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Innovations and advances in modelling and measuring pain in animals

Nature Reviews Neuroscience volume 23, pages 70–85 (2022)Cite this article

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Abstract

Best practices in preclinical algesiometry (pain behaviour testing) have shifted over the past decade as a result of technological advancements, the continued dearth of translational progress and the emphasis that funding institutions and journals have placed on rigour and reproducibility. Here we describe the changing trends in research methods by analysing the methods reported in preclinical pain publications from the past 40 years, with a focus on the last 5 years. We also discuss how the status quo may be hampering translational success. This discussion is centred on four fundamental decisions that apply to every pain behaviour experiment: choice of subject (model organism), choice of assay (pain-inducing injury), laboratory environment and choice of outcome measures. Finally, we discuss how human tissues, which are increasingly accessible, can be used to validate the translatability of targets and mechanisms identified in animal pain models.

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Fig. 1: Analysis of rodent use in pain studies from 1980 to 2020.
Fig. 2: Analysis of animal pain assays used from 1980 to 2020.
Fig. 3: Environmental considerations for pain testing.
Fig. 4: Behavioural measures of pain and an analysis of their use in studies from 1980 to 2020.
Fig. 5: Recommendations for increased translational relevance of animal pain models.

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Data availability

The data supporting the findings of the analysis described in this Review are available in the files in Supplementary information.

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Acknowledgements

K.E.S. and C.L.S. are supported by grants from the US National Institutes of Health. J.S.M. is supported by funding from the Canadian Institutes of Health Research, the Natural Sciences and Engineering Research Council of Canada and the Louise and Alan Edwards Foundation.

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Authors and Affiliations

  1. Department of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, Milwaukee, WI, USA

    Katelyn E. Sadler & Cheryl L. Stucky

  2. Department of Psychology, McGill University, Montreal, QC, Canada

    Jeffrey S. Mogil

  3. Department of Anesthesia, McGill University, Montreal, QC, Canada

    Jeffrey S. Mogil

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J.S.M. researched data for the article. All authors contributed substantially to discussion of the content and reviewed and/or edited the manuscript before submission. K.E.S wrote the article.

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Correspondence to Cheryl L. Stucky.

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Supplementary information

Glossary

Habituation periods

Time spent in the testing room/apparatus before commencement of testing procedures.

Randall-Selitto deep pressure test

A behaviour test that measures deep tissue mechanical sensitivity via the application of calipers or a weight to a part of the animal’s body (generally the hind paw of a rat).

Outbred strains

Strains in which direct brother–sister mating is avoided to minimize inbreeding.

Neuropathic pain

Pain caused by a lesion or disease of the somatosensory nervous system.

Chemotherapy-induced peripheral neuropathy (CIPN) assays

Neuropathic pain assays in which nerve damage is caused by the administration of chemotherapeutic drugs.

Face validity

A subjective assessment of whether an assay replicates the patient population that it is attempting to model.

Musculosketal pain

Pain affecting bones, joints, ligaments, tendons or muscles.

Osteoarthritis

A form of arthritis involving the degeneration of joint cartilage and the underlying bone.

Rheumatoid arthritis

A form of arthritis featuring inflammation in the joints and resulting in painful deformity and immobility.

Nociplastic pain

Pain that arises form altered nociception despite no clear evidence of actual or threatened tissue damage.

Mechanical allodynia

Mechanical pain due to a stimulus that does not usually provoke pain.

Stress-induced hyperalgesia

Higher sensitivity to pain due to stress-induced activation of descending pain modulatory circuitry.

Stress-induced analgesia

(SIA). Reduced sensitivity to pain due to stress-induced activation of descending pain modulatory circuitry.

Von Frey monofilaments

A set of calibrated nylon filaments used for measuring mechanical sensitivity.

Machine learning

Computer systems that are able to learn without following explicit instructions, by using algorithms that analyse and draw inferences from patterns in data.

Hargreaves test

An assay of thermal pain, also known as the radiant-heat paw withdrawal test.

Writhing

A measure of visceral pain, characterized by stereotypical abdominal constrictions.

Formalin test

An assay of chemical/inflammatory pain in which dilute formaldehyde is injected into the hind paw; subsequent recuperative behaviours are directed towards the injected paw.

Grimace scales

Scales to quantify animal pain levels on the basis of facial expressions.

Conditioned place aversion

An indirect measure of pain based on an animal learning an association between an environment with distinct cues and pain; the animal will avoid the environment paired with pain.

Conditioned place preference

An indirect measure of pain based on an animal learning an association between an environment with distinct cues and pain relief via analgesic administration; the animal will spend more time in the environment paired with the analgesic.

Operant conditioning assays

Associative learning processes through which the strength of a behaviour is modified by reinforcement or punishment (for example, pain).

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Sadler, K.E., Mogil, J.S. & Stucky, C.L. Innovations and advances in modelling and measuring pain in animals. Nat Rev Neurosci 23, 70–85 (2022). https://doi.org/10.1038/s41583-021-00536-7

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