Dissociating pain dimensions in cold allodynia: subanesthetic ketamine reveals heritable affective-motivational traits in mice.
Nicole Richter, Stefanie Schmidt, Glauce Regina Pigatto, Roland Chike Eluaka Francis, Jürgen Schüttler, Thiago Mattar Cunha, Katharina Zimmermann
Pain January 29, 2026 DOI: 10.1097/j.pain.0000000000003912 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Observational study Peer reviewed |
|---|---|
| Population | 6 inbred mouse strains (129S1/SvlmJ, A/J, Balb/cJ, C3H/HeJ, C57BL/6NJ, SJL/J) |
| Intervention | Subanesthetic ketamine |
| Topics | Esketamine Ketamine |
| Keywords | Affective-motivational pain Cold allodynia Inbred mouse strains Ketamine metabolism Multidimensional pain Oxaliplatin-induced neuropathy Sexual dimorphism |
| Key findings | Subanesthetic ketamine reduces affective pain behaviors (bites and licks) but not somatosensory responses (paw lifts and shakes and flinches) in oxaliplatin-induced cold allodynia, with sex differences in ketamine metabolism and analgesic efficacy. |
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.
Comparable studies
Other preclinical and animal studies on ketamine, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| mTOR-Dependent Synapse Formation Underlies the Rapid Antidepressant Effects of NMDA Antagonists Rats | 2010 | Observational study | |
| Activation of Glutamatergic Neurotransmission by Ketamine: A Novel Step in the Pathway from NMDA Receptor Blockade to Dopaminergic and Cognitive Disruptions Associated with the Prefrontal Cortex Conscious rats | 1997 | Dose-response study with microdialysis and behavioral testing | |
| NMDAR inhibition-independent antidepressant actions of ketamine metabolites Mice | 2016 | Preclinical study | |
| The dissociative anaesthetics, ketamine and phencyclidine, selectively reduce excitation of central mammalian neurones by N‐methyl‐aspartate Spinal neurons in decerebrate or pentobarbitone-anaesthetized cats and rats | 1983 | Experimental study | |
| R-ketamine: a rapid-onset and sustained antidepressant without psychotomimetic side effects Mice | 2015 | Experimental study |
Citations in the library
Cites 5
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- Ketamine Pharmacology: An Update (Pharmacodynamics and Molecular Aspects, Recent Findings) CNS Neuroscience & Therapeutics April 10, 2013
- Deep posteromedial cortical rhythm in dissociation Nature September 16, 2020
- A randomized, double-blind, active placebo-controlled study of efficacy, safety, and durability of repeated vs single subanesthetic ketamine for treatment-resistant depression Translational Psychiatry June 26, 2020
- The role of dissociation in ketamine's antidepressant effects. Nature Communications December 22, 2020