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Animal models of pain: progress and challenges

Key Points

  • Animal models of pain are crucially important for progress in the field, but the poor translation record of pain research has led to a re-evaluation of the appropriateness of current models.

  • The accuracy and relevance of data obtained using current animal pain assays can be improved by choosing subjects and conditions that have more in common, epidemiologically and contextually, with pain patients: both sexes, multiple strains, a wider age range, and with attention paid to social factors.

  • Pain assays have been developed in four successive and overlapping 'waves': acute assays, inflammatory assays, neuropathic assays and the modelling of diseases featuring pain.

  • Current animal models of pain are overly reliant on innate reflexes as dependent measures. Recently developed operant assays may provide a superior alternative.

  • Pain researchers seriously under-study spontaneous pain, and are overly reliant on the measurement of hypersensitivity states. A consensus as to which spontaneously emitted behaviours truly reflect pain in laboratory rodents is sorely needed.

  • Current animal studies of pain largely neglect to measure complex states comorbid with, affected by, and/or contributing to pain.

Abstract

Many are frustrated with the lack of translational progress in the pain field, in which huge gains in basic science knowledge obtained using animal models have not led to the development of many new clinically effective compounds. A careful re-examination of animal models of pain is therefore warranted. Pain researchers now have at their disposal a much wider range of mutant animals to study, assays that more closely resemble clinical pain states, and dependent measures beyond simple reflexive withdrawal. However, the complexity of the phenomenon of pain has made it difficult to assess the true value of these advances. In addition, pain studies are importantly affected by a wide range of modulatory factors, including sex, genotype and social communication, all of which must be taken into account when using an animal model.

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Figure 1: Species selected for pain experiments from 1963 to 2007.

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The author would like to thank G. Bennett and the anonymous reviewers for helpful comments on this manuscript.

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Pain Genes Database

Glossary

Therapeutic index

The ratio of the minimum dose of a drug that causes toxic effects to the therapeutic dose, used as a relative measure of drug safety.

Neuropathic pain

Pain arising as a direct consequence of a lesion or disease affecting the somatosensory system.

Reflexive measures

Measures of involuntary movements made in response to a stimulus. For example, the nociceptive withdrawal reflex is a spinal (segmental) reflex intended to protect the body from potentially damaging noxious stimuli. Spino-bulbospinal reflexes, lost after spinal transection but preserved after decerebration, include licking, guarding, vocalizing and jumping.

Non-reflexive (operant) measures

Measures of behaviours that require spinal-cerebrospinal integration, which are lost after decerebration. The use of operant measures specifically requires a learned, motivated behaviour that terminates exposure to the noxious stimulus.

Biomarker

A specific physical or chemical entity used to measure or indicate the effects or progress of a disease or condition.

Face validity

A property of a model that seems to obviously ('on its face') measure what it is supposed to measure.

Small interfering RNA knockdown technology

A sequence-specific gene-silencing tool used for RNA interference. Small interfering RNAs are short fragments of synthetic double-stranded RNA with 21–23 pairs of nucleotides that have sequence specificity to the gene of interest. They trigger degradation of the target RNA, thereby creating a partial loss-of-function by decreasing the amount of translatable RNA.

Hyperalgesia

An increased response to a stimulus which is normally painful.

Nociceptive pain

Somatic or visceral pain processed by a normal, unaltered nervous system.

Quantitative trait locus (QTL) mapping

A statistical technique used to identify particular regions of the genome containing DNA variants responsible for between-strain variation on a quantitative (complex) trait.

Formalin test

An assay of acute and tonic pain in which a dilute solution of formalin (37% w/w formaldehyde) is injected into the dorsal or plantar hindpaw. Formalin produces two 'phases' of pain behaviour separated by a quiescent period: the early phase is probably due to direct activation of nociceptors through TRPA1 channels; the second phase is due to ongoing inflammatory input and central sensitization.

Allodynia

Pain resulting from a stimulus that does not normally provoke pain.

von Frey fibres

Nylon monofilaments that, when pressed against tissue until they bend, exert a calibrated amount of force. They are used to measure mechanical sensibility.

Conditioned place preference or aversion

A behavioural task during which a subject learns to associate an experience with a specific physical environment. A subject will choose to spend more time in an environment in which it previously had a rewarding experience (for example, an analgesic drug) and less time in an environment in which it had an aversive experience (for example, inflammatory pain).

Ethogram

A catalogue of discrete behaviours displayed by an organism.

Anthropomorphism

The attribution of human characteristics to non-human organisms. Whereas this attribution is often mistaken, people can also make the opposite error, anthropodenial, denying our commonalities with other species.

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Mogil, J. Animal models of pain: progress and challenges. Nat Rev Neurosci 10, 283–294 (2009). https://doi.org/10.1038/nrn2606

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