Vertical climbing in mice: a translationally relevant measure of pain-related impact on natural behaviour

Abstract

Despite urgent need for better analgesics, drug development has been complicated by incomplete bench-to-bedside translation. A likely contributing factor is the poor connection between the experimenter-evoked pain-related measures often used in preclinical models, and the clinical symptoms, like broader functional impairment, reported by patients. Here, we asked whether vertical climbing, a species-specific elective behaviour in mice, could serve as a measure of pain-related impairment. We tested male and female mice in a wide range of pain-related models including models of post-operative pain, inflammatory injury, osteoarthritis, rheumatoid arthritis, cancer-induced bone pain, fibrous dysplasia, neuropathic pain, migraine-related pain and facial neuropathy. Vertical climbing was reduced in all models, across five different laboratories, demonstrating the robustness and consistency of this type of behaviour as a novel pain-related outcome measure. Reduced climbing correlated significantly with established pain-related measures, but its time course diverged from that of evoked mechanical allodynia, while aligned more closely with other non-evoked behaviours, like burrowing, home cage activity, wheel running or weight bearing. Pharmacological validation was bidirectional: gabapentin restored climbing in mice with neuropathic injury, and naltrexone reinstated the climbing deficit in mice that had recovered from intraplantar CFA, consistent with persistent pain held in remission by endogenous opioid signalling. Overall, our results indicate that voluntary vertical climbing is a stable, elective behaviour that provides a robust and translationally relevant measure of pain-related functional impairment in mice.