|
Items in cart [1] |
Questions? Call 888-624-8373 |
PREPUB + PDF PREPUB PAPERBACK PDF BOOK PREPUB PDF CHAPTER PREPUB Free Resources |
||||||||||||||||
|
||||||||||||||||
|
|
|||||||||||||||
| ||||||||||||||||||||||||||||||
|
||||||||||||||||||||||||||||||
| Copyright © 2009. National Academy of Sciences. All rights reserved. Terms of Use and Privacy Statement |
Below are the first 10 and last 10 pages of uncorrected machine-read text (when available) of this chapter, followed by the top 30 algorithmically extracted key phrases from the chapter as a whole.
Intended to provide our own search engines and external engines with highly rich, chapter-representative searchable text on the opening pages of each chapter.
Because it is UNCORRECTED material, please consider the following text as a useful but insufficient proxy for the authoritative book pages.
Do not use for reproduction, copying, pasting, or reading; exclusively for search engines.
OCR for page 147
APPENDIX 1. Models of pain
Introduction
Pain can be characterized by its duration (from momentary to chronic),
location (e.g., muscle, viscera), or cause (e.g., nerve injury, inflammation).
Characterization of pain by duration can be arbitrary (i.e., when does pain
become chronic?), but is useful because most significant human pain conditions
are long-lasting, whether referred to as persistent or chronic.
Appreciating that most animal models of pain, when pain is the subject
of study, do not address the most difficult-to-control human pain conditions,
numerous animal models of persistent pain have been developed to explore
mechanism(s) and mediators. The rationale for developing and using such
models is severalfold. First, mechanisms of momentary pain differ significantly
from those of persistent pain, and differ further by the source of the persistent
pain. Knowledge of these mechanisms is necessary to address the second
objective of such studies, namely the development of usually pharmacological
strategies for targeted, improved pain management. Here we briefly present
commonly used models of persistent pain in animals and provide an overview of
response measures and other features of these models. Most were developed
in rodents (rats or mice) unless specified, and behavioral and other response
measures are described for these species alone. Momentary, stimulus-evoked
pain is not discussed because stimulus duration is typically short, responses are
generally reflexive in nature (e.g., tail withdrawal), and the stimulus intensity
is not injurious to tissue. Animal models of momentary pain are fully described
in a comprehensive review by LeBars and colleagues (2001).
Prepublication copy 147
OCR for page 148
148 Recognition and Alleviation of Pain in Laboratory Animals
Animal models of persistent pain
Table A-1 Animal models of persistent pain14
Insult15
Location References
Inflammatory Pain Models
Hindpaw Hong and Abbott 1994
carrageenan Honoré et al 1995
zymosan Meller and Gebhart
1997
complete Freund’s adjuvant Iadarola et al. 1998
(CFA)
bee venom Lariviere and Melzack
1996
formalin Dubuisson and Dennis
1997
Hunskaar and Hole 1987
Allen and Yaksh 2004
Capsaicin Caterina et al 2000
ultraviolet-B irradiation Bishop et al.
Joints
cruciate ligament transection Vilensky et al. 1994
intra-articular (arthritis) Sluka and Westlund
models 1993
Bendele et al. 1999
Neugebauer et al. 2007
collagen-induced arthritis Brand et al. 2004
Neuropathic Pain Models
Central nervous system
spinal cord trauma (blunt) Young 2002
spinal cord insult (chemical) Yezierski et al. 1998
Experimental allergic Olechowski et al. 2009
encephalomyelitis
Peripheral nervous system
mononeuropathies (chronic Bennett and Xie 1988
14
Most of these models are provided here for completeness and are not discussed further in
this report.
15
The majority of these models are provided for completeness purposes and are not discussed
further in the report.
Prepublication Copy
OCR for page 149
APPENDIX 1: ANIMAL MODELS OF PAIN 149
constriction injury)
spinal nerve Kim and Chung 1992
ligation/transection
spared nerve preparation Decosterd and Woolf
2000
Shields et al. 2003
partial nerve Seltzer et al. 1990
ligation/transection Malmberg and Basbaum
1998
Aley et al. 1996
Polomano et al. 2001
Smith et al. 2004
dorsal root ganglion Hu and Xing 1998
compression
complex regional pain Coderre et al. 2004
syndrome (CRPS)
streptozotocin-induced Rakieten et al. 1963
diabetic neuropathy Wuarin-Bierman et al.
1987
HIV (gp120)/anti-retrovirals Wallace et al. 2007
Herpes zoster/postherpetic Sadzot-Delvaux et al.
neuralgia 1990
Visceral Pain Models - many of these models are inflammatory in nature, but response
measures differ significantly from non-visceral inflammatory models
Stomach (ulceration, gastritis) Ozaki et al. 2002
Lamb et al. 2003
Urinary bladder (cyclophosphamide, Lanteri-Minet et al.
zymosan) 1995
Randich et al. 2006
Colon (acetic acid, Morris et al. 1989
trinitrobenzesulfonic acid, zymosan) Burton and Gebhart
1995
Coutinho et al. 1996
Al-Chaer et al. 2000
Kamp et al. 2003
Jones et al. 2007
Ureteral calculosis Giamberardino et al.
1995
Pancreatitis Vera-Portocarrero et
al. 2003
Female reproductive organs Wesselmann et al.
1998
Berkley et al. 1995
Berkley et al. 2007
Muscle Pain Models
Intramuscular injection (chemical) Radhakrishnan et al.
2003
Sluka et al. 2001
Prepublication Copy
OCR for page 150
150 Recognition and Alleviation of Pain in Laboratory Animals
Post-operative (incisional) Pain Models
Glabrous skin Brennan et al. 1996
Banik et al. 2006
Hairy skin Duarte et al. 2005
Cancer Pain Models - these models are likely associated with both inflammation and
nerve injury
Bone cancer Schwei et al. 1999
Pancreatic cancer Lindsay et al. 2005
Review of animal models Pacharinsak and Beitz
2008
Orofacial Pain Models
Inferior alveolar nerve or Vos et al. 1994
infraorbital nerve ligation Tsuboi et al. 2004
Tooth preparation Law et al. 1999
Orofacial inflammation Clavelou et al. 1995
Morgan and Gebhart
2008
Temporomandibular joint Hartwig et al. 2003
inflammation
Models of Head Pain (headache, migraine)
Subarachnoid blood Ebersberger et al.
1999
Chemical irritation of the dura Burstein et al. 1998
(inflammatory soup)
Traumatic head injury Browne et al. 2006
Burn models
Skin (52º C thermal stimulation Nozaki-Taguchi and
for 45 sec to anesthetized rat) Yaksh 1998
Allen and Yaksh 2004
Inflammatory pain models
Rodent hindpaw inflammation is a commonly used model of persistent
inflammatory pain in which noxious stimuli are applied to the glabrous
(thermal) or glabrous and hairy (mechanical) skin of the hindpaw. Response
measures are typically hindpaw withdrawal latency to heat (seconds) or
mechanical withdrawal threshold (g or mN). After determining baseline
response measures, an inflammogen is injected into either the dorsal hairy or
ventral glabrous skin and withdrawal responses are assessed over time (hours to
days). Post-treatment response measures are hyperalgesic, meaning that
response latency to heat is faster and mechanical withdrawal thresholds
(typically assessed using von Frey-like nylon monofilaments, each of which has
a different bending force) are reduced. Edema, which is also a consequence of
such an injection, is greatest following carrageenan (or carrageenan plus
Prepublication Copy
OCR for page 151
APPENDIX 1: ANIMAL MODELS OF PAIN 151
kaolin) injection and least following complete Freund’s adjuvant (CFA). The
nature and duration of hyperalgesia produced differs between the
inflammogens; some produce greater thermal hyperalgesia and others greater
mechanical hyperalgesia. The hyperalgesia produced by carrageenan is
typically assessed over 4 to 6 hours, but can persist more than 24 hours,
whereas that produced by CFA peaks at 1 to 2 days, although it may remain
present for more than 1 week, during which the hyperalgesia decreases in
magnitude.
Hindpaw injection of formalin or capsaicin is also used to assess intense,
short-lasting (minutes to tens of minutes) persistent pain. The effect of
formalin is concentration-dependent (Kaneko et al. 2000; Saddi and Abbott
2000) and is expressed by hindlimb licking and shaking that occurs principally in
two phases. The first phase is short-lasting (~10 min), followed by a brief (~5
min) period of relative quiescence, after which a second phase of hindlimb
shaking and licking develops that lasts for an additional 50 minutes or so. . The
formalin test has also been characterized in infant rats (Abbott and Guy 1995).
Capsaicin selectively activates a subset of nociceptors that express the
transient receptor potential vanilloid receptor (TRPV1), an ion channel that
responds to capsaicin, protons, and heat. Intradermal injection of capsaicin
produces a relatively short-lasting (minutes) but intense pain associated with
hyperalgesia that persists for hours after the capsaicin-produced pain has
resolved.
Joint inflammation models
Physical, chemical, and biologic means are used to produce
inflammatory states that mimic painful conditions of joints. Anterior (cranial)
cruciate ligament transection is a physical means of producing instability of the
knee joint and is a common model of osteoarthritis in dogs and rabbits.
Immediately after ligament disruption, animals exhibit joint swelling as well as
a dramatic reduction in weight bearing on the unstable limb although there will
be a return to some degree of weight bearing accompanied by chronic joint
instability.
Intra-articular injection of inflammogens (e.g., kaolin, carrageenan,
iodoacetate, collagenase, urate crystals) causes synovitis, varying degrees of
cartilage destruction and subsequent joint swelling, lameness, and decreased
activity. Hyperalgesia develops rapidly (i.e., within 4 hours); both
inflammation and the duration of inflammation depend on the agent and dose
used.
Antigen-induced arthritis develops after intra-articular injection of a
protein antigen against which animals have been previously immunized (e.g.,
methylated bovine serum albumin), appearing only in the injected joints, as
soon as 3 to 5 days after injection. The acute form of this arthritis is
characterized by joint and soft-tissue swelling, reduced weight bearing, and
altered activity until the joint swelling declines typically after 1 week. A
longer-lasting chronic arthritis model (30 to 300 days), established after intra-
Prepublication Copy
OCR for page 152
152 Recognition and Alleviation of Pain in Laboratory Animals
articular antigen, involves reactivation of arthritis (arthritis flare) by
reinjection of the antigen 1 month after the initial intra-articular injection
(Moran and Bogoch 1999; van den Berg et al. 2007).
Models of rheumatoid arthritis are achieved by activating an immune
response that targets multiple joints. One example is adjuvant arthritis, a
polyarticular disease that develops 10 – 45 days after intravenous or
intraperitoneal injection of CFA and typically resolves over a month. Another
example is collagen-induced arthritis produced by immunizing animals with
type II collagen. The time course of collagen-induced arthritis differs between
rats and mice, but onset generally occurs 2 – 4 weeks after immunization.
Resolution of clinical signs occurs in rats after 30 – 45 days, whereas
susceptible mice will demonstrate disease at 8 – 12 weeks post immunization.
Duration, severity and location of arthritis following immunization with
collagen depend upon genetic background of the animals being used, as well as
the source of the collagen (autologous vs heterologous) (Griffiths et al. 2007;
van den Berg et al. 2007).
In general, pain associated with inflammatory joint models is assessed by
documenting changes in body weight, joint circumference, joint mobility,
degree of weight bearing, soft tissue swelling, general activity, and gait.
Investigators often quantify latency to withdrawal or vocalization in response
to pressure applied across the joint or, as a model of secondary hyperalgesia,
responses to heat or mechanical stimulation of the hindpaw.
Visceral pain models
Although once considered models of visceral pain, irritants such as
acetic acid, hypertonic saline, phenylquinone, and others injected
intraperitoneally do not selectively act on the viscera, and moreover produce a
behavior (writhing) that is inescapable. Accordingly, such models have fallen
into disfavor and have been largely replaced with hollow organ balloon
distension, which reproduces in humans the quality, location, and intensity of
their visceral pain (Ness and Gebhart 1990) and has been widely adopted.
Hollow organ distension produces several quantifiable responses, including
contraction of skeletal (nonvisceral) muscles (termed the visceromotor
response) and increases in blood pressure and heart rate. Electromyographic
(EMG) recordings of muscle contraction, which requires the surgical
implantation of EMG recording electrodes in appropriate muscles, generally
provide the most reliable response measure. Blood pressure and heart rate
measurement require either surgical implantation of an arterial catheter,
which can be difficult to keep patent in rodents, or expensive telemetric
methods for long-term recording of these measures. These response measures
to organ distension are organized in the brainstem (and thus are not simple
nociceptive reflexes) and are best assessed in unanesthetized animals because
anesthetic drugs affect responses (e.g., pressor effects are converted to
depressor effects; Ness and Gebhart 1990). Methods for distension of rat
stomach (Ozaki et al. 2002), rat (Ness et al. 2001) and mouse (Ness and Elhefni
Prepublication Copy
OCR for page 153
APPENDIX 1: ANIMAL MODELS OF PAIN 153
2004) urinary bladder, and rat (Gebhart and Sengupta 1996) and mouse
(Christianson and Gebhart 2007) colon have been fully described. As indicated
previously in Chapter 2 (see Ontogeny of Pain), organ insult or stress (e.g.,
maternal separation) in early life can lead to visceral hypersensitivity when
assessed in adults (see Al Chaer et al. 2000; Coutinho et al. 2002; Randich et
al. 2006).
Because non-ulcer dyspepsia, interstitial cystitis/painful bladder
syndrome, and inflammatory and irritable bowel syndromes are relatively
common human diseases for which management of pain is poor, hollow organs
are irritated or inflamed in many models to assess mechanisms that underlie
the hypersensitivity that characterizes these human disorders. Thus, models of
lower esophageal irritation (usually with HCl), stomach ulceration (acetic acid-
produced lesions) and inflammation (oral ingestion of 0.1% iodoacetic acid;
Ozaki et al. 2002), colon inflammation (e.g., intracolonic
trinitrobenzenesulfonic acid or acetic acid), hypersensitivity in the absence of
inflammation (intracolonic zymosan; Jones et al. 2007), urinary bladder
inflammation (intraperitoneal administration of cyclophosphamide, which is
metabolized to the bladder irritant acrolein and produces cystitis; Lanteri-
Minet et al. 1995), and uterine inflammation (Wesselmann et al. 1998) have
been developed to study mechanisms of visceral hypersensitivity. In
unanesthetized rodents, baseline responses to balloon distension are acquired
before organ insult and monitored over time (days to weeks) after the insult.
Responses are typically exaggerated (increased) and occur at reduced response
thresholds (i.e., they are hyperalgesic or hypersensitive).
Inflammatory models of the pancreas have also been developed (e.g.,
Vera-Portocarrero et al. 2003). The response measure in these models is
typically mechanical hypersensitivity (e.g., von Frey probing) determined in the
area of referred sensation (thorax and abdominal skin). Similarly, one response
measure in a kidney stone (ureteral calculosis) model is mechanical
hypersensitivity, including of the paraspinous muscles. This model is also
associated with episodes of lordosis-like stretching and hunching, which can be
quantified as to frequency as well as intensity (Giamberardino et al. 1995).
Postoperative (incisional) pain models
Models of postoperative pain have elucidated the fact that the
mechanisms and subsequent control of postoperative pain differ significantly
from those of inflammatory pain. These models involve an incision of glabrous
or hairy skin of controlled length and depth to determine the relative
contributions of skin, fascia, and underlying muscle to postoperative pain. To
eliminate any possible contribution of infection, the incisions are made under
aseptic conditions. Response measures include both thermal (heat) and
mechanical (von Frey probing) hyperalgesia at (primary hyperalgesia) and
adjacent to (secondary hyperalgesia) the incision. An incision of glabrous
hindpaw skin and fascia leads to both thermal and mechanical hyperalgesia
that is maximal within the first 24 to 48 hrs after incision and typically lasts 3
Prepublication Copy
OCR for page 154
154 Recognition and Alleviation of Pain in Laboratory Animals
to 4 days. When underlying muscle is included in the incision, the duration of
hyperalgesia is usually extended by 1 day without an increase in the magnitude
of hyperalgesia.
Orofacial pain models
Injection of inflammogens into the temporomandibular joint (TMJ) or
subcutaneous tissues of the face are methods for models of orofacial pain.
Injection of mustard oil into the TMJ produces rapid onset of swelling and
behavioral changes; initially, freezing behavior is seen, followed by a second
phase of active behaviors such as facial rubbing or grooming, chewing
movements, and headshaking. These active behaviors peak at 1.5 to 2 hours
and return to baseline by 5 hours after the injection (Hartwig et al. 2003).
Subcutaneous formalin injection into the facial whisker pad results in acute
onset of facial rubbing in rats that lasts for at least 45 minutes. The duration
of grooming activity and edema following formalin injection is concentration-
dependent (Clavelou et al. 1995). Whisker pad injection of CFA produces a
longer-lasting (2 weeks) thermal and mechanical orofacial hyperalgesia (Morgan
and Gebhart 2008).
Transection or injury of the trigeminal nerve is commonly used to model
neuropathic pain of the face and mouth. Transection of the inferior alveolar
nerve, a branch of the trigeminal nerve, produces mechanical allodynia in rats
after 2 to 3 days (Tsuboi et al. 2004). Similarly, nerve constriction results in
nerve injury and mechanical hyperalgesia. Unilateral chronic constriction
injury (CCI) has been used in rats to study orofacial allodynia. Following
unilateral loose ligation of the infraorbital nerve, rats develop a biphasic
behavioral response. In the early post-ligature phase (days 1 to 15), rats
demonstrate increased grooming activity at the site of nerve injury but are
hyporesponsive to mechanical stimuli. On post-constriction days 15 to 130, the
rats become hyper-responsive to mechanical stimuli, demonstrating maximal
escape responses to all stimulus intensities. Decreased weight gain and altered
activity are also seen in this constriction injury model (Vos et al. 1994).
Muscle pain models
Models of persistent muscle pain include intramuscular injection of
carrageenan and of acidic saline. Unilateral injection of carrageenan into the
gastrocnemius muscle of rats produces acute inflammation with edema and
reduced withdrawal latencies in the first 4 to 24 hours. Hyperalgesia also
develops in the contralateral limb 1 to 2 weeks after injection, suggesting
involvement of central nervous system mechanisms. Mechanical and thermal
hyperalgesia are carrageenan concentration-dependent and may last for 7 to 8
weeks (Radhakrishnan et al. 2003).
Injection of acidic saline into the gastrocnemius produces secondary
mechanical but not thermal hyperalgesia (in tests on the hindpaw). The
magnitude and contralateral spread of hyperalgesia are directly related to
Prepublication Copy
OCR for page 155
APPENDIX 1: ANIMAL MODELS OF PAIN 155
acidity and also depend on the timing of repeated intramuscular injections.
Reductions in mechanical threshold occur in the absence of behavioral changes
(i.e., normal gait, equal weight bearing, and no guarding of the limb) or muscle
histological changes (Sluka et al. 2001).
Neuropathic pain models
Of the two major classes of clinical pain conditions -those produced by
tissue injury and those produced by nerve injury- the latter for many years
proved very difficult to model in animals. The human clinical condition can
result from traumatic, metabolic, or drug-induced injury to either the
peripheral nervous system (e.g., diabetic neuropathy, postherpetic neuralgia,
complex regional pain syndrome, or chemotherapy-induced neuropathy) or the
CNS (e.g., from multiple sclerosis, destruction of tissue due to sroke, or spinal
cord injury). Although there have been many attempts (e.g., the use of
streptozotocin to produce an animal model of diabetes and its associated
neuropathy) to model the different clinical conditions, most studies have built
on the principle that neuropathic pain arises from partial nerve injury (e.g., of
a peripheral nerve) or abnormal neuronal activity. The first model of pain
induced by nerve injury (Bennett and Xie 1988) demonstrated that constriction
of the sciatic nerve of the rat leads to persistent pain with significant
mechanical and thermal (warm and cold) hypersensitivity as well as signs of
recurrent spontaneous pain. Researchers inferred the latter from the animals’
apparent protection of the partially denervated hindlimb. There have been
many variations of the original neuropathic pain model, and these are now
more commonly used largely because they are highly reproducible and involve
a relatively short surgical procedure. Among these are models in which (1)
one-half to two-thirds the diameter of the sciatic nerve is cut (Seltzer et al.
1990), (2) one or two spinal nerves (usually L5 and L6) are ligated and/or cut
just distal to the dorsal root ganglion (Kim and Chung 1992), and (3) two of the
three branches of the sciatic nerve are cut distal to its trifurcation (Decosterd
and Woolf 2000). In general, these models are associated with a more
pronounced mechanical allodynia than heat hyperalgesia; cold hypersensitivity
is prominent. These models were developed in the rat, and, importantly,
several have been adapted for the mouse, which has proven very valuable for
the study of the genetic basis of different nerve injury-induced pain conditions
(Malmberg and Basbaum 1998; Shields et al. 2003).
Although there may be spontaneous pain associated with these models
(see below), this is not readily appreciated, and is certainly difficult to
document. There is rarely any significant change in behavior or weight loss
that might be indicative of ongoing pain. Thus testing of the animals typically
involves assessment of changes in mechanical paw withdrawal thresholds (using
von Frey-like nylon monofilaments or the Randall Selitto apparatus) and paw
withdrawal latencies for assessment of heat hyperalgesia. Cold
hypersensitivity is very difficult to assess in rodents. Some laboratories rely on
the evaporation of acetone applied to the affected hindpaw; the end point is
Prepublication Copy
OCR for page 156
156 Recognition and Alleviation of Pain in Laboratory Animals
shaking of the paw. Responses on a single cold plate are often used, but
typically very cold temperatures are necessary in order to generate any
behavioral response. For this reason, better results are reported using a two-
plate method in which an animal can escape to the plate that is less cold.
That these different approaches to modeling neuropathic pain are
reliable comes largely from the demonstration that drugs that are effective in
the clinic for neuropathic pain are effective in the animal models. In
particular, there is a general agreement that non-steroidal anti-inflammatory
drugs are quite ineffective in humans with neuropathic pain; the same is true
in the animal models. Similarly, opioids are less effective in neuropathic pain
models than in inflammatory models, and this is commonly observed in the
clinic. In contrast, many anticonvulsant drugs, which either block sodium
channels or enhance GABAergic inhibitory tone, are effective in the animal
models and also are the mainstay for neuropathic pain relief in humans.
As noted above, one of the problematic adverse side effects of
chemotherapy treatment for cancer pain is the development of a profound
peripheral neuropathy with mechanical allodynia, thermal hypersensitivity, and
ongoing, often burning pain. In recent years several laboratories have
developed neuropathic pain models based on treatment with vincristine or
taxol. The treatment typically involves weeks of drug administration to
gradually produce in the animals a significant mechanical and thermal
hypersensitivity to both warm and cold stimuli (the hypersensitivity disappears
when the drug treatment ends). Very recently, a somewhat comparable
condition has been reported following the administration of antiretroviral
drugs, which are used in the treatment of HIV and are also often associated
with the development of severe neuropathic pain.
The drive to model as closely as possible the clinical conditions in which
pain occurs in humans has also led to the development of animal models that
are directed at reproducing the conditions that contribute to the neuropathic
pains associated with spinal or foraminal stenosis and disk herniations, many of
which are considered critical to the development of chronic back pain
conditions. In these animal models, an L-shaped rod is placed unilaterally into
the intravertrebral foramin, one at L4 and the other at L5 (Hu and Xing 1998).
The rod remains in place from 1 to 14 days, after which behavioral,
electrophysiological, and anatomical studies are performed to document that
there is mechanical and thermal hypersensitivity and to elucidate the
underlying causes of the pain that is manifest. To what extent the pain that
results from this condition reflects the compression and associated block of
activity of subpopulations of afferent nerve fibers or whether there is an active
inflammatory process that activates nerve fibers is a critical focus of study. In
this regard it is of interest that application of a variety of cytokines to the
peripheral nerve (Sorkin et al. 1997) or even application of autologous nucleus
pulposus to the DRG of the rabbit (Cavanaugh et al. 1997) can recapitulate
features of a neuropathic pain condition.
Prepublication Copy
OCR for page 157
APPENDIX 1: ANIMAL MODELS OF PAIN 157
Cancer pain
As cancer pain is one of the most severe and most difficult pains to treat
in humans, particularly in late stages of the disease, it is perhaps surprising
that animal models of pain associated with cancer have only recently been
developed. In part, the paucity of cancer pain models reflects the difficulty of
creating a reliable and reproducible condition. The last decade, however, has
seen the development of models of cancer pain in both rats and mice (for a
review Pacharinsak and Beitz 2008). Rather than studying the pain associated
with destruction of a particular organ (e.g., lung, stomach), attention has
focused on the pain that develops after metastasis of tumors to, for example,
bone, which is among the most painful conditions experienced by patients. To
this end, Mantyh and colleagues (Schwei et al. 1999) initially described a model
that involved the implantation of osteolytic sarcoma cells into the femur of a
mouse and the sealing of the femur to restrict tumor growth. Pathological
studies as the tumor developed revealed characteristic osteoclast destruction
of bone, presumably in the relatively acidic environment that promotes
osteoclast function. Over time there was bone destruction concurrent with the
development of a clear hypersensitivity to mechanical probing of the affected
limb. Importantly, to date this model has proven very useful for the testing of
novel pharmaceuticals for the treatment of pain associated with tumor
metastasis to bone. Ongoing studies are directed at assessing the nature of the
pathology that generates the pain. It was originally assumed that such cancer
pains are largely inflammatory in nature, but animal studies indicate that there
is a nerve injury-associated component as well. The peripheral nerve endings
of fibers that innervate bone are unquestionably involved and these likely
contribute to the mechanical hypersensitivity and ongoing pain that develops.
More recently, attention has turned to pains likely associated with the
more traditional models of cancer that are used to study the biological basis
for the generation and treatment of tumor development. For example, Lindsay
and colleagues (2005) used a well-studied transgenic model of pancreatic
cancer produced by expression of the simian virus 40 large T antigen under
control of the rat elastase-1 promoter to monitor behavioral changes that
might indicate ongoing pain. Interestingly, they found that when there were
cellular changes characteristic of an inflammatory response, the mice did not
manifest any behavior indicative of ongoing pain or hypersensitivity. A
comparable magnitude of inflammatory changes in the skin would typically be
associated with clear mechanical and thermal hypersensitivity. Signs of pain,
including hunching and vocalization, did eventually occur at 16 weeks of age,
at which point the pancreatic cancer was severe. Whether there is a masking
of the pain in the early stages of the disease remains to be determined, but
this model illustrates that the mechanism(s) of development of the pains
associated with different types of cancer are not the same and likely have
multiple etiologies.
Prepublication Copy
OCR for page 158
158 Recognition and Alleviation of Pain in Laboratory Animals
Spontaneous pain
Most of the persistent pain models described above measure pain
provoked by thermal, mechanical, or (less frequently) chemical stimuli.
However, many of these models are also presumed to be associated with
ongoing, spontaneous pain, which frequently manifests as reduced activity.
For example, in inflammatory visceral pain models mice and rats with inflamed
stomachs, bladders, or colons tend to sit quietly in their cages and do not
explore in open field tests (although they do not become difficult to handle
and they continue to eat and gain weight). Similarly, animals with inflamed or
incised hindpaws commonly ‘guard’ the paw by raising it above the floor and
hold it in an unnatural posture. In tests these animals will not readily bear
weight on the affected hindpaw until resolution of the insult. In both of the
above examples, and in inflammatory models in general (e.g., joint, muscle,
orofacial), the effects of the inflammation or incision are reversible and
relatively short-lived (days to weeks). Whether ongoing pain at rest is present
in these models is unknown. In analogous inflammatory and post-surgical
circumstances in humans, pain at rest is either minimal or acceptable, but – as
in these animal models – hypersensitivity and pain can be easily provoked by
appropriate stimuli (e.g., forced movement, application of noxious stimuli)
In models of peripheral neuropathic pain, in which mechanical allodynia
is present, nail growth and changes in hindpaw temperature (indicative of
altered sympathetic efferent function) along with limb guarding are common.
Cancer pain models are also associated with increasing discomfort and
spontaneous pain as tumor burden increases. In both of these models, the
effects of either nervous system insult or cancer are long lasting (weeks to
months) and minimally reversible; therefore, animals are generally euthanized
according to humane endpoint principles.
Readers are urged to consult Chapter 5 for an extensive discussion of
humane endpoints. Further, an analysis of the ethical conflicts associated with
research with persistent pain models is presented in the section on “Animal
welfare considerations of research with persistent pain models” in Chapter 4).
References
Abbott FV, Guy ER. 1995. Effects of morphine, pentobarbital and amphetamine
on formalin-induced behaviours in infant rats: Sedation versus specific
suppression of pain. Pain 62:303-12.
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.
Aley KO, Reichling DB, Levine JD. 1996. Vincristine hyperalgesia in the rat: A
model of painful vincristine neuropathy in humans. Neuroscience
73(1):259-265.
Prepublication Copy
OCR for page 159
APPENDIX 1: ANIMAL MODELS OF PAIN 159
Allen JW, Yaksh TL. 2004. Tissue injury models of persistent nociception in
rats. Methods Mol Med 99:25-34.
Banik RK, Woo YC, Park SS, Brennan TJ. 2006. Strain and sex influence on pain
sensitivity after plantar incision in the mouse. Anesthesiology
105(6):1246-1253.
Bendele A, McComb J, Gould T, McAbee T, Sennello G, Chlipala E, Guy M. 1999.
Animal models of arthritis: Relevance to human disease. Toxicol Pathol
27(1):134-142.
Bennett GJ, Xie YK. 1988. A peripheral mononeuropathy in rat that produces
disorders of pain sensation like those seen in man. Pain 33(1):87-107.
Berkley KJ, McAllister SL, Accius BE, Winnard KP. 2007. Endometriosis-induced
vaginal hyperalgesia in the rat: Effect of estropause, ovariectomy, and
estradiol replacement. Pain 132 Suppl 1:S150-S159.
Berkley KJ, Wood E, Scofield SL, Little M. 1995. Behavioral responses to uterine
or vaginal distension in the rat. Pain 61(1):121-131.
Bishop T, Hewson DW, Yip PK, Fahey MS, Dawbarn D, Young AR, McMahon SB.
2007. Characterisation of ultraviolet-B-induced inflammation as a model
of hyperalgesia in the rat. Pain 131(1-2):70-82.
Brand DD, Kang AH, Rosloniec EF. 2004. The mouse model of collagen-induced
arthritis. Methods Mol Med 2004;102:295-312.
Brennan TJ, Vandermeulen EP, Gebhart GF. 1996. Characterization of a rat
model of incisional pain. Pain 64(3):493-501.
Browne KD, Iwata A, Putt ME, Smith DH. 2006. Chronic ibuprofen
administration worsens cognitive outcome following traumatic brain
injury in rats. Exp Neurol 201(2):301-7.
Burstein R, Yamamura H, Malick A, Strassman AM. 1998. Chemical stimulation
of the intracranial dura induces enhanced responses to facial stimulation
in brain stem trigeminal neurons. J Neurophysiol. 79(2):964-82.
Burton MB, Gebhart GF. 1995. Effects of intracolonic acetic acid on responses
to colorectal distension in the rat. Brain Res 672(1-2):77-82.
Caterina MJ, Leffler A, Malmberg AB, Martin WJ, Trafton J, Petersen-Zeitz KR,
Koltzenburg M, Basbaum AI, Julius D. 2000. Impaired nociception and
pain sensation in mice lacking the capsaicin receptor. Science
288(5464):306-13.
Cavanaugh JM, Ozaktay AC, Yamashita T, Avramov A, Getchell TV, King AI.
1997. Mechanisms of low back pain: A neurophysiologic and
neuroanatomic study. Clin Orthop Relat Res (335):166-180.
Christianson JA, Gebhart GF. 2007. Assessment of colon sensitivity by luminal
distension in mice. Nat Protoc 2(10):2624-2631.
Clavelou P, Dallel R, Orliaguet T, Woda A, Raboisson P. 1995. The orofacial
formalin test in rats: Effects of different formalin concentrations. Pain
62(3):295-301.
Coderre TJ, Xanthos DN, Francis L, Bennett GJ. 2004. Chronic post-ischemia
pain (CPIP): A novel animal model of complex regional pain syndrome-
type I (CRPS-I; reflex sympathetic dystrophy) produced by prolonged
hindpaw ischemia and reperfusion in the rat. Pain 112(1-2):94-105.
Prepublication Copy
OCR for page 160
160 Recognition and Alleviation of Pain in Laboratory Animals
Coutinho SV, Meller ST, Gebhart GF. 1996. Intracolonic zymosan produces
visceral hyperalgesia in the rat that is mediated by spinal NMDA and non-
NMDA receptors. Brain Res 736(1-2):7-15.
Coutinho SV, Plotsky PM, Sablad M. 2002. Neonatal maternal separation alters
stress-induced responses to viscerosomatic nociceptive stimuli in rat. Am
J Physiol 282:G307-G16.
Decosterd I, Woolf CJ. 2000. Spared nerve injury: An animal model of
persistent peripheral neuropathic pain. Pain 87(2):149-158.
Duarte AM, Pospisilova E, Reilly E, Mujenda F, Hamaya Y, Strichartz GR. 2005.
Reduction of postincisional allodynia by subcutaneous bupivacaine:
Findings with a new model in the hairy skin of the rat. Anesthesiology
103(1):113-125.
Dubuisson D, Dennis SG. 1977. The formalin test: A quantitative study of the
analgesic effects of morphine, meperidine, and brain stem stimulation in
rats and cats. Pain 4(2):161-174.
Ebersberger A, Handwerker HO, Reeh PW. 1999. Nociceptive neurons in the rat
caudal trigeminal nucleus respond to blood plasma perfusion of the
subarachnoid space: The involvement of complement. Pain 81(3):283-
288.
Gebhart GF, Sengupta JN. 1996. Evaluation of visceral pain. In: Handbook of
Methods in Gastrointestinal Pharmacology. Gaginella T, ed. Boca Raton,
FL: CRC Press. pp 359-373.
Giamberardino MA, Valente R, de Bigontina P, Vecchiet L. 1995. Artificial
ureteral calculosis in rats: Behavioural characterization of visceral pain
episodes and their relationship with referred lumbar muscle
hyperalgesia. Pain 61(3):459-469.
Griffiths MM, Cannon GW, Corsi T, Reese V, Kunzler K. 2007. Collagen-induced
arthritis in rats. In Arthritis: Methods and Protocols, Vol. II, Cope A, ed.
Humana Press. p. 201-214.
Hartwig AC, Mathias SI, Law AS, Gebhart GF. 2003. Characterization and opioid
modulation of inflammatory temporomandibular joint pain in the rat. J
Oral Maxillofac Surg 61(11):1302-1309.
Hong Y, Abbott FV. 1994. Behavioural effects of intraplantar injection of
inflammatory mediators in the rat. Neuroscience 63(3):827-836.
Honoré P, Buritova J, Besson JM. 1995. Aspirin and acetaminophen reduced
both Fos expression in rat lumbar spinal cord and inflammatory signs
produced by carrageenin inflammation. Pain 63(3):365-75
Hu SJ, Xing JL. 1998. An experimental model for chronic compression of dorsal
root ganglion produced by intervertebral foramen stenosis in the rat.
Pain 77(1):15-23.
Hunskaar S, Hole K. 1987. The formalin test in mice: Dissociation between
inflammatory and non-inflammatory pain. Pain 30(1):103-114.
Iadarola MJ, Brady LS, Draisci G, Dubner R. 1988. Enhancement of dynorphin
gene expression in spinal cord following experimental inflammation:
Stimulus specificity, behavioral parameters and opioid receptor binding.
Pain 35(3):313-326.
Prepublication Copy
OCR for page 161
APPENDIX 1: ANIMAL MODELS OF PAIN 161
Jones RC, Otsuka E, Wagstrom E, Jensen CS, Price MP, Gebhart GF. 2007.
Short-term sensitization of colon mechanoreceptors is associated with
long-term hypersensitivity to colon distention in the mouse.
Gastroenterology 133(1):184-194.
Kamp EH, Jones RC 3rd, Tillman SR, Gebhart GF. 2003. Quantitative assessment
and characterization of visceral nociception and hyperalgesia in mice.
Am J Physiol Gastrointest Liver Physiol 284(3):G434-444.
Kaneko M, Mestre C, Sanchez EH, Hammond DL. 2000. Intrathecally
administered gabapentin inhibits formalin-evoked nociception and the
expression of Fos-like immunoreactivity in the spinal cord of the rat. J
Pharmacol Exp Therap 292:743-751.
Kim SH, Chung JM. 1992. An experimental model for peripheral neuropathy
produced by segmental spinal nerve ligation in the rat. Pain 50(3):355-
363.
Lamb K, Kang YM, Gebhart GF, Bielefeldt K. 2003. Gastric inflammation
triggers hypersensitivity to acid in awake rats. Gastroenterology
125(5):1410-1418.
Lanteri-Minet M, Bon K, de Pommery J, Michiels JF, Menetrey D. 1995.
Cyclophosphamide cystitis as a model of visceral pain in rats: Model
elaboration and spinal structures involved as revealed by the expression
of c-Fos and Krox-24 proteins. Exp Brain Res 105(2):220-232.
Lariviere WR, Melzack R. 1996. The bee venom test: A new tonic-pain test.
Pain 66(2-3):271-277.
Law AS, Baumgardner KR, Meller ST, Gebhart GF. 1999. Localization and
changes in NADPH-diaphorase reactivity and nitric oxide synthase
immunoreactivity in rat pulp following tooth preparation. J Dent Res
78(10):1585-1595.
LeBars D, Gozuriu M, Cadden SW. 2001. Animal models of nociception.
Pharmacol Rev 53:597-652.
Lindsay TH, Jonas BM, Sevcik MA, Kubota K, Halvorson KG, Ghilardi JR,
Kuskowski MA, Stelow EB, Mukherjee P, Gendler SJ, Wong GY, Mantyh
PW. 2005. Pancreatic cancer pain and its correlation with changes in
tumor vasculature, macrophage infiltration, neuronal innervation, body
weight and disease progression. Pain 119(1-3):233-246.
Malmberg AB, Basbaum AI. 1998. Partial sciatic nerve injury in the mouse as a
model of neuropathic pain: Behavioral and neuroanatomical correlates.
Pain 76(1-2):215-222.
Meller ST, Gebhart GF. 1997. Intraplantar zymosan as a reliable, quantifiable
model of thermal and mechanical hyperalgesia in the rat. Eur J Pain
1(1):43-52.
Moran EL, Bogoch ER. 1999. Animal models of rheumatoid arthritis. In Animal
Models in Orthopaedic Research, An YH, Friedman, RJ, eds. CRC Press,
p. 369-393.
Morgan JR, Gebhart GF. 2008. Characterization of a model of chronic orofacial
hyperalgesia in the rat: Contribution of NA(V) 1.8. J Pain 9(6):522-531.
Prepublication Copy
OCR for page 162
162 Recognition and Alleviation of Pain in Laboratory Animals
Morris GP, Beck PL, Herridge MS, Depew WT, Szewczuk MR, Wallace JL. 1989.
Hapten-induced model of chronic inflammation and ulceration in the rat
colon. Gastroenterology 96(3):795-803.
Ness TJ, Elhefni H. 2004. Reliable visceromotor responses are evoked by
noxious bladder distention in mice. J Urol 171(4):1704-1708.
Ness TJ, Gebhart GF. 1990. Visceral pain: A review of experimental studies.
Pain 41(2):167-234.
Ness TJ, Lewis-Sides A, Castroman P. 2001. Characterization of pressor and
visceromotor reflex responses to bladder distention in rats: Sources of
variability and effect of analgesics. J Urol 165(3):968-974.
Neugebauer V, Han JS, Adwanikar H, Fu Y, Ji G. 2007. Techniques for assessing
knee joint pain in arthritis. Mol Pain 3:8.
Nozaki-Taguchi N, Yaksh TL. 1998. A novel model of primary and secondary
hyperalgesia after mild thermal injury in the rat. Neurosci Lett
254(1):25-28.
Olechowski CJ, Truong JJ, Kerr BJ. 2009. Neuropathic pain behaviours in a
chronic-relapsing model of experimental autoimmune encephalomyelitis
(EAE). Pain 141(1-2):156-64.
Ozaki N, Bielefeldt K, Sengupta JN, Gebhart GF. 2002. Models of gastric
hyperalgesia in the rat. Am J Physiol Gastrointest Liver Physiol
283(3):G666-G676.
Pacharinsak C, Beitz A. 2008. Animal models fo cancer pain. Comp Med
58(3):220-233.
Polomano RC, Mannes AJ, Clark US, Bennett GJ. 2001. A painful peripheral
neuropathy in the rat produced by the chemotherapeutic drug,
paclitaxel. Pain 94(3):293-304.
Radhakrishnan R, Moore SA, Sluka KA. 2003. Unilateral carrageenan injection
into muscle or joint induces chronic bilateral hyperalgesia in rats. Pain
104(3):567-577.
Rakieten N, Rakieten ML, Nadkarni MV. 1963. Studies on the diabetogenic
action of streptozotocin (NSC-37917). Cancer Chemother Rep 29:91-98.
Randich A, Uzzell T, DeBerry JJ, Ness TJ. 2006. Neonatal uniranry bladder
inflammation produces adult bladder hypersensitivity. J Pain 7(7):469-
479.
Randich A, Uzzell T, Cannon R, Ness TJ. 2006. Inflammation and enhanced
nociceptive responses to bladder distension produced by intravesical
zymosan in the rat. BMC Urol 6:2.
Saddi G-M, Abbott FV. 2000. The formalin test in the mouse: A parametric
analysis of scoring properties. Pain 89:53-63.
Sadzot-Delvaux C, Merville-Louis MP, Delree P, Marc P, Piette J, Moonen G,
Rentier B. 1990. An in vivo model of varicella-zoster virus latent
infection of dorsal root ganglia. J Neurosci Res 26(1):83-89.
Schwei MJ, Honore P, Rogers SD, Salak-Johnson JL, Finke MP, Ramnaraine ML,
Clohisy DR, Mantyh PW. 1999. Neurochemical and cellular reorganization
of the spinal cord in a murine model of bone cancer pain. J Neurosci
19(24):10886-10897.
Prepublication Copy
OCR for page 163
APPENDIX 1: ANIMAL MODELS OF PAIN 163
Seltzer Z, Dubner R, Shir Y. 1990. A novel behavioral model of neuropathic pain
disorders produced in rats by partial sciatic nerve injury. Pain 43(2):205-
218.
Shields SD, Eckert WA 3rd, Basbaum Al. 2003. Spared nerve injury model of
neuropathic pain in the mouse: A behavioral and anatomic analysis. J
Pain 4(8):465-470.
Sluka KA, Kalra A, Moore SA. 2001. Unilateral intramuscular injections of acidic
saline produce a bilateral, long-lasting hyperalgesia. Muscle Nerve
24(1):37-46.
Sluka KA, Westlund KN. 1993. Behavioral and immunohistochemical changes in
an experimental arthritis model in rats. Pain 55(3):367-377.
Smith SB, Crager SE, Mogil JS. 2004. Paclitaxel-induced neuropathic
hypersensitivity in mice: Responses in 10 inbred mouse strains. Life Sci
74(21):2593-2604.
Sorkin LS, Xiao WH, Wagner R, Myers RR. 1997. Tumour necrosis factor-alpha
induces ectopic activity in nociceptive primary afferent fibres.
Neuroscience 81(1):255-262.
Tsuboi Y, Takeda M, Tanimoto T, Ikeda M, Matsumoto S, Kitagawa J, Teramoto
K, Simizu K, Yamazaki Y, Shima A, Ren K, Iwata K. 2004. Alteration of
the second branch of the trigeminal nerve activity following inferior
alveolar nerve transection in rats. Pain 111(3):323-334.
Vera-Portocarrero LP, Lu Y, Westlund KN. 2003. Nociception in persistent
pancreatitis in rats: Effects of morphine and neuropeptide alterations.
Anesthesiology 98(2):474-484.
Vilensky JA, O'Connor BL, Brandt KD, Dunn EA, Rogers PI, DeLong CA. 1994.
Serial kinematic analysis of the unstable knee after transection of the
anterior cruciate ligament: Temporal and angular changes in a canine
model of osteoarthritis. J Orthop Res 12(2):229-237.
Vos BP, Strassman AM, Maciewicz RJ. 1994. Behavioral evidence of trigeminal
neuropathic pain following chronic constriction injury to the rat's
infraorbital nerve. J Neurosci 14(5 Pt 1):2708-2723.
Wallace VC, Blackbeard J, Segerdahl AR, Hasnie F, Pheby T, McMahon SB, Rice
AS. 2007. Characterization of rodent models of HIV-gp120 and anti-
retroviral-associated neuropathic pain. Brain 130(Pt 10):2688-2702.
Wesselmann U, Czakanski PP, Affaitati G, Giamberardino MA. 1998. Uterine
inflammation as a noxious visceral stimulus: Behavioral characterization
in the rat. Neurosci Lett 246(2):73-76.
Van den Berg WB, Joosten LAB, van Lent PLEM. 2007. Murine antigen-induced
arthritis. In Arthritis: Methods and Protocols, Vol. II, Cope A, ed.
Humana Press. p. 243-253.
Wuarin-Bierman L, Zahnd GR, Kaufmann F, Burcklen L, Adler J. 1987.
Hyperalgesia in spontaneous and experimental animal models of diabetic
neuropathy. Diabetologia 30(8):653-658.
Yezierski RP, Liu S, Ruenes GL, Kajander KJ, Brewer KL. 1998. Excitotoxic
spinal cord injury: Behavioral and morphological characteristics of a
central pain model. 1998 Mar; 75(1):141-55.
Prepublication Copy
OCR for page 164
164 Recognition and Alleviation of Pain in Laboratory Animals
Young W. Spinal cord contusion models. Prog Brain Res. 2002; 137:231-55.
Prepublication Copy
