Dissociating pain dimensions in cold allodynia: subanesthetic ketamine reveals heritable affective-motivational traits in mice
Richter N, Schmidt S, Pigatto GR, Francis R, Schüttler J, Cunha TM, Zimmermann K (2026)
Publication Type: Journal article
Publication year: 2026
Journal
Book Volume: Publish Ahead of Print
DOI: 10.1097/j.pain.0000000000003912
Abstract
Abstract – Pain perception involves somatosensory-discriminative and affective-motivational components, mediated by separate brain circuits. Traditional mouse behavioral assays lack the resolution to disentangle this complexity. Recent studies using subanesthetic ketamine doses in the hot-plate test revealed a dissociation between paw lifts (somatosensory) and bites & licks (affective). In this study, we investigated these pain components in a mouse model of oxaliplatin-induced cold allodynia. Behavioural endpoints included paw lifts, bites & licks, toe spreads, and shakes & flinches. Data were collected from 6 inbred mouse strains (129S1/SvlmJ, A/J, Balb/cJ, C3H/HeJ, C57BL/6NJ, SJL/J). Ketamine plasma levels and metabolites norketamine and hydroxynorketamine were quantified using liquid chromatography-mass spectrometry. Subanaesthetic ketamine significantly reduced affective bites & licks across all strains and toe spreads in most, but had no significant effect on somatosensory responses (paw lifts and shakes & flinches). These effects were transient and reversed within minutes. Notably, ketamine-induced suppression of affective behaviours exhibited sex differences, whereas somatosensory behaviours did not. Ketamine plasma concentrations ranged from 2600 to 6200 ng/mL in male mice and 1300 to 3900 ng/mL in female mice, with significant sex differences in A/J, Balb/cJ, C3H/HeJ, C57BL/6NJ, and SJL/J. Hydroxynorketamine levels were significantly higher in female mice compared with male mice in the A/J, C3H/HeJ, Balb/cJ, and SJL/J strains (1700-2900 ng/mL in male mice and 2200-3300 ng/mL in female mice), whereas norketamine levels (3000-5100 ng/mL) showed no sex differences. These findings demonstrate that subanesthetic ketamine parses cold allodynia pain responses into somatosensory and affective components, similar to the hot-plate pain model. Additionally, sex-dependent metabolic differences influence analgesic efficacy.
Authors with CRIS profile
Nicole Richter
Department of Anaesthesiology
Stefanie Schmidt
Department of Anaesthesiology
Roland Francis
Department of Anaesthesiology
Jürgen Schüttler
Department of Anaesthesiology
Katharina Zimmermann
Department of Anaesthesiology
Involved external institutions
Brazil (BR)How to cite
APA:
Richter, N., Schmidt, S., Pigatto, G.R., Francis, R., Schüttler, J., Cunha, T.M., & Zimmermann, K. (2026). Dissociating pain dimensions in cold allodynia: subanesthetic ketamine reveals heritable affective-motivational traits in mice. Pain, Publish Ahead of Print. https://doi.org/10.1097/j.pain.0000000000003912
MLA:
Richter, Nicole, et al. "Dissociating pain dimensions in cold allodynia: subanesthetic ketamine reveals heritable affective-motivational traits in mice." Pain Publish Ahead of Print (2026).
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