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National Research Council (US) Committee on Recognition and Alleviation of Pain in Laboratory Animals. Recognition and Alleviation of Pain in Laboratory Animals. Washington (DC): National Academies Press (US); 2009.

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Recognition and Alleviation of Pain in Laboratory Animals.

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2Mechanisms of Pain

This chapter provides an analysis of the differences between nociception and pain, on the basis of the anatomy of the peripheral and central nervous systems and the role of nociceptors in pain perception. It includes discussion of the concept of persistent pain and presents information on the embryologic origins of pain. Finally it addresses the modulatory role of anxiety, fear, and stress on pain.

NOCICEPTION OR PAIN

Before discussing the anatomical and physiological bases for the generation of pain, it is important to reiterate the difference between nociception and pain. Nociception refers to the peripheral and central nervous system (CNS) processing of information about the internal or external environment, as generated by the activation of nociceptors. Typically, noxious stimuli, including tissue injury, activate nociceptors that are present in peripheral structures and that transmit information to the spinal cord dorsal horn or its trigeminal homologue, the nucleus caudalis. From there, the information continues to the brainstem and ultimately the cerebral cortex, where the perception of pain is generated (Figure 2-1).

FIGURE 2-1. Anatomical distribution of nociception and pain.

FIGURE 2-1

Anatomical distribution of nociception and pain. This figure schematizes the major neuroanatomical structures that differentiate nociception and pain, an understanding of which is essential for studies in which the animals may experience pain. Nociception (more...)

Pain is a product of higher brain center processing, whereas nociception can occur in the absence of pain. For example, the spinal cord of an individual who suffered a complete spinal cord transection can still process information transmitted by nociceptors, but because the information cannot be transmitted beyond the transection stimulus-evoked pain is unlikely (see Chapter 1 for additional discussion).

The distinction between nociception and pain is also important for behavioral studies in which an understanding of pain mechanisms is the ultimate goal. Many behavioral tests involve assessment of reflex responses to noxious stimuli, typically applied at threshold or just suprathreshold intensities (such as heating of the tail or the hindpaw) to incite a brief withdrawal of the tail (e.g., in the tail flick test) or paw. These are principally tests of nociceptive processing because stimulus duration is limited by the animal’s response (e.g., a nociceptive withdrawal reflex). On the other hand, the endpoints of more complex behaviors (e.g., those involved in operant tests) are presumed to involve supraspinal areas of the brain and as such are tests of both nociception and pain. In that respect, operant tests in which animals perform a particular behavior (e.g., press a bar) to escape a stimulus provide information about both nociceptive processing and pain (see also Box 1-4 in Chapter 1).

Mechanisms of Nociception and Pain

Nociceptors

The anatomical basis for the generation of momentary pain is very well understood (Basbaum and Jessell 2000). Nociceptors are unusual neurons because they have a cell body with a peripheral axon and terminal (ending) that responds to the stimulus and a central branch that carries the information into the CNS. Briefly, there are two major classes of nociceptors that respond to different modalities of noxious stimuli.

The largest group of nociceptors is associated with unmyelinated axons, also called C-fibers, that conduct slowly and that respond to noxious thermal, mechanical, or chemical stimulation. Proteins in the membrane of these nociceptors transduce natural thermal, mechanical, or chemical stimulus energy into electrical impulses, which in turn are propagated along the peripheral and central axon of the nociceptor into the CNS (the spinal cord for the body and the trigeminal nucleus for the head). Importantly, biochemical and molecular analysis of the nociceptor has identified many of the transducer molecules that are activated by noxious stimuli, such as TRPV1, which responds to noxious heat, reduced pH as occurs in inflammation, and the chemical capsaicin. Another channel, TRPM8, responds to cold (Julius and Basbaum 2001). Many of these molecules are targets for therapeutic intervention in clinical pain conditions.

The second major nociceptor population is associated with thinly myelinated axons (A-delta fibers). These nociceptors conduct more rapidly than do unmyelinated C-fibers and likely convey “fast” (or sharp) momentary pain, as opposed to slow, diffuse pain, which is transmitted by the C-fibers.1

There is yet one more category of nociceptors characterized by unique properties. “Sleeping” or “silent” nociceptors are typically unresponsive to noxious intensities of mechanical stimulation except at extreme ranges of intensity. Although silent nociceptors are difficult to activate within the normal range of noxious stimulus intensities, after tissue insult these nociceptors “wake up” in response to endogenous chemical mediators associated with tissue injury. Silent nociceptors are typically associated with increased spontaneous activity and responsiveness to noxious and even innocuous stimulus intensities.

Spontaneous activity in nociceptors (whether A-delta, C-, or silent) is undesirable and pain producing; moreover, awakening silent nociceptors creates essentially new, additional nociceptive input to the CNS. All nociceptors have the capacity to sensitize. When they become more easily excitable (i.e., the threshold for activation is lowered), hyperalgesia (an increased response to a noxious stimulus) with or without allodynia develops and normally innocuous stimuli may provoke pain, thus directly affecting animal welfare. The consequences of such activities are discussed below in the section on persistent pain.

The Central Nervous System

The central branch of the nociceptor terminates in the dorsal horn of the spinal cord (or its trigeminal homologue in the brainstem), where it makes synaptic connections with a complex array of neurons that play different roles in nociceptive processing and pain. Some interneurons make connections with motor neurons that generate nociceptive withdrawal reflexes. Output neurons of the spinal cord, on the other hand, project rostrally and transmit the nociceptive message to the brainstem reticular formation and thalamus. Among the ascending pathways arising from the spinal cord (and its trigeminal homologue) are the spinothalamic and spinoreticulothalamic tracts, as well as the spinoparabrachial-amygdala pathway, which provides more direct access to limbic emotional circuits in the brain (via the amygdala) (Basbaum and Jessell 2000). Note that there is not a unitary pathway for generation of the affective component of the pain experience. Rather it is likely that different aspects of the nociceptive message are conveyed via different pathways and widely distributed to the cerebral cortex from the reticular formation, thalamus, and amygdala.

Until recently, remarkably little was understood about the cortical mechanisms that underlie the perception of pain. Although electrophysiological studies have demonstrated that some neurons in the cortex respond to noxious stimuli, the extent to which this response represents or even correlates with pain was not clear. The development of powerful imaging methods, however, has provided critical information about the cortical processing of pain-related information (e.g., Apkarian et al. 2005; Bingel and Tracey 2008; Tracey and Mantyh 2007) and revealed that pain is not processed in a single area of the brain. Rather, the activity of different regions of the cortex underlies various features of the pain percept and cognitive recall for responses or emotional reactions. This information comes largely from human studies, in which a verbal correlate of pain perception is possible. For example, activity in the somatosensory cortices (S1 and S2) correlates best with the sensory-discriminative properties of the stimulus (e.g., location and intensity), and the affective components of the pain experience correlate with activity in the anterior cingulate gyrus and the insular cortex. Unfortunately, the activity of these regions cannot be used as a biomarker for pain, as it can also be generated by conditions that are clearly not painful (for additional discussion see Chapter 1).

Further Comments on the Distinction between Nociception and Pain

An unusual model to investigate the brain circuitry involved in nociception and pain was developed at the beginning of the 20th century by Charles Sherrington (1906), who appreciated early on the distinction between nociception and pain. Use of a “decerebrate preparation” (cerveau isolé) in laboratory animal research was more common years ago, but it remains useful for recording the activity of spinal cord or brainstem neurons under conditions not compromised by anesthetics or analgesics. With the animals under deep general anesthesia, the procedure involves transection of the brainstem at the level of the midbrain (typically between the inferior and superior colliculi), after which the rostral part of the brain (particularly subcortical structures and the cortex) no longer receives direct neuronal input from the spinal cord or brainstem trigeminal structures and a state of permanent unconsciousness is induced.

Using the decerebrate preparation, Woodworth and Sherrington (1904) illustrated the essential contribution of the cortex to the perception of pain and defined the “pseudaffective” reflex. In response to a noxious stimulus, this reflex corresponds to a remarkable behavioral repertoire, even including occasional vocalization, due to the fact that its pathways are coordinated at spinal and supraspinal brainstem levels below the midbrain transection (i.e., it is a spino-bulbo-spinal reflex; Woodworth and Sherrington 1904). Despite the behaviors observed, no pain is experienced. In fact, the AVMA Guidelines on Euthanasia state that “for pain to be experienced, the cerebral cortex and subcortical structures must be functional” (AVMA 2007, p. 2). The pseudaffective reflex is useful in animal studies that investigate neurons of the spinal cord without the influence of anesthesia (e.g., the decerebrate animal preparation). It should be noted that decerebrate preparations are necessarily nonsurvival experiments; Silverman and colleagues (2005, p. 1) note that an animal that recovers from the anesthesia for this procedure typically provides research data “for a period of a few hours or a day” after which it must be euthanized.

Because decerebration severs the connection between the rostral part of the brain and lower CNS structures, it also eliminates the powerful modulatory control mechanisms that descend from supraspinal sites. These descending control mechanisms are predominantly inhibitory and act as a “brake” on spinal cord neurons and circuits that process nociceptive information. Their removal via decerebration leads to enhanced nociceptive reflexes and spinal neuron responses to nociceptive input. Accordingly, spinal cord transection often follows decerebration to enable physiological studies in unanesthetized animals, but it is not a prerequisite of the decerebrate preparation.

Finally, it is important to distinguish the decerebrate from the decorticate preparation. In the latter, only the cerebral cortex is removed, leaving intact the underlying subcortical structures (i.e., the thalamus, brainstem, and spinal cord). Because there have been suggestions that under some conditions pain processing can occur even at the level of the thalamus (e.g., Merker 2007), studies of decorticate animals (which these days are rare) must be performed under general anesthesia.

THE DEVELOPMENT OF PERSISTENT PAIN

The mechanisms that contribute to the development of postoperative/postprocedural and persistent pain are far more complicated than the rather simple anatomical and physiological underpinnings of momentary pain. It is important to appreciate that these types of pain are not merely instances of momentary pain that do not resolve quickly. Rather, they arise in the context and environment of tissue or nerve injury and involve changes in the properties not only of nociceptors but also of the circuits that these receptors engage in the spinal cord and at other levels of the neuraxis (Basbaum and Woolf 1999; Urban and Gebhart 1999; Basbaum and Jessell 2000; Julius and Basbaum 2001). These changes generally enhance signals in “pain” transmission circuits, such that innocuous stimuli can evoke behaviors indicative of pain (extensive discussion of the sickness syndrome, an underappreciated postoperative occurrence, is in Chapter 4). As a result of advances in scientific understanding of these mechanisms, many pharmacological treatments for postoperative/-procedural and persistent pain in humans are directed at interfering with the development and duration of hyperalgesia and allodynia.

Hyperalgesia is a hallmark of inflammatory pain and is a consequence of many types of tissue insults (ranging from a skin incision to nerve injury). It is defined as an increased response to a noxious stimulus and manifests as an increased sensitivity to pain (Treede et al. 1992; Campbell and Meyer 2006). Because the threshold for response also typically decreases, sometimes even nonnoxious stimuli can cause pain, a phenomenon called allodynia.

There are two types of hyperalgesia, primary and secondary, each associated with different mechanisms. Primary hyperalgesia is characterized by increased excitability of nociceptors at the site of the insult (e.g., the site of an incision). It occurs most commonly after skin injury, but may also develop following insults to joints, muscle, or viscera. For example, when an incision in the skin is examined, the response to stimuli applied to that site typically increases. Surrounding the site of injury, and often at sites rather distant from the injury (particularly when joints and especially the viscera are involved), is an area of increased sensitivity referred to as the area of secondary hyperalgesia. This is most evident with visceral insult, where sensations are referred or perceived to arise from overlying structures, most notably skin. The classic example is myocardial oxygen deficiency (angina) in which the pain is referred to the shoulder, down the left arm, and occasionally up to the jaw.

When either primary or secondary hyperalgesia occurs, it is accompanied by an increase in the excitability and responses of neurons in the nervous system. Primary hyperalgesia is largely attributed to an increase in the excitability of nociceptors (i.e., the peripheral afferent sensory ending and fiber), whereas secondary hyperalgesia is associated with changes in the excitability of neurons in the CNS, including the spinal cord and supra-spinal sites in the brain. Accordingly, primary hyperalgesia is associated with peripheral sensitization of nociceptors and secondary hyperalgesia with central sensitization. The terms indicate an increase in the excitability and responses of peripheral (i.e., nociceptor) and central neurons because of tissue insult.

Numerous mediators in both the peripheral and central nervous systems contribute to the processes of sensitization (Basbaum and Jessell 2000; Basbaum and Woolf 1999; Julius and Basbaum 2001; Treede et al. 1992; see McMahon et al. 2005 for an overview). At the injury site, primary hyperalgesia is induced by the release of numerous inflammatory mediators including the products of cyclooxygenase enzyme activation. The critical contribution of these enzymes accounts for the beneficial effects of non-steroidal anti-inflammatory drugs, which, by inhibiting the enzyme, reduce peripheral sensitization and help alleviate persistent or postoperative/-procedural pain.

Central sensitization is a considerably more complicated process that can result from changes in the amount of neurotransmitter released from nociceptor terminals in the spinal cord or brainstem, notably glutamate and the neuropeptide substance P (Basbaum and Jessell 2000; Basbaum and Woolf 1999; Woolf 1983); from loss of inhibitory regulation exerted by inhibitory interneurons in the spinal cord and at supraspinal loci; and from biochemical changes in the “pain” transmission neurons that increase their responsiveness to peripheral inputs. It is likely that the pain-alleviating effects of drugs such as ketamine are partly due to the reduction of central sensitization produced by the release of glutamate. In contrast, the beneficial effects of anticonvulsants for pain treatment are likely related to their blockade of neurotransmitter release from primary afferents or the enhancement of inhibitory controls.

The remarkable number of molecules implicated in central sensitization (whether produced by tissue or nerve injury) may lead to the development of new pharmacological approaches to managing persistent pain. Of particular interest is the recent understanding of the contribution of glia to the process of central sensitization. In fact, there is considerable evidence that glia, notably microglia and astrocytes, are activated in the setting of nerve injury and that they are the source of mediators that enhance the central consequences of nociceptor activity (Thacker et al. 2007; Watkins et al. 2007). For this reason, there are now several pharmaceutical programs for the development of novel pain therapies that attempt to interfere with the biochemistry of the “activated” glial cell.

ONTOGENY OF PAIN

Large numbers of developmental neurobiology studies have increased knowledge of the origin and maturation of nociceptive circuitry and behavior. Importantly, it is now possible to identify subpopulations of sensory neurons, including nociceptors, early in embryonic development, well before they project to central and peripheral targets (Fitzgerald 2005).

Neurogenesis and subsequent maturation and synaptogenesis of sensory neurons occur in two waves. In rats, outgrowth of myelinated A-delta fibers from the neuraxis precedes outgrowth of unmyelinated C-fibers. These processes occur during embryonic days 15 to 17 (E15-17) and 18 to 20 (E18-20) respectively and coincide with the first appearance of reflex responses to mechanical stimuli (Fitzgerald 2005). A-delta fiber synapses have been identified in the spinal dorsal horn at E13 in rats, whereas the terminals of C-fibers do not appear until E18-19 (ibid.). In fact, physiological recordings of nociceptive fibers in rat pups during the first few postnatal days demonstrate responses to noxious chemical, mechanical, and thermal stimuli that are similar to those of mature C-fibers.

Neonates of multiple species demonstrate exaggerated spinally mediated reflex responses to noxious stimuli compared to adults (see Fitzgerald 2005 and Hathway and Fitzgerald 2008 for reviews). For example, in rat pups it is not until postnatal day 10 (P10) that these reflexes develop spatial precision; they then achieve adult levels of both spatial and temporal precision by P21. Nonnoxious tactile stimuli are important for fine-tuning of nociceptive reflexes during this critical postnatal period. Likewise, maturation of ascending and descending neuronal pathways, at approximately P10 in rat pups, contributes to the development of mature nociceptive processing. Hyperalgesia can be documented in rat pups as young as 3 days of age, but it is significantly less prominent, both in magnitude and duration, at early ages than it is in the adult animal. By approximately 34 to 40 days of age, adult-like hyperalgesia is evident (Jiang and Gebhart 1998). Taken together, these observations demonstrate the maturation of synaptic connections in the superficial laminae of the dorsal horn during the first 3 postnatal weeks (Fitzgerald 2005).

Both somatic and visceral tissue insults in the neonate appear to alter processing of nociceptive inputs in adulthood. Neonatal injury has thus been associated with either hyperalgesia or hypoalgesia, depending on the type and severity of injury and the sensory modality tested (Bhutta et al. 2001). Colorectal distension in neonatal rats (P8-12) results in colon hypersensitivity in adults (Al-Chaer et al. 2000). In addition to altered nociceptive processing, repetitive or persistent pain in the neonatal period leads to changes in brain development, widespread alterations in animal behavior, and increased vulnerability to stress and anxiety disorders or chronic pain syndromes (Anand et al. 1999, 2007; Al-Chaer et al. 2000; Bhutta et al. 2001).

Specifically, inflammation produced by repeated injections of complete Freund’s adjuvant in rat pups (P0, P3, P14) leads to hyperalgesia and lasting changes in nociceptive circuitry of the adult dorsal horn (Ruda et al. 2000). Similarly, rat pups that received repeated formalin injections in the paw developed generalized thermal hypoalgesia as they aged (Bhutta et al. 2001). When noxious formalin stimuli were preceded by morphine analgesia in neonatal rats, hyperalgesia in adulthood was significantly reduced (ibid.). In other models of persisent pain, rat pups less than 21 days old did not develop signs of neuropathic pain after nerve injury (Howard et al. 2005).

Whereas a growing number of studies have demonstrated altered pain processing after neonatal injury in humans, not all outcomes reported are necessarily applicable to the laboratory animal (e.g., see Grunau and Tu 2007). However, an important conclusion from this body of research is that untreated neonatal pain can permanently alter sensitivity to pain, consistent with modulation of primary afferent activation and central sensitization in response to subsequent nociceptive challenges in adulthood. Thus measures to minimize pain in neonates may reduce alterations in neuronal development and long-term sensitivity to sensory stimuli.

MODULATORY INFLUENCES ON PAIN: ANXIETY, FEAR, AND STRESS

As noted above, pain is not merely the appreciation of the presence, location, and magnitude of nociceptive input but rather a complex event with an important emotional/affective component. In addition, psychological factors can significantly influence the experience of pain (also discussed in Chapter 1, text and Figure 1-1). For example, fear and anxiety can enhance responses to and interpretation of pain-producing events (Hunt and Mantyh 2001; Linton 2000; Morley 1999; Munro 2007; Perkins and Kehlet 2000; Ploghaus et al. 2001). For these reasons, the predisposition of certain strains of animals or individuals to anxiety should be considered in efforts to assess the possible contribution of anxiety to the experience of pain (Ulrich-Lai et al. 2006). In humans, measures to reduce anxiety can reduce pain—this is true for both behavioral (cognitive) interventions and anxiolytic drugs (Belzung 2001). Similarly, behavioral interventions to reduce anxiety in animals can include acclimation to human handlers, training to withstand some research procedures, socialization and housing with cage mates, or training and exercise. Reliable and reproducible testing of animals is best achieved in a situation in which the animal is habituated to the test apparatus and the test environment (e.g., light, noise, temperature, humidity).

The extent to which stress is present in normal laboratory situations should also be considered. There are numerous examples in which exposure to stressors can influence the response to a noxious stimulus. Somewhat paradoxically, the response can manifest as an apparent reduction of pain, a phenomenon referred to as “stress-induced analgesia” (Amit and Galina 1986; Keogh and Cochrane 2002; for commentary on how exposure to a predator reduces nociceptive responses in rats see Lester and Fanselow 1985). Moreover, environmental enrichment may also affect stress-related nociceptive responses. A recent study reported that C3H mice exposed to environmental enrichment, which can reduce stress compared with a standard environment (i.e., standard plastic cages with bedding), reacted more quickly (i.e., exhibited a shorter freezing time) to electric shock training than did mice habituated in standard housing conditions. Such an outcome, possibly due to decreased fearfulness or anxiety, may require more nuanced staff training in recognizing modulatory influences on painful situations (Benaroya-Milshtein et al. 2004).

Whether the magnitude of stress experienced in typical laboratory settings is sufficient to significantly alter the perception of pain is difficult to determine. A priori one would assume that reducing stress is a good objective for both experimental outcomes and animal welfare, since perturbation of the latter may lead to stress/distress (see the 2008 NRC report Recognition and Alleviation of Distress in Laboratory Animals for detailed information on the effects of stress/distress on animal welfare). The stressors typically used to evoke stress-induced analgesia are intense and rather unnatural and can be useful for evaluating pain behavior in response to an applied stimulus. How data from such studies translate into the normal behavioral repertoire of animals in a laboratory environment and in other types of experimental studies remains to be determined. Nevertheless, it is important to keep in mind the possibility of stress-induced effects when assessing pain in animals because the absence of response to a noxious stimulus or of pain-indicative behavior may be due to significant stress and misleadingly suggest the absence of pain. Because pain can be enhanced by anxiety or fear, readers should consult the discussion of the role of anxiolytics in pain management in Chapter 4.

CONCLUSIONS AND RECOMMENDATIONS

Pain is not a foregone outcome when an animal is exposed to a noxious stimulus, because, as discussed in Chapter 1, the experience of pain is informed by the perceptive abilities of the brain.

  1. It is critical to appreciate that nociception is not equivalent to pain. Noxious stimuli trigger several levels of information processing as the activity of primary afferent nociceptors is conveyed to the spinal cord and from there to the higher centers of the brain. Neurons at many levels of the neuraxis respond to noxious stimuli, but that response does not necessarily indicate or lead to pain. In fact, studies of animals with transections of the neuraxis at various levels illustrate that complex responses can be elicited in the absence of pain (i.e., when the cortex is disconnected from the nociceptive processing networks).
  2. Until better methods (e.g., biomarkers, imaging) are available to objectively measure pain, behavioral indices and to some extent extrapolation from the human experience are the best sources of information and the only methods available to assess pain in laboratory animals (see Chapter 3).
  3. Pain is not exclusively associated with noxious stimuli. After some injuries (e.g., nerve injury), even innocuous stimuli can cause pain, and repeated exposure to noxious stimuli can lead to sensitization and enhance responses to subsequent stimuli both innocuous and noxious.
  4. Injury may have long-term consequences to the neural systems that process nociceptive information. This is particularly true of procedures performed in the neonatal animal, but it may also be relevant in the adult. This information underscores the importance of adequate postoperative pain management and to some extent provides the rationale for preemptive analgesia (see Chapter 4). Psychological factors also likely contribute to the pain experienced during and after an injury; their effect is perhaps more difficult to assess and address in the context of laboratory experiments, but its recognition is important.
  5. Pain represents a cascade of physiological, immunological, cognitive, and behavioral effects that may confound experimental results in addition to being detrimental to the animals’ welfare.

Finally, and as discussed in Chapter 1, unless not recommended due to experimental outcomes, relief from pain is an ethical and regulatory obligation. Further, the committee emphasizes that effective pain management is scientifically advantageous, as unalleviated pain may adversely influence scientific projects and research outcomes in a number of ways. The reader is referred to Box 1-4 of Chapter 1 and to Chapter 4 for an extended discussion of the consequences of unrelieved pain.

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Whereas virtually all nociceptors are A-delta and C-fibers, not all A-delta and C-fibers are nociceptors. It is thus both inaccurate and incorrect to generically refer to C-fibers as “pain” fibers.

Footnotes

1

Whereas virtually all nociceptors are A-delta and C-fibers, not all A-delta and C-fibers are nociceptors. It is thus both inaccurate and incorrect to generically refer to C-fibers as “pain” fibers.

Copyright © 2009, National Academy of Sciences.
Bookshelf ID: NBK32659
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