Dissociating pain dimensions in cold allodynia: subanesthetic ketamine reveals heritable affective-motivational traits in mice.

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.