor that mediates neurturin and GDNF signaling through Ret. Neuron. 1997;18:793–802. [PubMed: 9182803]
  • Banik RK, Brennan TJ. Spontaneous discharge and increased heat sensitivity of rat C-fiber nociceptors are present in vitro after plantar incision. Pain. 2004;112:204–213. [PubMed: 15494202]
  • Banik RK, Brennan TJ. TRPV1 mediates spontaneous firing and heat sensitization of cutaneous primary afferents after plantar incision. Pain. 2009;141:41–51. [PMC free article: PMC2654272] [PubMed: 19010598]
  • Baumann TK, Simone DA, Shain CN, LaMotte RH. Neurogenic hyperalgesia: the search for the primary cutaneous afferent fibers that contribute to capsaicin-induced pain and hyperalgesia. J Neurophysiol. 1991;66:212–227. [PubMed: 1919668]
  • Bennett DL. Neurotrophic factors: important regulators of nociceptive function. Neuroscientist. 2001;7:13–17. [PubMed: 11486340]
  • Bennett DL, Averill S, Clary DO, Priestley JV, McMahon SB. Postnatal changes in the expression of the trkA high-affinity NGF receptor in primary sensory neurons. Eur J Neurosci. 1996;8:2204–2208. [PubMed: 8921312]
  • Bennett DL MG, Ramachandran N, Munson JB, Averill S, Yan Q, McMahon SB, Priestly JV. A distinct subgroup of small DRG cells express GDNFF receptor components and GDNF is protective for these neurons after nerve injury. J Neurosci. 1998;18:3059–3072. [PubMed: 9526023]
  • Boucher TJ, Okuse K, Bennett DL, Munson JB, Wood JN, McMahon SB. Potent analgesic effects of GDNF in neuropathic pain states. Science. 2000;290:124–127. [PubMed: 11021795]
  • Braun A, Appel E, Baruch R, Herz U, Botchkarev V, Paus R, Brodie C, Renz H. Role of nerve growth factor in a mouse model of allergic airway inflammation and asthma. Eur J Immunol. 1998;28:3240–3251. [PubMed: 9808193]
  • Brisby H. Pathology and possible mechanisms of nervous system response to disc degeneration. J Bone Joint Surg Am. 2006;2:68–71. 88 Suppl. [PubMed: 16595447]
  • Campana WM, Li X, Dragojlovic N, Janes J, Gaultier A, Gonias SL. The low-density lipoprotein receptor-related protein is a pro-survival receptor in Schwann cells: possible implications in peripheral nerve injury. J Neurosci. 2006;26:11197–11207. [PubMed: 17065459]
  • Caterina MJ, Schumacher MA, Tominaga M, Rosen TA, Levine JD, Julius D. The capsaicin receptor: a heat-activated ion channel in the pain pathway. Nature. 1997;389:816–824. [PubMed: 9349813]
  • Caterina MJ, Leffler A, Malmberg AB, Martin WJ, Trafton J, Petersen-Zeitz KR, Koltzenburg M, Basbaum AI, Julius D. Impaired nociception and pain sensation in mice lacking the capsaicin receptor. Science. 2000;288:306–313. [PubMed: 10764638]
  • Cavanaugh DJ, Lee H, Lo L, Shields SD, Zylka MJ, Basbaum AI, Anderson DJ. Distinct subsets of unmyelinated primary sensory fibers mediate behavioral responses to noxious thermal and mechanical stimuli. PNAS. 2009 In press. [PMC free article: PMC2683885] [PubMed: 19451647]
  • Ceyhan GO, Bergmann F, Kadihasanoglu M, Erkan M, Park W, Hinz U, Giese T, et al. The neurotrophic factor artemin influences the extent of neural damage and growth in chronic pancreatitis. Gut. 2007;56:534–544. [PMC free article: PMC1856869] [PubMed: 17047099]
  • Cheng JK, Ji RR. Intracellular signaling in primary sensory neurons and persistent pain. Neurochem Res. 2008;33:1970–1978. [PMC free article: PMC2570619] [PubMed: 18427980]
  • Coimbra A, Sodre-Borges BP, Magalhaes MM. The substantia gelatinosa Rolandi of the rat. Fine structure, cytochemistry (acid phosphatase) and changes after dorsal root section. J Neurocytol. 1974;3:199–217. [PubMed: 4366333]
  • Davis BM, Albers KM, Seroogy KB, Katz DM. Overexpression of nerve growth factor in transgenic mice induces novel sympathetic projections to primary sensory neurons. J Comp Neurol. 1994;349:464–474. [PubMed: 7852636]
  • Davis BM, Wang HS, Albers KM, Carlson SL, Goodness TP, McKinnon D. Effects of NGF overexpression on anatomical and physiological properties of sympathetic postganglionic neurons. Brain Res. 1996;724:47–54. [PubMed: 8816255]
  • Deng YS, Zhong JH, Zhou XF. Effects of endogenous neurotrophins on sympathetic sprouting in the dorsal root ganglia and allodynia following spinal nerve injury. Exp Neurol. 2000;164:344–350. [PubMed: 10915573]
  • Diamond J, Holmes M, Coughlin M. Endogenous NGF and nerve impulses regulate the collateral sprouting of sensory axons in the skin of the adult rat. J Neurosci. 1992;12:1454–1466. [PubMed: 1556603]
  • Djouhri L, Koutsikou S, Fang X, McMullan S, Lawson SN. Spontaneous pain, both neuropathic and inflammatory, is related to frequency of spontaneous firing in intact C-fiber nociceptors. J Neurosci. 2006;26:1281–1292. [PubMed: 16436616]
  • Donnerer J, Liebmann I, Schicho R. Differential regulation of 3-beta-hydroxysteroid dehydrogenase and vanilloid receptor TRPV1 mRNA in sensory neurons by capsaicin and NGF. Pharmacology. 2005;73:97–101. [PubMed: 15492487]
  • Dussor G, Koerber HR, Oaklander AL, Rice FL, Molliver DC. Nucleotide signaling and cutaneous mechanisms of pain transduction. Brain Res Rev. 2008 [PMC free article: PMC3201739] [PubMed: 19171165]
  • Elitt CM, McIlwrath SL, Lawson JJ, Malin S A, Molliver DC, Cornuet PK, Koerber HR, Davis BM, Albers KM. Artemin overexpression in skin enhances expression of TRPV1 and TRPA1 in cutaneous sensory neurons and leads to behavioral sensitivity to heat and cold. J Neurosci. 2006;26:8578–8587. [PubMed: 16914684]
  • Elshamy WM, Ernfors P. A local action of neurotrophin-3 prevents the death of proliferating sensory neuron precursor cells. Neuron. 1996;16:963–972. [PubMed: 8630254]
  • Enokido Y, de Sauvage F, Hongo JA, Ninkina N, Rosenthal A, Buchman VL, Davies AM. GFR alpha-4 and the tyrosine kinase Ret form a functional receptor complex for persephin. Curr Biol. 1998;8:1019–1022. [PubMed: 9740802]
  • Flamig G, Engele J, Geerling I, Pezeshki G, Adler G, Reinshagen M. Neurotrophin and GDNF expression increases in rat adrenal glands during experimental colitis. Neuro Endocrinol Lett. 2001;22:461–466. [PubMed: 11781545]
  • Funakoshi K, Nakano M, Atobe Y, Goris RC, Kadota T, Yazama F. Differential development of TRPV1-expressing sensory nerves in peripheral organs. Cell Tissue Res. 2006;323:27–41. [PubMed: 16142452]
  • Gardell LR, Wang R, Ehrenfels C, Ossipov MH, Rossomando AJ, Miller S, Buckley C, et al. Multiple actions of systemic artemin in experimental neuropathy. Nat Med. 2003;9:1383–1389. [PubMed: 14528299]
  • Goodness TP, Albers KM, Davis FE, Davis BM. Overexpression of nerve growth factor in skin increases sensory neuron size and modulates Trk receptor expression. Eur J Neurosci. 1997;9:1574–1585. [PubMed: 9283812]
  • Hilz MJ. Assessment and evaluation of hereditary sensory and autonomic neuropathies with autonomic and neurophysiological examinations. Clin Auton Res. 2002;1:133–143. 12 Suppl. [PubMed: 12102461]
  • Hoke A, Redett R, Hameed H, Jari R, Zhou C, Li ZB, Griffin JW, Brushart TM. Schwann cells express motor and sensory phenotypes that regulate axon regeneration. J Neurosci. 2006;26:9646–9655. [PubMed: 16988035]
  • Hsieh JC, Belfrage M, Stone-Elander S, Hansson P, Ingvar M. Central representation of chronic ongoing neuropathic pain studied by positron emission tomography. Pain. 1995;63:225–236. [PubMed: 8628589]
  • Huang EJ WG, Farinas I, Backus C, Zang K, Wong SL, Reichardt LF. Expression of trk receptors in the developing mouse trigeminal ganglion: in vivo evidence for NT-3 activation of trkA and trkB in addition to trkC. Development. 2001;126:2191–2203. [PMC free article: PMC2710120] [PubMed: 10207144]
  • Jankowski MP, Lawson JJ, McIlwrath SL, Rau KK, Anderson CE, Albers KM, Koerber HR. Sensitization of cutaneous nociceptors after nerve transection and regeneration: possible role for target derived neurotrophic factor signaling. J Neurosci. 2009a;29:1636–1647. [PMC free article: PMC2768416] [PubMed: 19211871]
  • Jankowski MP, McIlwrath SL, Cornuet PK, Jing X, Salerno KM, Koerber HR, Albers KM. Soxll transcription factor regulates peripheral nerve regeneration in the adult. Brain Res. 2009b;1256:43–54. [PMC free article: PMC2666926] [PubMed: 19133245]
  • Jankowski MP, Rau KK, Soneji DJ, Anderson CE, Molliver DC, Koerber HR. Purinergic receptor P2Y1 regulates polymodal C-fiber sensitivity during peripheral inflammation. Soc Neurosci Abs. 2008;38 [PMC free article: PMC3264839] [PubMed: 22137295]
  • Ji RR, Samad TA, Jin SX, Schmoll R, Woolf CJ. p38 MAPK activation by NGF in primary sensory neurons after inflammation increases TRPV1 levels and maintains heat hyperalgesia. Neuron. 2002;36:57–68. [PubMed: 12367506]
  • Jimenez-Andrade JM, Martin CD, Koewler NJ, Freeman KT, Sullivan LJ, Halvorson KG, Barthold CM, et al. Nerve growth factor sequestering therapy attenuates non-malignant skeletal pain following fracture. Pain. 2007;133:183–196. [PubMed: 17693023]
  • Jing S, Yu Y, Fang M, Hu Z, Holst PL, Boone T, Delaney J, Schultz H, Zhou R, Fox GM. GFRαlpha-2 and GFRαlpha-3 are two new receptors for ligands of the GDNF family. J Biol Chem. 1997;272:33111–33117. [PubMed: 9407096]
  • Kerr BJ, Souslova V, McMahon SB, Wood JN. A role for the TTX-resistant sodium channel Nav 1.8 in NGF-induced hyperalgesia, but not neuropathic pain. Neuroreport. 2001;12:3077–3080. [PubMed: 11568640]
  • Klein RD, Sherman D, Ho WH, Stone D, Bennett GL, Moffat B, Vandlen R, et al. A GPI-linked protein that interacts with Ret to form a candidate neurturin receptor. Nature. 1997;387:717–721. [PubMed: 9192898]
  • Koltzenburg M, Bennett DL, Shelton DL, McMahon SB. Neutralization of endogenous NGF prevents the sensitization of nociceptors supplying inflamed skin. Eur J Neurosci. 1999;11:1698–1704. [PubMed: 10215923]
  • Kullander K, Ebendal T. Neurotrophin-3 acquires NGF-like activity after exchange to five NGF amino acid residues: molecular analysis of the sites in NGF mediating the specific interaction with the NGF high affinity receptor. J Neurosci Res. 1994;39:195–210. [PubMed: 7837289]
  • Lawson JJ, McIlwrath SL, Woodbury CJ, Davis BM, Koerber HR. TRPV1 unlike TRPV2 is restricted to a subset of mechanically insensitive cutaneous nociceptors responding to heat. J Pain. 2008;9:298–308. [PMC free article: PMC2372162] [PubMed: 18226966]
  • Lee P, Zhuo H, Helke CJ. Axotomy alters neurotrophin and neurotrophin receptor mRNAs in the vagus nerve and nodose ganglion of the rat. Brain Res Mol Brain Res. 2001;87:31–41. [PubMed: 11223157]
  • Lewin GR, Ritter AM, Mendell LM. Nerve growth factor-induced hyperalgesia in the neonatal and adult rat. J Neurosci. 1993;13:2136–2148. [PubMed: 8478693]
  • Lewin GR, Rueff A, Mendell LM. Peripheral and central mechanisms of NGF-induced hyperalgesia. Eur J Neurosci. 1994;6:1903–1912. [PubMed: 7704300]
  • Li D, Ren Y, Xu X, Zou X, Fang L, Lin Q. Sensitization of primary afferent nociceptors induced by intradermal capsaicin involves the peripheral release of calcitonin gene-related Peptide driven by dorsal root reflexes. J Pain. 2008;9:1155–1168. [PMC free article: PMC2642671] [PubMed: 18701354]
  • Lindfors PH, Voikar V, Rossi J, Airaksinen MS. Deficient nonpeptidergic epidermis innervation and reduced inflammatory pain in glial cell line-derived neurotrophic factor family receptor alpha2 knock-out mice. J Neurosci. 2006;26:1953–1960. [PubMed: 16481427]
  • Liu Y, Yang FC, Okuda T, Dong X, Zylka MJ, Chen CL, Anderson DJ, Kuner R, Ma Q. Mechanisms of compartmentalized expression of Mrg class G-protein coupled sensory receptors. J Neurosci. 2008;28:125–132. [PubMed: 18171930]
  • Lowe EM, Anand P, Terenghi G, Williams-Chestnut RE, Sinicropi DV, Osborne JL. Increased nerve growth factor levels in the urinary bladder of women with idiopathic sensory urgency and interstitial cystitis. Br J Urol. 1997;79:572–577. [PubMed: 9126085]
  • Malin S A, Molliver DC, Koerber HR, Cornuet P, Frye R, Albers KM, Davis BM. Glial cell line-derived neurotrophic factor family members sensitize nociceptors in vitro and produce thermal hyperalgesia in vivo. J Neurosci. 2006;26:8588–8599. [PubMed: 16914685]
  • McIlwrath SL, Lawson JJ, Anderson CE, Albers KM, Koerber HR. Overexpression of neurotrophin-3 enhances the mechanical response properties of slowly adapting type 1 afferents and myelinated nociceptors. Eur J Neurosci. 2007;26:1801–1812. [PubMed: 17897394]
  • McMahon SB. NGF as a mediator of inflammatory pain. Philos Trans R Soc Lond B Biol Sci. 1996;351:431–440. [PubMed: 8730782]
  • Michael GJ, Priestley JV. Differential expression of the mRNA for the vanilloid receptor subtype 1 in cells of the adult rat dorsal root and nodose ganglia and its downregula-tion by axotomy. J Neurosci. 1999;19:1844–1854. [PubMed: 10024368]
  • Michalski B, Bain JR, Fahnestock M. Long-term changes in neurotrophic factor expression in distal nerve stump following denervation and reinnervation with motor or sensory nerve. J Neurochem. 2008;105:1244–1252. [PMC free article: PMC3414532] [PubMed: 18194437]
  • Milbrandt J, de Sauvage FJ, Fahrner TJ, Baloh RH, Leitner ML, Tansey MG, Lampe PA, et al. Persephin, a novel neurotrophic factor related to GDNF and neurturin. Neuron. 1998;20:245–253. [PubMed: 9491986]
  • Milligan ED, Zapata V, Chacur M, Schoeniger D, Biedenkapp J, O’Connor KA, Verge GM, et al. Evidence that exogenous and endogenous fractalkine can induce spinal nociceptive facilitation in rats. Eur J Neurosci. 2004;20:2294–2302. [PubMed: 15525271]
  • Molliver DC, Immke DC, Fierro L, Pare M, Rice FL, McCleskey EW. ASIC3, an acid-sensing ion channel, is expressed in metaboreceptive sensory neurons. Mol Pain. 2005b:1–35. [PMC free article: PMC1308857] [PubMed: 16305749]
  • Molliver DC, Lindsay J, Albers KM, Davis BM. Overexpression of NGF or GDNF alters transcriptional plasticity evoked by inflammation. Pain. 2005a;113:277–284. [PubMed: 15661434]
  • Molliver DC, Snider WD. Nerve growth factor receptor TrkA is down-regulated during postnatal development by a subset of dorsal root ganglion neurons. J Comp Neurol. 1997;381:428–438. [PubMed: 9136800]
  • Molliver DC, Wright DE, Leitner ML, Parsadanian AS, Doster K, Wen D, Yan Q, Snider WD. IB4-binding DRG neurons switch from NGF to GDNF dependence in early postnatal life. Neuron. 1997;19:849–861. [PubMed: 9354331]
  • Mujenda FH, Duarte AM, Reilly EK, Strichartz GR. Cutaneous endothelin-A receptors elevate post-incisional pain. Pain. 2007;133:161–173. [PMC free article: PMC2753884] [PubMed: 17467172]
  • Nagy JI, Hunt SP. Fluoride-resistant acidphosphatase-containing neurones in dorsal root ganglia are separate from those containing substance P or somatostatin. Neuroscience. 1982;7:89–97. [PubMed: 6176904]
  • Nakamura-Craig M, Gill BK. Effect of neurokinin A, substance P and calcitonin gene related peptide in peripheral hyperalgesia in the rat paw. Neurosci Lett. 1991;124:49–51. [PubMed: 1713317]
  • Nicol GD, Vasko MR. Unraveling the story of NGF-mediated sensitization of nociceptive sensory neurons: ON or OFF the Trks? Mol Interv. 2007;7:26–41. [PubMed: 17339604]
  • Oku R, Satoh M, Fujii N, Otaka A, Yajima H, Takagi H. Calcitonin gene-related peptide promotes mechanical nociception by potentiating release of substance P from the spinal dorsal horn in rats. Brain Res. 1987;403:350–354. [PubMed: 2435372]
  • Orozco OE, Walus L, Sah DW, Pepinsky RB, Sanicola M. GFRαlpha3 is expressed predominantly in nociceptive sensory neurons. Eur J Neurosci. 2001;13:2177–2182. [PubMed: 11422460]
  • Orstavik K, Namer B, Schmidt R, Schmelz M, Hilliges M, Weidner C, Carr RW, Handwerker H, Jorum E, Torebjork HE. Abnormal function of C-fibers in patients with diabetic neuropathy. J Neurosci. 2006;26:11287–11294. [PubMed: 17079656]
  • Orstavik K, Weidner C, Schmidt R, Schmelz M, Hilliges M, Jorum E, Handwerker H, Torebjork E. Pathological C-fibres in patients with a chronic painful condition. Brain. 2003;126:567–578. [PubMed: 12566278]
  • Park SY, Choi JY, Kim RU, Lee YS, Cho HJ, Kim DS. Downregulation of voltage-gated potassium channel alpha gene expression by axotomy and neurotrophins in rat dorsal root ganglia. Mol Cells. 2003;16:256–259. [PubMed: 14651270]
  • Patapoutian A, Reichardt LF. Trk receptors: mediators of neurotrophin action. Curr Opin Neurobiol. 2001;11:272–280. [PubMed: 11399424]
  • Paterson S, Schmelz M, McGlone F, turn er G, Rukwied R. Facilitated neurotrophin release in sensitized human skin. Eur J Pain. 2008 [PubMed: 18571954]
  • Pertens E, Urschel-Gysbers BA, Holmes M, Pal R, Foerster A, Kril Y, Diamond J. Intraspinal and behavioral consequences of nerve growth factor-induced nociceptive sprouting and nerve growth factor-induced hyperalgesia compared in adult rats. J Comp Neurol. 1999;410:73–89. [PubMed: 10397396]
  • Pogatzki EM, Gebhart GF, Brennan TJ. Characterization of Adelta- and C-fibers innervating the plantar rat hindpaw one day after an incision. J Neurophysiolol. 2002;87:721–731. [PubMed: 11826041]
  • Price TJ, Flores CM. Critical evaluation of the colocalization between calcitonin gene-related peptide, substance P, transient receptor potential vanilloid subfamily type 1 immunoreactivities, and isolectin B4 binding in primary afferent neurons of the rat and mouse. J Pain. 2007;8:263–272. [PMC free article: PMC1899162] [PubMed: 17113352]
  • Ramer MS, Priestley JV, McMahon SB. Functional regeneration of sensory axons into the adult spinal cord. Nature. 2000;403:312–316. [PubMed: 10659850]
  • Reeh PW, Kress M. Molecular physiology of proton transduction in nociceptors. Curr Opin Pharmacol. 2001;1:45–51. [PubMed: 11712534]
  • Rihl M, Kruithof E, Barthel C, De Keyser F, Veys EM, Zeidler H, Yu DT, Kuipers JG, Baeten D. Involvement of neurotrophins and their receptors in spondyloar-thritis synovitis: relation to inflammation and response to treatment. Ann Rheum Dis. 2005;64:1542–1549. [PMC free article: PMC1755273] [PubMed: 15817657]
  • Ringkamp M, Peng YB, Wu G, Hartke TV, Campbell JN, Meyer RA. Capsaicin responses in heat-sensitive and heat-insensitive A-fiber nociceptors. J Neurosci. 2001;21:4460–4468. [PubMed: 11404433]
  • Ryden M, Ibanez CF. Binding of neurotrophin-3 to p75LNGFR, TrkA, and TrkB mediated by a single functional epitope distinct from that recognized by trkC. J Biol Chem. 1996;271:5623–5627. [PubMed: 8621424]
  • Saldanha G, Hongo J, Plant G, Acheson J, Levy I, Anand P. Decreased CGRP, but preserved Trk A immunoreactivity in nerve fibres in inflamed human superficial temporal arteries. J Neurol Neurosurg Psychiatry. 1999;66:390–392. [PMC free article: PMC1736259] [PubMed: 10084541]
  • Sanicola M, Hession C, Worley D, Carmillo P, Ehrenfels C, Walus L, Robinson S, et al. Glial cell line-derived neurotrophic factor-dependent RET activation can be mediated by two different cell-surface accessory proteins. Proc Natl Acad Sci USA. 1997;94:6238–6243. [PMC free article: PMC21033] [PubMed: 9177201]
  • Sann H, Pierau FK. Efferent functions of C-fiber nociceptors. J Rheumatol. 1998;2:8–13. 57 Suppl. [PubMed: 10025074]
  • Schmelz M, Schmid R, Handwerker HO, Torebjork HE. Encoding of burning pain from capsaicin-treated human skin in two categories of unmyelinated nerve fibres. Brain. 2000;3:560–571. 123. [PubMed: 10686178]
  • Schmidt R, Schmelz M, Forster C, Ringkamp M, Torebjork E, Handwerker H. Novel classes of responsive and unresponsive C nociceptors in human skin. J Neurosci. 1995;15:333–341. [PubMed: 7823139]
  • Sena CB, Salgado CG, Tavares CM, Da Cruz CA, Xavier MB, Do Nascimento JL. Cyclosporine A treatment of leprosy patients with chronic neuritis is associated with pain control and reduction in antibodies against nerve growth factor. Lepr Rev. 2006;77:121–129. [PubMed: 16895068]
  • Sevcik MA, Ghilardi JR, Peters CM, Lindsay TH, Halvorson KG, Jonas BM, Kubota K, et al. Anti-NGF therapy profoundly reduces bone cancer pain and the accompanying increase in markers of peripheral and central sensitization. Pain. 2005;115:128–141. [PubMed: 15836976]
  • Shim B, Kim DW, Kim BH, Nam TS, Leem JW, Chung JM. Mechanical and heat sensitization of cutaneous nociceptors in rats with experimental peripheral neuropathy. Neuroscience. 2005;132:193–201. [PubMed: 15780478]
  • Shu X, Mendell LM. Nerve growth factor acutely sensitizes the response of adult rat sensory neurons to capsaicin. Neurosci Lett. 1999;274:159–162. [PubMed: 10548414]
  • Silverman JD, Kruger L. Selective neuronal glycoconjugate expression in sensory and autonomic ganglia: relation of lectin reactivity to peptide and enzyme markers. J Neurocytol. 1990;19:789–801. [PubMed: 2077115]
  • Snider WD, McMahon SB. Tackling pain at the source: new ideas about nociceptors. Neuron. 1998;20:629–32. [PubMed: 9581756]
  • Stucky CL, Lewin GR. Isolectin B(4)-positive and -negative nociceptors are functionally distinct. J Neurosci. 1999;19:6497–6505. [PubMed: 10414978]
  • Todd AJ, Koerber HR. Textbook of Pain: Churchill Livingstone: 2005. Neuroanatomical substrates of spinal nociception. Wall and Melzack’s ; pp. 73–90.
  • Tominaga M, Caterina MJ, Malmberg AB, Rosen TA, Gilbert H, Skinner K, Raumann BE, Basbaum AI, Julius D. The cloned capsaicin receptor integrates multiple pain-producing stimuli. Neuron. 1998;21:531–543. [PubMed: 9768840]
  • Treanor JJ, Goodman L, de Sauvage F, Stone DM, Poulsen KT, Beck CD, Gray C, et al. Characterization of a multicomponent receptor for GDNF. Nature. 1996;382:80–83. [PubMed: 8657309]
  • Trupp M, Raynoschek C, Belluardo N, Ibanez CF. Multiple GPI-anchored receptors control GDNF-dependent and independent activation of the c-Ret receptor tyrosine kinase. Mol Cell Neurosci. 1998;11:47–63. [PubMed: 9608533]
  • Weskamp G, Otten U. An enzyme-linked immunoassay for nerve growth factor (NGF): a tool for studying regulatory mechanisms involved in NGF production in brain and in peripheral tissues. J Neurochem. 1987;48:1779–1786. [PubMed: 3572400]
  • White DM. Neurotrophin-3 antisense oligonucleotide attenuates nerve injury-induced A-beta-fibre sprouting. Brain Res. 2000;885:79–86. [PubMed: 11121532]
  • Wilson-Gerwing TD, Dmyterko MV, Zochodne DW, Johnston JM, Verge VM. Neurotrophin-3 suppresses thermal hyperalgesia associated with neuropathic pain and attenuates transient receptor potential vanilloid receptor-1 expression in adult sensory neurons. J Neurosci. 2005;25:758–767. [PubMed: 15659614]
  • Wilson-Gerwing TD, Stucky CL, McComb GW, Verge VM. Neurotrophin-3 significantly reduces sodium channel expression linked to neuropathic pain states. Exp Neurol. 2008;213:303–314. [PMC free article: PMC2751854] [PubMed: 18601922]
  • Wilson-Gerwing TD, Verge VM. Neurotrophin-3 attenuates galanin expression in the chronic constriction injury model of neuropathic pain. Neuroscience. 2006;141:2075–2085. [PubMed: 16843605]
  • Woo YC, Park SS, Subieta AR, Brennan TJ. Changes in tissue pH and temperature after incision indicate acidosis may contribute to postoperative pain. Anesthesiology. 2004;101:468–475. [PubMed: 15277931]
  • Woodbury CJ, Zwick M, Wang S, Lawson JJ, Caterina MJ, Koltzenburg M, Albers KM, Koerber HR, Davis BM. Nociceptors lacking TRPV1 and TRPV2 have normal heat responses. J Neurosci. 2004;24:6410–6415. [PubMed: 15254097]
  • Woolf CJ, Ma QP, Allchorne A, Poole S. Peripheral cell types contributing to the hyper-algesic action of nerve growth factor in inflammation. J Neurosci. 1996;16:2716–2723. [PubMed: 8786447]
  • Woolf CJ, Safieh-Garabedian B, Ma QP, Crilly P, Winter J. Nerve growth factor contributes to the generation of inflammatory sensory hypersensitivity. Neuroscience. 1994;62:327–331. [PubMed: 7530342]
  • Wright DE, Snider WD. Neurotrophin receptor mRNA expression defines distinct populations of neurons in rat dorsal root ganglia. J Comp Neurol. 1995;351:329–338. [PubMed: 7706545]
  • Wu G, Ringkamp M, Murinson BB, Campbell JN, Griffin JW, Meyer RA. Early onset of spontaneous activity in uninjured C-fiber nociceptors after injury to neighboring nerve fibers. J Neurosci. 2001;21:RC140. [PubMed: 11306646]
  • Xue Q, Jong B, Chen T, Schumacher MA. Transcription of rat TRPV1 utilizes a dual promoter system that is positively regulated by nerve growth factor. J Neurochem. 2007 [PubMed: 17217411]
  • Zhang A, Xu C, Liang S, Gao Y, Li G, Wei J, Wan F, Liu S, Lin J. Role of sodium ferulate in the nociceptive sensory facilitation of neuropathic pain injury mediated by P2X(3) receptor. Neurochem Int. 2008;53:278–282. [PubMed: 18805451]
  • Zhang X, Huang J McNaughton PA. NGF rapidly increases membrane expression of TRPV1 heat-gated ion channels. EMBO. 2005;24:4211–4223. [PMC free article: PMC1356334] [PubMed: 16319926]
  • Zhou XF, Deng YS, Chie E, Xue Q, Zhong JH, McLachlan EM, Rush RA, Xian CJ. Satellite-cell-derived nerve growth factor and neurotrophin-3 are involved in noradrenergic sprouting in the dorsal root ganglia following peripheral nerve injury in the rat. Eur J Neurosci. 1999;11:1711–1722. [PubMed: 10215925]
  • Zhu W, Galoyan SM, Petruska JC, Oxford GS, Mendell LM. A developmental switch in acute sensitization of small dorsal root ganglion (DRG) neurons to capsaicin or noxious heating by NGF. J Neurophysiol. 2004;92:3148–3152. [PubMed: 15201308]
  • Zwick M, Davis BM, Woodbury CJ, Burkett JN, Koerber HR, Simpson JF, Albers KM. Glial cell line-derived neurotrophic factor is a survival factor for isolectin B4-positive, but not vanilloid receptor 1-positive, neurons in the mouse. J Neurosci. 2002;22:4057–4065. [PubMed: 12019325]
  • Zwick M, Molliver DC, Lindsay J, Fairbanks CA, Sengoku T, Albers KM, Davis BM. Transgenic mice possessing increased numbers of nociceptors do not exhibit increased behavioral sensitivity in models of inflammatory and neuropathic pain. Pain. 2003;106:491–500. [PubMed: 14659533]
  • Zylka MJ, Dong X, Southwell AL, Anderson DJ. Atypical expansion in mice of the sensory neuron-specific Mrg G protein-coupled receptor family. PNAS. 2003;100:10043–10048. [PMC free article: PMC187757] [PubMed: 12909716]
  • Zylka MJ, Rice FL, Anderson DJ. Topographically distinct epidermal nociceptive circuits revealed by axonal tracers targeted to Mrgprd. Neuron. 2005;45:17–25. [PubMed: 15629699]
  • Al-Chaer ED, Kawasaki M, Pasricha PJ. A new model of chronic visceral hypersensitivity in adult rats induced by colon irritation during postnatal development. Gastroenterology. 2000;119:1276–1285. [PubMed: 11054385]
  • Al-Chaer ED, Traub RJ. Biological basis of visceral pain: recent developments. Pain. 2002;96:221–225. [PubMed: 11972993]
  • Alagiri M, Chottiner S, Ratner V, Slade D, Hanno PM. Interstitial cystitis: unexplained associations with other chronic disease and pain syndromes. Urology. 1997;49:52–57. [PubMed: 9146002]
  • Anand KJ. Clinical importance of pain and stress in preterm neonates. Biol Neonate. 1998;73:1–9. [PubMed: 9458936]
  • Anand KJ. Consensus statement for the prevention and management of pain in the newborn. Arch Pediatr Adolesc Med. 2001;155:173–180. [PubMed: 11177093]
  • Andersson DA, Gentry C, Moss S, Bevan S. Transient receptor potential Al is a sensory receptor for multiple products of oxidative stress. J Neurosci. 2008;28:2485–2494. [PMC free article: PMC2709206] [PubMed: 18322093]
  • Bahns E, Halsband U, Janig W. Responses of sacral visceral afferents from the lower urinary tract, colon and anus to mechanical stimulation. Pflugers Arch. 1987;410:296–303. [PubMed: 3684516]
  • Bartocci M, Bergqvist LL, Lagercrantz H, Anand KJ. Pain activates cortical areas in the preterm newborn brain. Pain. 2006;122:109–117. [PubMed: 16530965]
  • Bennett DL, Dmietrieva N, Priestley JV, Clary D, McMahon SB. trkA, CGRP and IB4 expression in retrogradely labelled cutaneous and visceral primary sensory neurones in the rat. Neurosci Lett. 1996;206:33–36. [PubMed: 8848275]
  • Bercik P, Verdu EF, Collins SM. Is irritable bowel syndrome a low-grade inflammatory bowel disease? Gastroenterol Clin North Am. 2005;34:235–245. vi–vii. [PubMed: 15862932]
  • Berkley KJ, Hotta H, Robbins A, Sato Y. Functional properties of afferent fibers supplying reproductive and other pelvic organs in pelvic nerve of female rat. J Neurophysiol. 1990;63:256–272. [PubMed: 2313344]
  • Berkley KJ, Hubscher CH, Wall PD. Neuronal responses to stimulation of the cervix, uterus, colon, and skin in the rat spinal cord. J Neurophysiol. 1993a;69:545–556. [PubMed: 8459285]
  • Berkley KJ, Robbins A, Sato Y. Functional differences between afferent fibers in the hypogastric and pelvic nerves innervating female reproductive organs in the rat. J Neurophysiol. 1993b;69:533–544. [PubMed: 8459284]
  • Bielefeldt K, Davis BM. Differential effects of ASIC3 and TRPV1 deletion on gastroesophageal sensation in mice. Am J Physiol Gastrointest Liver Physiol. 2008;294:G130–138. [PubMed: 17975130]
  • Birder LA. Urinary bladder urothelium: molecular sensors of chemical/thermal/mechanical stimuli. Vascul Pharmacol. 2006;45:221–226. [PubMed: 16891158]
  • Birder LA, Nakamura Y, Kiss S, Nealen ML, Barrick S, Kanai AJ, Wang E, et al. Altered urinary bladder function in mice lacking the vanilloid receptor TRPV1. Nat Neurosci. 2002;5:856–860. [PubMed: 12161756]
  • Brierley SM, Jones RC 3rd, Gebhart GF, Blackshaw LA. Splanchnic and pelvic mecha-nosensory afferents signal different qualities of colonic stimuli in mice. Gastroenterology. 2004;127:166–178. [PubMed: 15236183]
  • Brierley SM, Jones RC 3rd, Xu L, Gebhart GF, Blackshaw LA. Activation of splanchnic and pelvic colonic afferents by bradykinin in mice. Neurogastroenterol Motil. 2005;17:854–862. [PubMed: 16336501]
  • Brierley SM, Page AJ, Hughes PA, Adam B, Liebregts T, Cooper NJ, Holtmann G, Liedtke W, Blackshaw LA. Selective role for TRPV4 ion channels in visceral sensory pathways. Gastroenterology. 2008 [PMC free article: PMC2504007] [PubMed: 18343379]
  • Brunsden AM, Jacob S, Bardhan KD, Grundy D. Mesenteric afferent nerves are sensitive to vascular perfusion in a novel preparation of rat ileum in vitro. Am J Physiol Gastrointest Liver Physiol. 2002;283:G656–665. [PubMed: 12181180]
  • Burnstock G. Purine-mediated signalling in pain and visceral perception. Trends Pharmacol Sci. 2001;22:182–188. [PubMed: 11282418]
  • Carobi C. Capsaicin-sensitive vagal afferent neurons innervating the rat pancreas. Neurosci Lett. 1987;77:5–9. [PubMed: 2439955]
  • Cenac N, Altier C, Chapman K, Liedtke W, Zamponi G, Vergnolle N. Transient receptor potential vanilloid-4 has a major role in visceral hypersensitivity symptoms. Gastroenterology. 2008;135946:937–946. e931–932. [PubMed: 18565335]
  • Cenac N, Andrews CN, Holzhausen M, Chapman K, Cottrell G, Andrade-Gordon P, Steinhoff M, et al. Role for protease activity in visceral pain in irritable bowel syndrome. J Clin Invest. 2007;117:636–647. [PMC free article: PMC1794118] [PubMed: 17304351]
  • Ceyhan GO, Demir IE, Altintas B, Rauch U, Thiel G, Muller MW, Giese NA, Friess H, Schafer KH. Neural invasion in pancreatic cancer: a mutual tropism between neurons and cancer cells. Biochem Biophys Res Commun. 2008b;374:442–447. [PubMed: 18640096]
  • Ceyhan GO, Giese NA, Erkan M, Kerscher AG, Wente MN, Giese T, Buchler MW, Friess H. The neurotrophic factor artemin promotes pancreatic cancer invasion. Ann Surg. 2006;244:274–281. [PMC free article: PMC1602177] [PubMed: 16858191]
  • Ceyhan GO, Michalski CW, Demir IE, Muller MW, Friess H. Pancreatic pain. Best Pract Res Clin Gastroenterol. 2008a;22:31–44. [PubMed: 18206811]
  • Chan CL, Facer P, Davis JB, Smith GD, Egerton J, Bountra C, Williams NS, Anand P. Sensory fibres expressing capsaicin receptor TRPV1 in patients with rectal hypersensitivity and faecal urgency. Lancet. 2003;361:385–391. [PubMed: 12573376]
  • Charrua A, Cruz CD, Cruz F, Avelino A. Transient receptor potential vanilloid subfamily 1 is essential for the generation of noxious bladder input and bladder overactivity in cystitis. J Urol. 2007;177:1537–1541. [PubMed: 17382774]
  • Christianson JA, Liang R, Ustinova EE, Davis BM, Fraser MO, Pezzone MA. Convergence of bladder and colon sensory innervation occurs at the primary afferent level. Pain. 2007;128:235–243. [PMC free article: PMC1892845] [PubMed: 17070995]
  • Christianson JA, McIlwrath SL, Koerber HR, Davis BM. Transient receptor potential vanilloid 1-immunopositive neurons in the mouse are more prevalent within colon affer-ents compared to skin and muscle afferents. Neuroscience. 2006b;140:247–257. [PubMed: 16564640]
  • Christianson JA, Traub RJ, Davis BM. Differences in spinal distribution and neurochemical phenotype of colonic afferents in mouse and rat. J Comp Neurol. 2006a;494:246–259. [PubMed: 16320237]
  • Cignacco E, Hamers JP, Stoffel L, van Lingen RA, Gessler P, McDougall J, Nelle M. The efficacy of non-pharmacological interventions in the management of procedural pain in preterm and term neonates. A systematic literature review. Eur J Pain. 2007;11:139–152. [PubMed: 16580851]
  • Cockayne DA, Hamilton SG, Zhu QM, Dunn PM, Zhong Y, Novakovic S, Malmberg AB, et al. Urinary bladder hyporeflexia and reduced pain-related behaviour in P2X3-deficient mice. Nature. 2000;407:1011–1015. [PubMed: 11069181]
  • Collins SM, Barbaro G, Vallance B. Stress, inflammation and the irritable bowel syndrome. Can J Gastroenterol. 1999 13 Suppl A:47A-49A. [PubMed: 10202209]
  • Corey DP, Garcia-Anoveros J, Holt JR, Kwan KY, Lin SY, Vollrath MA, Amalfitano A, et al. TRPA1 is a candidate for the mechanosensitive transduction channel of vertebrate hair cells. Nature. 2004;432:723–730. [PubMed: 15483558]
  • Cruz-Orengo L, Dhaka A, Heuermann RJ, Young TJ, Montana MC, Cavanaugh EJ, Kim D, Story GM. Cutaneous nociception evoked by 15-delta PGJ2 via activation of ion channel TRPA1. Mol Pain. 2008;4:30. [PMC free article: PMC2515828] [PubMed: 18671867]
  • Daly D, Rong W, Chess-Williams R, Chapple C, Grundy D. Bladder afferent sensitivity in wild-type and TRPV1 knockout mice. J Physiol. 2007;583:663–674. [PMC free article: PMC2277033] [PubMed: 17627983]
  • Dang K, Bielfeldt K, Lamb K, Gebhart GF. Gastric ulcers evoke hyperexcitability and enhance P2X receptor function in rat gastric sensory neurons. J Neurophysiol. 2005;93:3112–3119. [PubMed: 15673552]
  • de Groat WC. Neuropeptides in pelvic afferent pathways. Experientia. 1987;43:801–813. [PubMed: 3297768]
  • DeBerry J, Ness TJ, Robbins MT, Randich A. Inflammation-induced enhancement of the visceromotor reflex to urinary bladder distention: modulation by endogenous opioids and the effects of early-in-life experience with bladder inflammation. J Pain. 2007;8:914–923. [PMC free article: PMC4012257] [PubMed: 17704007]
  • Eisenberg ER, Moldwin RM. Etiology: where does prostatitis stop and interstitial cystitis begin? World J Urol. 2003;21:64–69. [PubMed: 12774174]
  • Elitt CM, McIlwrath SL, Lawson JJ, Malin S A, Molliver DC, Cornuet PK, Koerber HR, Davis BM, Albers KM. Artemin overexpression in skin enhances expression of TRPV1 and TRPA1 in cutaneous sensory neurons and leads to behavioral sensitivity to heat and cold. J Neurosci. 2006;26:8578–8587. [PubMed: 16914684]
  • Fasanella KE, Christianson JA, Chanthaphavong RS, Davis BM. Distribution and neurochemical identification of pancreatic afferents in the mouse. J Comp Neurol. 2008;509:42–52. [PMC free article: PMC2677067] [PubMed: 18418900]
  • Fitzgerald M. Developmental biology of inflammatory pain. Br J Anaesth. 1995;75:177–185. [PubMed: 7577251]
  • Fitzgerald M, Beggs S. The neurobiology of pain: developmental aspects. Neuroscientist. 2001;7:246–257. [PubMed: 11499403]
  • Fitzpatrick CC, DeLancey JO, Elkins TE, McGuire EJ. Vulvar vestibulitis and interstitial cystitis: a disorder of urogenital sinus-derived epithelium? Obstet Gynecol. 1993;81:860–862. [PubMed: 8469499]
  • Gildenberg PL, Hirshberg RM. Limited myelotomy for the treatment of intractable cancer pain. J Neurol Neurosurg Psychiatry. 1984;47:94–96. [PMC free article: PMC1027651] [PubMed: 6693922]
  • Green T, Dockray GJ. Calcitonin gene-related peptide and substance P in afferents to the upper gastrointestinal tract in the rat. Neurosci Lett. 1987;76:151–156. [PubMed: 2438603]
  • Green T, Dockray GJ. Characterization of the peptidergic afferent innervation of the stomach in the rat, mouse and guinea-pig. Neuroscience. 1988;25:181–193. [PubMed: 2455875]
  • Guo A, Vulchanova L, Wang J, Li X, Elde R. Immunocytochemical localization of the vanilloid receptor 1 (VR1): relationship to neuropeptides, the P2X3 purinoceptor and IB4 binding sites. Eur J Neurosci. 1999;11:946–958. [PubMed: 10103088]
  • Gwee KA, Graham JC, McKendrick MW, Collins SM, Marshall JS, Walters SJ, Read NW. Psychometric scores and persistence of irritable bowel after infectious diarrhoea. Lancet. 1996;347:150–153. [PubMed: 8544549]
  • Hartel M, di Mola FF, Selvaggi F, Mascetta G, Wente MN, Felix K, Giese NA, et al. Vanilloids in pancreatic cancer: potential for chemotherapy and pain management. Gut. 2006;55:519–528. [PMC free article: PMC1856157] [PubMed: 16174661]
  • Hoogerwerf WA, Shenoy M, Winston JH, Xiao SY, He Z, Pasricha PJ. Trypsin mediates nociception via the proteinase-activated receptor 2: a potentially novel role in pancreatic pain. Gastroenterology. 2004;127:883–891. [PubMed: 15362043]
  • Hoogerwerf WA, Zou L, Shenoy M, Sun D, Micci MA, Lee-Hellmich H, Xiao SY, Winston JH, Pasricha PJ. The proteinase-activated receptor 2 is involved in nociception. J Neurosci. 2001;21:9036–9042. [PubMed: 11698614]
  • Houghton AK, Wang CC, Westlund KN. Do nociceptive signals from the pancreas travel in the dorsal column? Pain. 2001;89:207–220. [PubMed: 11166477]
  • Hughes PA, Brierley SM, Young RL, Blackshaw LA. Localization and comparative analysis of acid-sensing ion channel (ASIC1, 2, and 3) mRNA expression in mouse colonic sensory neurons within thoracolumbar dorsal root ganglia. J Comp. 2007;500:863–875. Neurol, [PubMed: 17177258]
  • Ishikura H, Nishimura S, Matsunami M, Tsujiuchi T, Ishiki T, Sekiguchi F, Naruse M, Nakatani T, Kamanaka Y, Kawabata A. The proteinase inhibitor camostat mesilate suppresses pancreatic pain in rodents. Life Sci. 2007;80:1999–2004. [PubMed: 17433371]
  • Ito Y, Okada Y, Sato M, Sawai H, Funahashi H, Murase T, Hayakawa T, Manabe T. Expression of glial cell line-derived neurotrophic factor family members and their receptors in pancreatic cancers. Surgery. 2005;138:788–794. [PubMed: 16269310]
  • Jones CA, Nyberg L. Epidemiology of interstitial cystitis. Urology. 1997;49:2–9. [PubMed: 9145997]
  • Jones RC 3rd, Otsuka E, Wagstrom E, Jensen CS, Price MP, Gebhart GF. Short-term sensitization of colon mechanoreceptors is associated with long-term hypersensitivity to colon distention in the mouse. Gastroenterology. 2007;133:184–194. [PubMed: 17553498]
  • Jones RC 3rd, Xu L, Gebhart GF. The mechanosensitivity of mouse colon afferent fibers and their sensitization by inflammatory mediators require transient receptor potential vanilloid 1 and acid-sensing ion channel 3. J Neurosci. 2005;25:10981–10989. [PubMed: 16306411]
  • Kapural L, Narouze SN, Janicki TI, Mekhail N. Spinal cord stimulation is an effective treatment for the chronic intractable visceral pelvic pain. Pain Med. 2006;7:440–443. [PubMed: 17014604]
  • Kawabata A, Matsunami M, Tsutsumi M, Ishiki T, Fukushima O, Sekiguchi F, Kawao N, Minami T, Kanke T, Saito N. Suppression of pancreatitis-related allodynia/hyper-algesia by proteinase-activated receptor-2 in mice. Br J Pharmacol. 2006;148:54–60. [PMC free article: PMC1617046] [PubMed: 16520745]
  • Keast JR, de Groat WC. Segmental distribution and peptide content of primary afferent neurons innervating the urogenital organs and colon of male rats. J Comp Neurol. 1992;319:615–623. [PubMed: 1619047]
  • Kim YS, Kwon SJ. High thoracic midline dorsal column myelotomy for severe visceral pain due to advanced stomach cancer. Neurosurgery. 2000;46:85–90. discussion 90-82. [PubMed: 10626939]
  • Kwong K, Kollarik M, Nassenstein C, Ru F, Undem BJ. P2X2 receptors differentiate placodal vs. neural crest C-fiber phenotypes innervating guinea pig lungs and esophagus. Am J Physiol Lung Cell Mol Physiol. 2008;295:L858–865. [PMC free article: PMC2584877] [PubMed: 18689601]
  • Laukkarinen JM, Weiss ER, van Acker GJ, Steer ML, Perides G. Protease-activated receptor-2 exerts contrasting model-specific effects on acute experimental pancreatitis. J Biol Chem. 2008;283:20703–20712. [PMC free article: PMC2475711] [PubMed: 18511423]
  • Lawson JJ, McIlwrath SL, Woodbury CJ, Davis BM, Koerber HR. Mouse cutaneous C-fibers containing TRPV1 are responsive to heat, but mechanically insensitive. Soc Neurosci Abstr. 2004 288.5.
  • Lidow MS. Long-term effects of neonatal pain on nociceptive systems. Pain. 2002;99:377–383. [PubMed: 12406512]
  • Lin C, Al-Chaer ED. Long-term sensitization of primary afferents in adult rats exposed to neonatal colon pain. Brain Res. 2003;971:73–82. [PubMed: 12691839]
  • Lindsay TH, Halvorson KG, Peters CM, Ghilardi JR, Kuskowski MA, Wong GY, Mantyh PW. A quantitative analysis of the sensory and sympathetic innervation of the mouse pancreas. Neuroscience. 2006;137:1417–1426. [PubMed: 16388907]
  • Lynn PA, Blackshaw LA. In vitro recordings of afferent fibres with receptive fields in the serosa, muscle and mucosa of rat colon. J Physiol. 1999;518:271–282. l. [PMC free article: PMC2269405] [PubMed: 10373708]
  • Ma J, Jiang Y, Jiang Y, Sun Y, Zhao X. Expression of nerve growth factor and tyrosine kinase receptor A and correlation with perineural invasion in pancreatic cancer. J Gastroenterol Hepatol. 2008;23:1852–1859. [PubMed: 19120874]
  • Malin SA, Christianson JA, Bielefeldt K, Davis BM. TRPV1 expression defines functionally distinct pelvic colon afferents. J Neurosci. 2009;29:743–752. [PMC free article: PMC2790201] [PubMed: 19158300]
  • Malin Sa A, Molliver DC, Koerber HR, Cornuet P, Frye R, Albers KM, Davis BM. Glial cell line-derived neurotrophic factor family members sensitize nociceptors in vitro and produce thermal hyperalgesia in vivo. J Neurosci. 2006;26:8588–8599. [PubMed: 16914685]
  • Malykhina AP, Qin C, Foreman RD, Akbarali HI. Colonic inflammation increases Na+ currents in bladder sensory neurons. Neuroreport. 2004;15:2601–2605. [PubMed: 15570160]
  • Malykhina AP, Qin C, Greenwood-van Meerveld B, Foreman RD, Lupu F, Akbarali HI. Hyperexcitability of convergent colon and bladder dorsal root ganglion neurons after colonic inflammation: mechanism for pelvic organ cross-talk. Neurogastroenterol Motil. 2006;18:936–948. [PubMed: 16961697]
  • Mitsui T, Kakizaki H, Matsuura S, Ameda K, Yoshioka M, Koyanagi T. Afferent fibers of the hypogastric nerves are involved in the facilitating effects of chemical bladder irritation in rats. J Neurophysiol. 2001;86:2276–2284. [PubMed: 11698518]
  • Morrison JF. Splanchnic slowly adapting mechanoreceptors with punctate receptive fields in the mesentery and gastrointestinal tract of the cat. J Physiol. 1973;233:349–361. [PMC free article: PMC1350570] [PubMed: 4747231]
  • Namkung W, Yoon JS, Kim KH, Lee MG. PAR2 exerts local protection against acute pancreatitis via modulation of MAP kinase and MAP kinase phosphatase signaling. Am J Physiol Gastrointest Liver Physiol. 2008;295:G886–894. [PubMed: 18755806]
  • Nathan JD, Peng RY, Wang Y, McVey DC, Vigna SR, Liddle RA. Primary sensory neurons: a common final pathway for inflammation in experimental pancreatitis in rats. Am J Physiol Gastrointest Liver Physiol. 2002;283:G938–946. [PubMed: 12223354]
  • Ness TJ, Gebhart GF. Characterization of neurons responsive to noxious colorectal distension in the T13-L2 spinal cord of the rat. J Neurophysiol. 1988;60:1419–1438. [PubMed: 3193164]
  • Noble MD, Romac J, Wang Y, Hsu J, Humphrey JE, Liddle RA. Local disruption of the celiac ganglion inhibits substance P release and ameliorates caerulein-induced pancreatitis in rats. Am J Physiol Gastrointest Liver Physiol. 2006;291:G128–134. [PubMed: 16769810]
  • Okada Y, Eibl G, Guha S, Duffy JP, Reber HA, Hines OJ. Nerve growth factor stimulates MMP-2 expression and activity and increases invasion by human pancreatic cancer cells. Clin Exp Metastasis. 2004;21:285–292. [PubMed: 15554384]
  • Orozco OE, Walus L, Sah DW, Pepinsky RB, Sanicola M. GFRαlpha3 is expressed predominantly in nociceptive sensory neurons. Eur J Neurosci. 2001;13:2177–2182. [PubMed: 11422460]
  • Ozaki N, Gebhart GF. Characterization of mechanosensitive splanchnic nerve afferent fibers innervating the rat stomach. Am J Physiol Gastrointest Liver Physiol. 2001;281:G1449–1459. [PubMed: 11705750]
  • Page AJ, Blackshaw LA. An in vitro study of the properties of vagal afferent fibres innervating the ferret oesophagus and stomach. J Physiol. 1998;512:907–916. 3. [PMC free article: PMC2231239] [PubMed: 9769431]
  • Page AJ, Brierley SM, Martin CM, Price MP, Symonds E, Butler R, Wemmie JA, Blackshaw LA. Different contributions of ASIC channels la, 2, and 3 in gastrointestinal mechanosensory function. Gut. 2005;54:1408–1415. [PMC free article: PMC1774697] [PubMed: 15987792]
  • Palecek J. The role of dorsal columns pathway in visceral pain. Physiol Res. 2004 53 Suppl LS125-130. [PubMed: 15119943]
  • Pezzone MA, Liang R, Fraser MO. A model of neural cross-talk and irritation in the pelvis: implications for the overlap of chronic pelvic pain disorders. Gastroenterology. 2005;128:1953–1964. [PubMed: 15940629]
  • Price MP, McIlwrath SL, Xie J, Cheng C, Qiao J, Tarr DE, Sluka KA, Brennan TJ, Lewin GR, Welsh MJ. The DRASIC cation channel contributes to the detection of cutaneous touch and acid stimuli in mice. Neuron. 2001;32:1071–1083. [PubMed: 11754838]
  • Prior A, Wilson K, Whorwell PJ, Faragher EB. Irritable bowel syndrome in the gynecological clinic. Survey of 798 new referrals. Dig Dis Sci. 1989;34:1820–1824. [PubMed: 2598751]
  • Qin C, Chen JD, Zhang J, Foreman RD. Characterization of T9-T10 spinal neurons with duodenal input and modulation by gastric electrical stimulation in rats. Brain Res. 2007;1152:75–86. [PMC free article: PMC2696195] [PubMed: 17433808]
  • Randich A, Uzzell T, DeBerry JJ, Ness TJ. Neonatal urinary bladder inflammation produces adult bladder hypersensitivity. J Pain. 2006;7:469–479. [PubMed: 16814686]
  • Razavi R, Chan Y, Afifiyan FN, Liu XJ, Wan X, Yantha J, Tsui H, et al. TRPV1+ sensory neurons control beta cell stress and islet inflammation in autoimmune diabetes. Cell. 2006;127:1123–1135. [PubMed: 17174891]
  • Reiter RC. A profile of women with chronic pelvic pain. Clin Obstet Gynecol. 1990;33:130–136. [PubMed: 2178830]
  • Ricco MM, Kummer W, Biglari B, Myers AC, Undem BJ. Interganglionic segregation of distinct vagal afferent fibre phenotypes in guinea-pig airways. J Physiol. 1996;496:521–530. 2. [PMC free article: PMC1160895] [PubMed: 8910234]
  • Robinson DR, McNaughton PA, Evans ML, Hicks GA. Characterization of the primary spinal afferent innervation of the mouse colon using retrograde labelling. Neurogastroenterol Motil. 2004;16:113–124. [PubMed: 14764211]
  • Romac JM, McCall SJ, Humphrey JE, Heo J, Liddle RA. Pharmacologic disruption of TRPV1-expressing primary sensory neurons but not genetic deletion of TRPV1 protects mice against pancreatitis. Pancreas. 2008;36:394–401. [PubMed: 18437086]
  • Rong W, Spyer KM, Burnstock G. Activation and sensitisation of low and high threshold afferent fibres mediated by P2X receptors in the mouse urinary bladder. J Physiol. 2002;541:591–600. [PMC free article: PMC2290323] [PubMed: 12042363]
  • Ruda MA, Ling QD, Hohmann AG, Peng YB, Tachibana T. Altered nociceptive neuronal circuits after neonatal peripheral inflammation. Science. 2000;289:628–631. [PubMed: 10915627]
  • Sandner-Kiesling A, Pan HL, Chen SR, James RL, DeHaven-Hudkins DL, Dewan DM, Eisenach JC. Effect of kappa opioid agonists on visceral nociception induced by uterine cervical distension in rats. Pain. 2002;96:13–22. [PubMed: 11932057]
  • Sawada Y, Hosokawa H, Matsumura K, Kobayashi S. Activation of transient receptor potential ankyrin 1 by hydrogen peroxide. Eur J Neurosci. 2008;27:1131–1142. [PubMed: 18364033]
  • Schneider G, Hamacher R, Eser S, Friess H, Schmid RM, Saur D. Molecular biology of pancreatic cancer-new aspects and targets. Anticancer Res. 2008;28:1541–1550. [PubMed: 18630509]
  • Sengupta JN, Gebhart GF. Characterization of mechanosensitive pelvic nerve afferent fibers innervating the colon of the rat. J Neurophysiol. 1994a;71:2046–2060. [PubMed: 7931501]
  • Sengupta JN, Gebhart GF. Mechanosensitive properties of pelvic nerve afferent fibers innervating the urinary bladder of the rat. J Neurophysiol. 1994b;72:2420–2430. [PubMed: 7884468]
  • Sharkey KA, Williams RG. Extrinsic innervation of the rat pancreas: demonstration of vagal sensory neurones in the rat by retrograde tracing. Neurosci Lett. 1983;42:131–135. [PubMed: 6664624]
  • Sharkey KA, Williams RG, Dockray GJ. Sensory substance P innervation of the stomach and pancreas. Demonstration of capsaicin-sensitive sensory neurons in the rat by combined immunohistochemistry and retrograde tracing. Gastroenterology. 1984;87:914–921. [PubMed: 6205934]
  • Silverman JD, Kruger L. Lectin and neuropeptide labeling of separate populations of dorsal root ganglion neurons and associated “nociceptor” thin axons in rat testis and cornea whole-mount preparations. Somatosens Res. 1988;5:259–267. [PubMed: 3358044]
  • Simons SH, van Dijk M, Anand KS, Roofthooft D, van Lingen RA, Tibboel D. Do we still hurt newborn babies? A prospective study of procedural pain and analgesia in neonates. Arch Pediatr Adolesc Med. 2003;157:1058–1064. [PubMed: 14609893]
  • Sipe WE, Brierley SM, Martin CM, Phillis BD, Cruz FB, Grady EF, Liedtke W, et al. Transient receptor potential vanilloid 4 mediates protease activated receptor 2-induced sensitization of colonic afferent nerves and visceral hyperalgesia. Am J Physiol Gastrointest Liver Physiol. 2008;294:G1288–1298. [PubMed: 18325985]
  • Slater R, Cantarella A, Gallella S, Worley A, Boyd S, Meek J, Fitzgerald M. Cortical pain responses in human infants. J Neurosci. 2006;26:3662–3666. [PubMed: 16597720]
  • Ständer S, Moormann C, Schumacher M, Buddenkotte J, Artuc M, Shpacovitch V, Brzoska T, et al. Expression of vanilloid receptor subtype 1 in cutaneous sensory nerve fibers, mast cells, and epithelial cells of appendage structures. Exp Dermatol. 2004;13:129–139. [PubMed: 14987252]
  • Starowicz K, Nigam S, Di Marzo V. Biochemistry and pharmacology of endovanilloids. Pharmacol Ther. 2007;114:13–33. [PubMed: 17349697]
  • Sternini C, De Giorgio R, Fµm ess JB. Calcitonin gene-related peptide neurons innervating the canine digestive system. Regul Pept. 1992;42:15–26. [PubMed: 1475404]
  • Stevens B, Yamada J, Beyene J, Gibbins S, Petryshen P, Stinson J, Narciso J. Consistent management of repeated procedural pain with sucrose in preterm neonates: Is it effective and safe for repeated use over time? Clin J Pain. 2005;21:543–548. [PubMed: 16215340]
  • Sugiura T, Dang K, Lamb K, Bielefeldt K, Gebhart GF. Acid-sensing properties in rat gastric sensory neurons from normal and ulcerated stomach. J Neurosci. 2005;25:2617–2627. [PubMed: 15758172]
  • Suh YG, Oh U. Activation and activators of TRPV1 and their pharmaceutical implication. Curr Pharm Des. 2005;11:2687–2698. [PubMed: 16101449]
  • Tan LL, Bornstein JC, Anderson CR. Distinct chemical classes of medium-sized transient receptor potential channel vanilloid 1-immunoreactive dorsal root ganglion neurons innervate the adult mouse jejunum and colon. Neuroscience. 2008;156:334–343. [PubMed: 18706490]
  • Traub RJ. Evidence for thoracolumbar spinal cord processing of inflammatory, but not acute colonic pain. Neuroreport. 2000;11:2113–2116. [PubMed: 10923654]
  • Traub RJ, Hutchcroft K, Gebhart GF. The peptide content of colonic afferents decreases following colonic inflammation. Peptides. 1999;20:267–273. [PubMed: 10422883]
  • Traub RJ, Murphy A. Colonic inflammation induces fos expression in the thoracolumbar spinal cord increasing activity in the spinoparabrachial pathway. Pain. 2002;95:93–102. [PubMed: 11790471]
  • Trevisani M, Siemens J, Materazzi S, Bautista DM, Nassini R, Campi B, Imamachi N, Andre E, Patacchini R, Cottrell GS, Gatti R, Basbaum AI, Bunnett NW, Julius D, Geppetti P. 4-Hydroxynonenal, an endogenous aldehyde, causes pain and neurogenic inflammation through activation of the irritant receptor TRPA1. Proc Natl Acad Sci USA. 2007;104:13519–13524. [PMC free article: PMC1948902] [PubMed: 17684094]
  • Undem BJ, Chuaychoo B, Lee MG, Weinreich D, Myers AC, Kollarik M. Subtypes of vagal afferent C-fibres in guinea-pig lungs. J Physiol. 2004;556:905–917. [PMC free article: PMC1665007] [PubMed: 14978204]
  • Van Der Stelt M, Di Marzo V. Endovanilloids. Putative endogenous ligands of transient receptor potential vanilloid 1 channels. Eur J Biochem. 2004;271:1827–1834. [PubMed: 15128293]
  • Walker SM. Pain in children: recent advances and ongoing challenges. Br J Anaesth. 2008;101:101–110. [PubMed: 18430745]
  • Wang HF, Shortland P, Park MJ, Grant G. Retrograde and transganglionic transport of horseradish peroxidase-conjugated cholera toxin B subunit, wheatgerm agglutinin and isolectin B4 from Griffonia simplicifolia I in primary afferent neurons innervating the rat urinary bladder. Neuroscience. 1998;87:275–288. [PubMed: 9722157]
  • Whitfield MF, Grunau RE. Behavior, pain perception, and the extremely low-birth weight survivor. Clin Perinatol. 2000;27:363–379. [PubMed: 10863655]
  • Willis WD, Al-Chaer ED, Quast MJ, Westlund KN. A visceral pain pathway in the dorsal column of the spinal cord. Proc Natl Acad Sci USA. 1999;96:7675–7679. [PMC free article: PMC33600] [PubMed: 10393879]
  • Willis WD Jr., Westlund KN. The role of the dorsal column pathway in visceral nociception. Curr Pain Headache Rep. 2001;5:20–26. [PubMed: 11252134]
  • Winston J, Shenoy M, Medley D, Naniwadekar A, Pasricha PJ. The vanilloid receptor initiates and maintains colonic hypersensitivity induced by neonatal colon irritation in rats. Gastroenterology. 2007;132:615–627. [PubMed: 17258716]
  • Won MH, Park HS, Jeong YG, Park HJ. Afferent innervation of the rat pancreas: retrograde tracing and immunohistochemistry in the dorsal root ganglia. Pancreas. 1998;16:80–87. [PubMed: 9436867]
  • Woo DH, Jung SJ, Zhu MH, Park CK, Kim YH, Oh SB, Lee CJ. Direct activation of transient receptor potential vanilloid l(TRPV1) by diacylglycerol (DAG) Mol Pain. 2008;4:42. [PMC free article: PMC2576176] [PubMed: 18826653]
  • Wood JD. Neuropathophysiology of irritable bowel syndrome. J Clin Gastroenterol. 2002;35:Sll–22. [PubMed: 12184133]
  • Xu GY, Shenoy M, Winston JH, Mittal S, Pasricha PJ. P2X receptor-mediated visceral hyperalgesia in a rat model of chronic visceral hypersensitivity. Gut. 2008 [PubMed: 18270243]
  • Xu GY, Winston JH, Shenoy M, Yin H, Pendyala S, Pasricha PJ. Transient receptor potential vanilloid 1 mediates hyperalgesia and is up-regulated in rats with chronic pancreatitis. Gastroenterology. 2007;133:1282–1292. [PubMed: 17698068]
  • Xu L, Gebhart GF. Characterization of mouse lumbar splanchnic and pelvic nerve urinary bladder mechanosensory afferents. J Neurophysiol. 2008;99:244–253. [PMC free article: PMC2659401] [PubMed: 18003875]
  • Yiangou Y, Facer P, Baecker PA, Ford AP, Knowles CH, Chan CL, Williams NS, Anand P. ATP-gated ion channel P2X(3) is increased in human inflammatory bowel disease. Neurogastroenterol Motil. 2001;13:365–369. [PubMed: 11576396]
  • Yu S, Undem BJ, Kollarik M. Vagal afferent nerves with nociceptive properties in guinea-pig oesophagus. J Physiol. 2005;563:831–842. [PMC free article: PMC1665603] [PubMed: 15649987]
  • Zhang L, Jones S, Brody K, Costa M, Brookes SJ. Thermosensitive transient receptor potential channels in vagal afferent neurons of the mouse. Am J Physiol Gastrointest Liver Physiol. 2004;286:G983–991. [PubMed: 14726308]
  • Zhong F, Christianson JA, Davis BM, Bielefeldt K. Dichotomizing axons in spinal and vagal afferents of the mouse stomach. Dig Dis Sci. 2008;53:194–203. [PubMed: 17510799]
  • Zhu Z, Friess H, diMola FF, Zimmermann A, Graber HU, Korc M, Buchler MW. Nerve growth factor expression correlates with perineural invasion and pain in human pancreatic cancer. J Clin Oncol. 1999;17:2419–2428. [PubMed: 10561305]
  • Zhu ZW, Friess H, Wang L, Bogardus T, Korc M, Kleeff J, Buchler MW. Nerve growth factor exerts differential effects on the growth of human pancreatic cancer cells. Clin Cancer Res. 2001;7:105–112. [PubMed: 11205897]
  • Zwick M, Davis BM, Woodbury CJ, Burkett JN, Koerber HR, Simpson JF, Albers KM. Glial cell line-derived neurotrophic factor is a survival factor for isolectin B4-positive, but not vanilloid receptor 1-positive, neurons in the mouse. J Neurosci. 2002;22:4057–4065. [PubMed: 12019325]
Copyright © 2010 by Taylor and Francis Group, LLC.
Bookshelf ID: NBK57265PMID: 21882462

Views

  • PubReader
  • Print View
  • Cite this Page

Other titles in this collection

Related information

  • PMC
    PubMed Central citations
  • PubMed
    Links to PubMed

Similar articles in PubMed

See reviews...See all...

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...