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OCR for page 35
CHAPTER 2. Mechanisms of pain
This chapter analyzes 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 discusses 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 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. The information is transmitted to the spinal cord dorsal horn or its
trigeminal homologue, the nucleus caudalis, and continues on to the brainstem
and ultimately the cerebral cortex, where the perception of pain is generated
(Figure 2-1). Pain is a product of higher brain center processing; nociception
by contrast 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 level of the spinal cord 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 supra-threshold
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 of the 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 end points of more complex behaviors (e.g., 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).
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36 Recognition and Alleviation of Pain in Laboratory Animals
Figure 2-1 Anatomical distribution of nociception and pain
Figure 2-1 schematizes the major neuroanatomical structures that differentiate
nociception and pain, an understanding of which is essential in studies where pain may
result during research with animals. Nociception refers to the process through which
information about peripheral stimuli are transmitted by primary afferent nociceptors
to spinal cord, brainstem, thalamus, and sub-cortical structures. By contrast, the
experience of pain can result only when there is activity of thalamo-cortical networks
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CHAPTER 2: MECHANISMS OF PAIN 37
(red) that process the information conveyed by pathways of nociception (light green).
The magnitude of pain is determined to a great extent by the strength of descending
inhibitory and indeed facilitatory controls (blue) that originate throughout the
neuraxis and regulate the processing of ascending nociceptive messages. The figure
also illustrates several important surgical preparations used to study nociceptive
processing under conditions in which different parts of the brain are disconnected
from afferent nociceptive input. Thus, transection of the spinal cord produces a
“spinal” preparation. Decerebrate preparation entails a transection of the brain
between the midbrain (at the level of the colliculi) and the thalamus. In the
decorticate preparation, connections from the thalamus to the cortex are severed. In
all of these conditions, information generated by the activity of nociceptors located
below the level of transection is unlikely to reach structures above the transection.
No evidence exists at present that hormonal or other non-neural mechanisms are able
to “bypass” the transection so as to access the brain to evoke a pain perception.
Mechanisms of nociception and pain
A. Nociceptors
The anatomical basis for the generation of momentary pain is now very
well understood (Basbaum and Jessell 2000). Briefly, there are two major
classes of nociceptors that respond to different modalities of noxious stimuli.
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. The largest group of
nociceptors are 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 now targets for therapeutic intervention in clinical pain conditions. There
is also a population of nociceptors associated with thinly myelinated axons (A-
delta fibers). These nociceptors conduct more rapidly than do unmyelinated C-
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38 Recognition and Alleviation of Pain in Laboratory Animals
fibers and likely convey “fast” (or sharp) momentary pain, as opposed to slow,
diffuse pain, which is transmitted by the C-fibers.10
There is yet one more class 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 painproducing; moreover, awakening
silent nociceptors creates essentially new, additional nociceptive input into the
CNS. Another characteristic of all nociceptors is their ability to sensitize.
When nociceptors become more easily excitable (i.e., the threshold for
activation is lowered), hyperalgesia (i.e., an increased response to a noxious
stimulus) with or without allodynia develops, therefore normally innocuous
stimuli may provoke pain and thus directly affect animal welfare. The
consequences of such activities are discussed below in the section dealing with
persistent pain.
B. 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 that provides a 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. The information
is widely distributed to the cerebral cortex from the reticular formation,
thalamus, and amygdala.
10
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.
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CHAPTER 2: MECHANISMS OF PAIN 39
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). What we have learned is that there is
not one area of the brain where pain is processed. 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 the 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. The affective components of the pain
experience correlate with activity in the anterior cingulate gyrus and the
insular cortex. Unfortunately, activity of these regions cannot be used as a
biomarker for pain, as it can be generated in these areas 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 in the beginning of the 20th century by
Sherrington (1906), who appreciated early on the distinction between
nociception and pain. Although use of a “decerebrate preparation” (cerveau
isolé) in laboratory animal research was more common years ago, it remains
useful for recording the activity of spinal cord or brainstem neurons under
conditions in which the experiment is not compromised by anesthetics or
analgesics. To this end, animals are first decerebrated under deep general
anesthesia. This involves transection of the brainstem at the level of the
midbrain (typically between the inferior and superior colliculi). After this
procedure, 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,
when they defined the “pseudaffective” reflex. In response to a noxious
stimulus, the “pseudaffective” 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 accepts that “for pain to be
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40 Recognition and Alleviation of Pain in Laboratory Animals
experienced, the cerebral cortex and subcortical structures must be
functional” (AVMA 2007, p.2). This 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, of course, that
decerebrate preparations are non-survival experiments; Silverman and
colleagues (2005, p.1) note that an animal that recovers from the anesthesia
used for this procedure typically provides research data “for a period of a few
hours or a day” after which it must be euthanized.
As a result of severing the connections between the rostral part of the
brain and lower CNS structures, decerebration 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 (Liu et al. 2004). Their removal during decerebration leads to
enhanced nociceptive reflexes and spinal neuron responses to nociceptive
input. Accordingly, decerebration is often followed by spinal cord transection
to enable physiological studies in unanesthetized animals. Spinal cord
transection, however, 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 the underlying sub-cortical structures (i.e., the thalamus, brainstem
and spinal cord) intact. 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 rarely used)
must be performed under general anesthesia.
The development of persistent pain
The mechanisms that contribute to the development of
postoperative/post-procedural and persistent pain are far more complicated
than the rather simple anatomical and physiological underpinnings of
momentary pain. It is important to appreciate that postoperative/post-
procedural and persistent pain are not merely instances of momentary pain
that do not resolve quickly. Rather, these conditions arise in the context and
environment of tissue or nerve injury and involve changes in the properties of
nociceptors as well as in the properties 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 serve to 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 our understanding of these mechanisms, many pharmacological
treatments for postoperative/post-procedural and persistent pain in humans
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CHAPTER 2: MECHANISMS OF PAIN 41
are directed at interfering with the development and duration of allodynia and
hyperalgesia.
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).
Hyperalgesia manifests as an increased sensitivity to pain (Treede et al. 1992;
Campbell and Meyer 2006) and is defined as an increased response to a noxious
stimulus. Because the threshold for response also typically decreases,
sometimes even non-noxious 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). Primary hyperalgesia is most commonly observed following skin
injury, but may also develop following insults to joints, muscle, and the
viscera. For example, when an incision in the skin is examined, the response to
stimuli applied to that site is typically increased. 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 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 central nervous system, including the spinal cord
and supraspinal 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 for an overview). At the injury site, primary hyperalgesia is
induced by the release of numerous inflammatory mediators including the
products of cyclooxygenase (COX enzymes) activation. The critical
contribution of these enzymes accounts for the beneficial effects of NSAIDs,
which, by inhibiting the enzyme, reduce peripheral sensitization and help
alleviate persistent or postoperative/post-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
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42 Recognition and Alleviation of Pain in Laboratory Animals
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 partially 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.
There is hope that the remarkable number of molecules implicated in
central sensitization (whether produced by tissue or nerve injury) will 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 now 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
our understanding of the origin and maturation of nociceptive circuitry and
behavior. Importantly, subpopulations of sensory neurons, including
nociceptors, can be identified 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 between
embryonic days 15 – 17 (E15-17) and 18 – 20 (E18-20) respectively and coincide
with the first appearance of reflex responses to mechanical stimuli (ibid). 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
Fitzgerlad 2005 and Hathway and Fitzgerlad 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
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CHAPTER 2: MECHANISMS OF PAIN 43
precision by P21. Non-noxious 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 34–40 days of age, adult-like
hyperalgesia can be observed (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 three postnatal weeks
(Fitzgerald 2005).
Both somatic and visceral tissue insult in the neonate appears to alter
processing of nociceptive inputs in adulthood. Thus, neonatal injury has 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; Al-Chaer et al. 2000; Bhutta et al. 2000; Anand et al. 2007).
Specifically, inflammation produced by repeated injections of Complete
Freund’s adjuvant (CFA) 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 into 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 of age did not
develop signs of neuropathic pain following 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 ae
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. Therefore, taking
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 that
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44 Recognition and Alleviation of Pain in Laboratory Animals
has an important emotional/affective component. And not only does pain
itself have an emotional quality, but psychological factors can also 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 both for 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, etc).
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 additional 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 to electric
shock training than did mice habituated in standard housing conditions. Such
an outcome, possibly due to decreased fearfulness or anxious behavior, 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
both for experimental outcomes and animal welfare, since the perturbation of
the latter may lead to stress/distress (detailed information on the effects of
stress/distress on animal welfare is included in the NRC report “Recognition
and Alleviation of Distress in Laboratory Animals; 2008). 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
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CHAPTER 2: MECHANISMS OF PAIN 45
due to significant sress and misleadingly suggest the absence of pain. Because
pain can be enhanced by anxiety or fear, readers should consult the discussion
on 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. Therefore,
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 is
not necessarily indicative of or necessarily 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. Therefore,
2. Until better methods are available to objectively measure pain (e.g.,
biomarkers, imaging), 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 also Chapter 3).
3. Pain is not exclusively associated with noxious stimuli. After some
injuries (e.g., nerve injury), even innocuous stimuli can also cause pain,
and repeated exposure to noxious stimuli can lead to sensitization and
enhance responses to subsequent innocuous and noxious stimuli.
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. This 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 make uncontrolled pain a source of
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46 Recognition and Alleviation of Pain in Laboratory Animals
experimental error 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 in addition scientifically advantageous, as constant 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 Chapter 4
for an extended discussion of the consequences of unrelieved pain.
References
Al-Chaer ED, Kawasaki M, Pasricha PJ. 2000. A new model of chronic visceral
hypersensitivity in adult rats induced by colon irritation during postnatal
development. Gastroenterology 119(5):1276-1285.
Amit Z, Galina ZH. 1986. Stress-induced analgesia: adaptive pain suppression.
Physiol Rev 66(4):1091-1120.
Apkarian AV, Bushnell MC, Treede RD, Zubieta JK. 2005. Human brain
mechanisms of pain perception and regulation in health and disease. Eur
J Pain 9(4):463-484.
Anand KJ, Coskun V, Thrivikraman KV, Nemeroff CB, Plotsky PM. 1999. Long-
term behavioral effects of repetitive pain in neonatal rat pups. Physiol
Behav 66:627-637.
Anand KJ, Garg S, Rovnaghi CR, Narsinghani U, Bhutta AT, Hall RW. 2007.
Ketamine reduces the cell death following inflammatory pain in newborn
rat brain. Pediatr Res 62:283-90.
AVMA [American Veterinary Medical Association]. 2007. AVMA Guidelines on
Euthanasia. Available online
(http://www.avma.org/issues/animal_welfare/euthanasia.pdf),
accessed June 9, 2008.
Basbaum A, Jessell T. 2000. The Perception of Pain. In Principles of Neural
Science, 4th edition, Kandel ER, Schwartz JH, Jessell TM eds. New York:
McGraw-Hill, Health Professions Division
Basbaum AI, Woolf CJ. 1999. Pain. Curr Biol 9:R429-R431.
Belzung C. 2001. The genetic basis of the pharmacological effects of
anxiolytics: A review based on rodent models. Behav Pharmacol 12(6-
7):451-460.
Benaroya-Milshtein N, Hollander N, Apter A, Kukulansky T, Raz N, Wilf A, Yaniv
I, Pick CG. 2004. Environmental enrichment in mice decreases anxiety,
attenuates stress responses and enhances natural killer cell activity. Eur
J Neurosci 20(5):1341-1347.
Prepublication Copy
OCR for page 47
CHAPTER 2: MECHANISMS OF PAIN 47
Bhutta AT, Rovnaghi C, Simpson PM, Gossett JM, Scalzo FM, Anand KJ. 2001.
Interactions of inflammatory pain and morphine in infant rats: Long-term
behavioral effects. Physiol Behav 73(1-2):51-58.
Bingel U, Tracey I. 2008. Imaging CNS modulation of pain in humans. Physiology
23(6):371-380.
Campbell JN, Meyer RA. 2006. Mechanisms of neuropathic pain. Neuron
52(1):77-92.
Fitzgerald M. 2005. The development of nociceptive circuits. Nat Rev Neurosci
6(7):507-520.
Grunau RE, Tu MT. 2007. Long-term consequences of pain in human neonates.
In: Pain in Neonates and Infants, 3rd Edition (Anand KJ, McGrath PJ,
Stevens B, eds.). Pain Research and Clinical Management. Elsevier:
Amsterdam. pp. 45-55.
Hathway GJ, Fitzgerald MF. 2008. The development of nociceptive systems. In:
The Senses: A Comprehensive Reference, Vol. 5. Pain (Bushnell MC and
Basbaum AI, Eds.). Academic Press: San Diego. pp. 133-145.
Howard RF, Walker SM, Mota PM, Fitzgerald M. 2005. The ontogeny of
neuropathic pain: Postnatal onset of mechanical allodynia in rat spared
nerve injury (SNI) and chronic constriction injury (CCI) models. Pain
115(3):382-389.
Hunt SP, Mantyh PW. 2001. The molecular dynamics of pain control. Nat Rev
Neurosci 2(2):83-91.
Jiang MC, Gebhart GF. 1998. Development of mustard oil-induced hyperalgesia
in rats. Pain 77(3):305-313.
Julius D, Basbaum Al. 2001. Molecular mechanisms of nociception. Nature
413:203-210.
Keogh E, Cochrane M. 2002. Anxiety sensitivity, cognitive biases, and the
experience of pain. J Pain 3(4):320-329.
Lester LS, Fanselow MS. 1985. Exposure to a cat produces opioid analgesia in
rats. Behav Neurosci 99(4):756-759.
Linton SJ. 2000. A review of psychological risk factors in back and neck pain.
Spine 25(9):1148-1156.
McMahon SB, Bennett DL, Bevan S. 2005. Inflammatory mediators and
modulators of pain. In Koltzenburg M and McMahon S, eds. Textbook of
Pain 5th ed. Churchill-Livingstone; pp. 49-72.
Merker B. 2007. Consciousness without a cerebral cortex: A challenge for
neuroscience and medicine. Behav Brain Sci 30(1):63-81; discussion 81-
134.
Morley JS. 1999. New perspectives in our use of opioids. Pain Forum 8(4):200-
205.
Munro G. 2007. Dopamine D(1) and D(2) receptor agonism enhances
antinociception mediated by the serotonin and noradrenaline reuptake
inhibitor duloxetine in the rat formalin test. Eur J Pharmacol 575(1-
3):66-74.
NRC [National Research Council]. 2008. Recognition and Alleviation of Distress
in Laboratory Animals. Washington, DC: National Academy Press.
Prepublication Copy
OCR for page 48
48 Recognition and Alleviation of Pain in Laboratory Animals
Perkins FM, Kehlet H. 2000. Chronic pain as an outcome of surgery: A review of
predictive factors. Anesthesiology 93(4):1123-1133.
Ploghaus A, Narain C, Beckmann CF, Clare S, Bantick S, Wise R, Matthews PM,
Rawlins JN, Tracey I. 2001. Exacerbation of pain by anxiety is associated
with activity in a hippocampal network. J Neurosci 21(24):9896-9903.
Ruda MA, Ling QD, Hohmann AG, Peng YB, Tachibana T. 2000. Altered
nociceptive neuronal circuits after neonatal peripheral inflammation.
Science 289(5479):628-631.
Sherrington CS. 1906. The Integrative Action of the Nervous System. New York:
Charles Scribner's Sons.
Silverman J, Garnett NL, Giszter SF, Heckman CJ, II, Kulpa-Eddy JA, Lemay MA,
Perry CK, Pinter M. 2005. Decerebrate mammalian preparations:
Unalleviated or fully alleviated pain? A review and opinion. Cont Topics
44(4):34-36.
Thacker MA, Clark AK, Marchand F, McMahon SB. 2007. Pathophysiology of
peripheral neuropathic pain: immune cells and molecules. Anesth Analg
105(3):838-847.
Tracey I, Mantyh PW. 2007. The cerebral signature for pain perception and its
modulation. Neuron 55(3):377-391.
Treede RD, Meyer RA, Raja SN, Campbell JN. 1992. Peripheral and central
mechanisms of cutaneous hyperalgesia. Prog Neurobiol 38(4):397-421.
Ulrich-Lai YM, Xie W, Meij JT, Dolgas CM, Yu L, Herman JP. 2006. Limbic and
HPA axis function in an animal model of chronic neuropathic pain.
Physiol Behav 88(1-2):67-76.
Urban MO, Gebhart GF. 1999. Supraspinal contributions to hyperalgesia. Proc
Natl Acad Sci 96:7687-7692.
Watkins LR, Hutchinson MR, Milligan ED, Maier SF. 2007. "Listening" and
"talking" to neurons: Implications of immune activation for pain control
and increasing the efficacy of opioids. Brain Res Rev 56(1):148-169.
Woodworth RS, Sherrington CS. 1904. A pseudoaffective reflex and its spinal
path. J Physiol (Lond.) 31:234-243.
Woolf CJ. 1983. Evidence for a central component of post-injury pain
hypersensitivity. Nature 306(5944):686-688.
Prepublication Copy
