Tests and Models of Nociception and Pain in Rodents

Neuroscience 211 (2012) 39–50 REVIEW TESTS AND MODELS OF NOCICEPTION AND PAIN IN RODENTS M. BARROT* Acknowledgments 48 Institut des Neurosciences Cellulaires et Intégratives, Centre National References 48 de la Recherche Scientifique, Strasbourg, France NOCICEPTION AND PAIN Abstract—Nociception and pain is a large field of both neu- The distinction between nociception and pain is important roscience and medical research. Over time, various tests and to consider when using preclinical murine models (Table 1). models were developed in rodents to provide tools for fun- According to the International Association for the Study of damental and translational research on the topic. Tests us- Pain (IASP), nociception is defined as “the neural pro- ing thermal, mechanical, and chemical stimuli, measures cesses of encoding and processing noxious stimuli,” of hyperalgesia and allodynia, models of inflammatory or neuropathic pain, constitute a toolbox available to re- whereas pain is “an unpleasant sensory and emotional searchers. These tests and models allowed rapid progress experience associated with actual or potential tissue dam- on the anatomo-molecular basis of physiological and path- age or described in terms of such damage” (Loeser and ological pain, even though they have yet to translate into Treede, 2008). new analgesic drugs. More recently, a growing effort has Nociception thus includes the mechanisms by which been put forth trying to assess pain in rats or mice, rather noxious stimuli are detected by the peripheral nervous than nociceptive reflexes, or at studying complex states affected by chronic pain. This aids to further improve the system, encoded, transferred, and unconsciously treated translational value of preclinical research in a field with by the nervous system. Detection is ensured by specific balanced research efforts between fundamental research, molecular transducers borne by nociceptive neurons preclinical work, and human studies. This review describes whose cell bodies are grouped in the dorsal root or trigem- classical tests and models of nociception and pain in ro- inal ganglia. This afferent signal is then treated by complex dents. It also presents some recent and ongoing develop- networks within the dorsal horn of the spinal cord (Todd, ments in nociceptive tests, recent trends for pain evalua- 2010) or its equivalent in the brainstem. This treatment is tion, and raises the question of the appropriateness between tests, models, and procedures. under the influence of both sensory information and de- This article is part of a Special Issue entitled: Neurosci- scending controls from the brain. Nociception also includes ence Disease Models. © 2012 IBRO. Published by Elsevier part of the information treatment by the brain as well as Ltd. All rights reserved. some reflex responses to protect the organism. In contrast, pain is a conscious experience that requires the cortical Key words: pain, nociception, test, model, rodents, analge- treatment and the aversive interpretation of the nociceptive sia. information. It is a subjective and complex experience with a necessary affective component, accompanied with sen- Contents Nociception and pain 39 sory-discriminative, autonomic, and cognitive components. Nociceptive tests 40 Although nociception and pain appear closely linked, clin- Electrical thresholds 40 ical evidence also proved that they can be dissociated one Nociceptive response to heat 41 from the other. In patients, pain is assessed and quantified Nociceptive response to cold 42 by verbal expression, which is not possible in rodents. Nociceptive response to mechanical stimuli: the von Frey Thus, what is commonly referred as “pain tests” in rodents test 42 are in fact nociceptive tests, and the preclinical measure of Nociceptive response to mechanical stimuli: other tests 44 Nociceptive response to chemical stimuli 44 pain itself still remains a challenge to the field. Pain models 44 When pertinent, nociception and pain are critical for Models of inflammatory pain 44 survival (Le Bars et al., 2001). They offer an alarm system Models of neuropathic pain 45 that has the capacity to initiate an immediate adapted Recent trends for pain evaluation in rodents 45 response, which can further evolve toward better adaptive Giving rodents the choice 45 responses through emotional associative learning. Despite Facial coding scales 46 Other approaches 46 this major physiological function, it is also critical to “si- Beyond tests and models procedures are critical 47 lence” nociception or pain when they lose their pertinence Conclusion 47 as an alarm system, which is the case when the lesion or risk of lesion is already identified, when pain is anticipated, *Corresponding author. Tel: ϩ33-368-851-450; fax: ϩ33-388-613-347. E-mail address: [email protected] (M. Barrot). or when pain becomes chronic or dissociated from an Abbreviation: CFA, complete Freund’s adjuvant. actual lesion. This requires adequate treatments, whose 0306-4522/12 $36.00 © 2012 IBRO. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.neuroscience.2011.12.041 39 40 M. Barrot / Neuroscience 211 (2012) 39–50 Table 1. Pain terminology (Loeser and Treede, 2008) dall–Selitto analgesimeter, and recent tests based on strain gauges held by forceps or fingers. The development Term Definition of dynamic hot and/or cold plates also allowed the assess- ment of thermal thresholds in awake rodents. Electrical Pain An unpleasant sensory and emotional experience associated with actual or potential tissue thresholds are also studied, particularly as a control for damage or described in terms of such damage other behavioral experiments. Lastly, some nociceptive Nociception The neural processes of encoding and tests can rely on the observation and scoring of specific processing noxious stimuli behaviors. This is the case for assessing cold allodynia Noxious stimulus An actually or potentially tissue-damaging event with acetone or for tests using inflammatory or irritating Nociceptive pain Pain arising from activation of nociceptors chemical stimuli. Neuropathic pain Pain arising as a direct consequence of a lesion or disease affecting the somatosensory system The results obtained in most nociceptive tests show a Allodynia Pain in response to a non-nociceptive stimulus relatively low interindividual variability compared with what Hyperalgesia Increased pain sensitivity is observed in other fields of behavioral studies, such as Pain threshold The minimal intensity of a stimulus that is mood disorder-related studies or operant behavior studies. perceived as painful As a consequence, experiments on nociceptive responses can often be conducted with fewer animals than what development may benefit from preclinical tests and models would be necessary for these other studies. Still, the mea- (Negus et al., 2006; Mogil et al., 2010a). sure of nociceptive response in rodents requires expertise in the behavioral field to avoid experimental pitfalls and NOCICEPTIVE TESTS potential artifacts. The choice of test is a critical step. Indeed, different nociceptive modalities are, at least par- For a long time, the basic science of pain and the preclin- tially, processed through different molecular transducers ical research on pain treatments essentially relied on no- and fibers (Delmas, 2008; Scherrer et al., 2009). More- ciceptive tests that were done on naive animals. Although over, genetic or pharmacological manipulation may disso- it brought major advances to the pain field, the benefit for ciate these various modalities (Scherrer et al., 2009). In developing new treatments was more limited. Thus, ther- this review, the classical tests performed in awake rodents apeutic preclinical research should associate pain models will be shortly presented (Table 2), and particular attention to nociceptive tests to be more relevant. will be given to the recent development of new tests and to Nociceptive tests use electrical, thermal, mechanical, yet unanswered needs in the field. or chemical stimuli (Le Bars et al., 2001). Some of them rely on the latency of appearance of an avoidance behav- Electrical thresholds ior, usually a withdrawal reflex of the paw or the tail. In this case the stimulus may be considered as fixed. The con- Electrical stimulation is an unnatural and non-specific stim- cerned tests that use thermal stimulation include the tail ulation, and electrical thresholds are rarely studied for flick test, the hot- or cold-plate tests, and the radiant heat themselves. They are more frequently evaluated as a con- paw-withdrawal test. Nociceptive tests can also rely on the trol for other behavioral experiments in which electric stimulus threshold necessary to elicit an avoidance behav- shocks are involved (Simen et al., 2006). This is, for ex- ior. In this case, the stimulus is either variable, with in- ample, the case with learned helplessness, fear condition- creasing value, or the test may use successive incremental ing, active or passive avoidance. When phenotypes are stimuli at a fixed value. These tests concern mechanical observed with these procedures, it may be necessary to stimulation and include the von Frey filaments, the Ran- control whether these phenotypes could result from differ- Table 2. Nociceptive tests Test Modality Stimulus Usual parameter Species Standard Tail flick Thermal, heat Fixed T° Withdrawal latency (s) Rat, Mouse ϩϩϩ Hot plate Thermal, heat Fixed T° (48–55 °C) Withdrawal/jump latency (s) Rat, Mouse ϩϩϩ Plantar® Thermal, heat Fixed T° Withdrawal latency (s)

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