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

Subanesthetic ketamine reduces the affective-motivational component of pain—bites and licks—in a mouse model of oxaliplatin-induced cold allodynia, but does not affect somatosensory responses such as paw lifts and shakes and flinches. This dissociation was observed across six inbred mouse strains. The effects were transient, reversing within minutes. Ketamine plasma levels ranged from 2600 to 6200 ng/mL in males and 1300 to 3900 ng/mL in females, with significant sex differences in five strains. Hydroxynorketamine levels were higher in females, while norketamine levels showed no sex differences. These results indicate that ketamine parses cold allodynia into separate pain components, and sex-dependent metabolism influences its efficacy.

Study at a glance

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.