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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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AModels 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 may 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.

Numerous animal models exist for the exploration of mechanism(s) and mediators of persistent pain in particular. The principal rationale for developing and using such models is that the sources and mechanisms of momentary pain differ significantly from those of 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.

Table A-1 presents commonly used models of persistent pain in animals and the subsequent sections provide an overview of response measures and other features of these models. Most of the models were developed in rodents (rats or mice), unless otherwise 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).

TABLE A-1. Animal Models of Persistent Pain.

TABLE A-1

Animal Models of Persistent Pain.

ANIMAL MODELS OF PERSISTENT PAIN

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). Once baseline response measures have been determined, 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 lower. Edema, which is also a consequence of such an injection, is greatest after the injection of carrageenan (or carrageenan plus kaolin) and least following complete Freund’s adjuvant (CFA). The nature and duration of hyperalgesia differ 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 it decreases.

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 occur principally in two phases. The first phase is short (~10 min), followed by a brief (~5 min) period of relative quiescence, after which a second phase of hindlimb shaking and licking lasts 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

There are physical, chemical, and biologic methods to produce inflammatory states that mimic painful conditions of joints. Among physical methods, anterior (cranial) cruciate ligament transection produces 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.

Chemical methods include the intra-articular injection of inflammogens (e.g., kaolin, carrageenan, iodoacetate, collagenase, urate crystals) to cause synovitis, varying degrees of cartilage destruction and subsequent joint swelling, lameness, and decreased activity. Hyperalgesia develops rapidly (within 4 hours); both inflammation and the duration of inflammation depend on the agent and dose.

An example of a biologic model is antigen-induced arthritis, which develops after intra-articular injection of a protein antigen against which animals have been previously immunized (e.g., methylated bovine serum albumin). The condition appears 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-articular antigen, involves reactivation of arthritis (arthritis flare) by reinjection 1 month later (Moran and Bogoch 1999; van den Berg et al. 2007).

Models of rheumatoid arthritis entail activation of an immune response that targets multiple joints. One example is adjuvant arthritis, a polyarticular disease that develops 10 to 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 the resulting arthritis differs between rats and mice, but onset generally occurs 2 to 4 weeks after immunization. Resolution of clinical signs occurs in rats after 30 to 45 days, whereas susceptible mice demonstrate disease 8 to 12 weeks postimmunization. The duration, severity, and location of arthritis after collagen immunization depends on the 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. In addition, 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 intra-peritoneally 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 actual visceral pain (Ness and Gebhart 1990). Methods for distension of rat stomach (Ozaki et al. 2002), rat (Ness et al. 2001) and mouse (Ness and Elhefni 2004) urinary bladder, and rat (Gebhart and Sengupta 1996) and mouse (Christianson and Gebhart 2007) colon have been fully described.

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 require 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 tele-metric methods for long-term recording of these measures. These responses 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).

Because nonulcer dyspepsia, interstitial cystitis/painful bladder syndrome, and inflammatory and irritable bowel syndromes are relatively common human diseases for which management of pain is poor, many models entail the irritation or inflammation of hollow organs to assess the mechanisms underlying the hypersensitivity that characterizes these human disorders.1 The following models have been developed to study these mechanisms:

  • 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).

In unanesthetized rodents, baseline responses to balloon distension are acquired before organ insult and monitored over time (days to weeks) after the insult, when they 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 by frequency as well as intensity (Giamberardino et al. 1995).

Postoperative (Incisional) Pain Models

Models of postoperative pain have revealed 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 hours after incision and typically lasts 3 to 4 days. When underlying muscle is included in the incision, the duration (but not the magnitude) of hyperalgesia is usually extended by 1 day.

Orofacial Pain Models

The injection of inflammogens into the temporomandibular joint (TMJ) or subcutaneous tissues of the face produces models of orofacial pain. Injection of mustard oil into the TMJ causes rapid onset of swelling and behavioral changes—initially, freezing behavior, followed by a second phase of active behaviors such as facial rubbing or grooming, chewing movements, and head shaking. 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 at least 45 minutes. The duration of grooming activity and edema after 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. After unilateral loose ligation of the infraorbital nerve, rats develop a biphasic behavioral response. In the early postligature phase (days 1 to 15), they demonstrate increased grooming activity at the site of nerve injury but are hyporesponsive to mechanical stimuli; on postconstriction days 15 to 130, the rats become hyperresponsive to mechanical stimuli, demonstrating maximal escape responses to all stimulus intensities. Decreased weight gain and altered activity also occur in this constriction injury model (Vos et al. 1994).

Muscle Pain Models

Models of persistent muscle pain include intramuscular injection of carrageenan or 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 dependent on the concentration of carrageenan and may last 7 to 8 weeks (Radhakrishnan et al. 2003).

Injection of acidic saline in 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 acidity and also depend on the timing of repeated intramuscular injections. Despite the reductions in mechanical threshold caused by acidic saline injection, changes do not appear in either behavior (i.e., gait and weight bearing remain normal, and there is no limb guarding) or muscle histology (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 were 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, stroke-induced destruction of tissue, 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 this model, and they are 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 spontaneous pain may be associated with these models (see below), this is not readily apparent and is certainly difficult to document. There is rarely any significant change in behavior or weight loss that might indicate 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 endpoint is 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.

The reliability of these different approaches to modeling neuropathic pain is evident primarily from the demonstration that drugs that are effective (or not) in the clinic for neuropathic pain are effective in the animal models. For example, 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. In contrast, there is general agreement that nonsteroidal anti-inflammatory drugs are quite ineffective in humans with neuropathic pain, and the same is true in the animal models. Opioids also are less effective in neuropathic pain models than in inflammatory models, and this is commonly observed in the clinic.

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 led to the development of animal models to reproduce the conditions for neuropathic pains associated with spinal or foraminal stenosis and disk herniations, many of which are considered critical to the development of chronic back pain. In these animal models, two L-shaped rods are placed unilaterally into the intravertebral foramin, one at L4 and the other at L5 (Hu and Xing 1998). The rods remain in place from 1 to 14 days, after which behavioral, electrophysiological, and anatomical studies are performed to document mechanical and thermal hypersensitivity and to elucidate the underlying causes of the pain. 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 the application of a variety of cytokines to the peripheral nerve (Sorkin et al. 1997) or even of autologous nucleus pulposus to the DRG of the rabbit (Cavanaugh et al. 1997) can recapitulate features of neuropathic pain.

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 models reflects the difficulty of creating a reliable and reproducible condition. The last decade, however, has seen the development of such models in both rats and mice (for a review, Pacharinsak and Beitz 2008). Rather than studying the pain associated with the destruction of a particular organ, attention has focused on the pain that develops after metastasis of tumors to, for example, bone, which is among the most painful conditions. To this end, Mantyh and colleagues (Schwei et al. 1999) initially described a model that involved implanting osteolytic sarcoma cells in the femur of a mouse and sealing 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, 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 develop.

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, eventually occurred at 16 weeks of age, at which point the pancreatic cancer was severe. Whether there is a masking of 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.

Spontaneous Pain

Most of the persistent pain models described above measure pain provoked by thermal, mechanical, or (less frequently) chemical stimuli. 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 holding 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 postsurgical 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 certain 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 and Chapter 4 for an analysis of the ethical conflicts associated with research using persistent pain models.

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As indicated in Chapter 2 (see Ontogeny of Pain), organ insult or stress (e.g., maternal separation) in early life can lead to visceral hypersensitivity in adults (Al-Chaer et al. 2000; Coutinho et al. 2002; Randich et al. 2006a).

Footnotes

1

As indicated in Chapter 2 (see Ontogeny of Pain), organ insult or stress (e.g., maternal separation) in early life can lead to visceral hypersensitivity in adults (Al-Chaer et al. 2000; Coutinho et al. 2002; Randich et al. 2006a).

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