How is Pain Measured in an Animal Model

Pain, of course, is a subjective human experience, and so it is more appropriate to refer to nonhuman animal models as nocifensive or nociceptive. By this, we mean that although the sensory receptors (nociceptors) and the neural encoding and processing of noxious stimuli are present in animals (and function as they do in humans), the affective and cognitive features that define human pain are missing. Semantics aside, because noxious stimuli commonly act to warn all animals, and responses are often marked and similar (e.g., muscular contraction and withdrawal), we consider here the two alike.

As indicated above, stimuli that are noxious to somatic structures (i.e., those that damage or threaten to damage) are not reliably so in the viscera. Instead, hollow organ distension, traction on the mesentery, ischemia, inflammation, and chemical stimuli are adequate, in the context proposed by Sherrington, for the activation of visceral nociceptors. To evaluate pain in an animal model, a suitably measured variable must be chosen that correlates with the pain evoked by a given stimulus. Candidates are numerous and range from pseudaffective responses such as vasomotor, visceromotor, and respiratory reflexes, to the expression of intermediate-early genes such as c-fos in the dorsal horn of the spinal cord or brainstem. Typically, contractile responses of the abdominal muscles are recorded using mechanical (force transduc-tion equipment) or electrophysiological [electromyography (EMG)] methods. It should be noted, however, that anesthesia will affect pseudaffective responses (6). More invasive in vivo electrophysiological techniques such as recording from primary afferent neurons, the dorsal horn neurons upon which they synapse, or the dorsal roots in which they travel, can be employed, which may result in a more detailed assessment.

So, what evidence is the most important with which to characterize an animal model as painful? Certainly, behavioral responses, where the experimental method allows, will give a sound indication of an aversive, "painful" experience, but in the absence of such a readout, other factors should be considered. Histological analysis will give an indication of a tissue insult that may lead to a painful pathology [e.g., inflammation, which may also be assessed by the detection of myeloperoxidase (MPO) activity]. But this is certainly not a definitive (or causative) measure of pain. For example, dextran sodium sulphate (DSS)-induced colitis produces marked inflammation, but no colonic hypersensitivity in at least two different strains of mouse (7). The electrophysiological recording of nerve bundles or individual neurons can be informative regarding peripheral pain mechanisms, but even here we cannot be certain of their direct relevance to pain in the absence of a behavioral correlate. One can record from neuronal populations that are believed to carry nociceptive information (e.g., based on the presence of certain receptors and peptides, or by diameter and conduction velocity), but even then we rely upon two assumptions: (i) these neurons are truly nociceptive and (ii) their activation would, indeed, be painful (i.e., their input is not prohibited from reaching central pain generation areas by one or more "gate" mechanisms). Some of these limitations may be improved by the pharmacological testing of models using (behaviorally) well-defined analgesics such as morphine. Dose-dependent inhibition of presumed pain-indicating responses to a particular test gives confidence that this may, indeed, represent a painful experience should the animal have been able to express the response behaviorally.

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