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

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Translational Pain Research: From Mouse to Man.

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Chapter 2Neurotrophic Factors and Nociceptor Sensitization

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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.


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.


2.1.1. 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.


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).


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.


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.


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