27: Sex-Specific Role of CB2 in Exercise Protection Against Chemotherapy-Induced Neuropathy

Topic: Basic Science
Subtopic: Pain category (ICD-11), Chronic neuropathic pain, , , , , , , , , , Non-pharmacological interventions, Animal imaging (includes Ca2+ imaging, fluorescence microscopy), Behavioral studies

Background and Aims: Chemotherapy-induced peripheral neuropathy (CIPN) and cognitive dysfunction are debilitating side effects of paclitaxel treatment that severely impact the quality of life in cancer patients. While voluntary exercise is a promising non-pharmacological strategy to alleviate these symptoms, the underlying neurobiological mechanisms and the specific role of the endocannabinoid system remain poorly understood. This study investigated the contribution of cannabinoid receptor 2 (CB2) to the beneficial effects of exercise on paclitaxel-induced mechanical hypersensitivity and cognitive deficits.

Methods: Young adult male and female C57BL/6J (WT) and CB2 knockout (CB2KO) mice were treated with paclitaxel (16mg/kg cumulative dose) or vehicle. During treatment, half of the animals were provided with free access to running wheels. Pain-related behavior was assessed via von Frey filaments, and cognitive function was evaluated using the Novel Object Recognition (NOR) test. In a separate cohort of male mice, hippocampal cell proliferation (Ki67+ cells) and cell survival (BrdU+ cells) were investigated using immunohistochemistry to assess the impact of exercise in neurogenesis following chemotherapy.

Results: Voluntary exercise prevented paclitaxel-induced mechanical hypersensitivity in male mice, an effect abolished in CB2KO males, suggesting a CB2-dependent mechanism. In females, exercise did not prevent mechanical hypersensitivity regardless of genotype. Interestingly, exercise significantly protected against paclitaxel-induced cognitive impairment in females but not in males. This cognitive benefit persisted without CB2, indicating a CB2-independent neuroprotective pathway in females. At the cellular level, paclitaxel reduced Ki67 expression in sedentary WT mice, which exercise reversed. Conversely, CB2KO mice exhibited basal Ki67 levels lower than WT counterparts, with no impact from paclitaxel or exercise. Furthermore, exercise preserved BrdU-labeled expression across vehicle and paclitaxel-treated groups

Conclusions: These findings reveal sexual dimorphism in the neurobiological circuits that drive the protective effects of exercise against CIPN. By identifying the divergent roles of the endocannabinoid system in male and female neural signaling, this study highlights the critical need for sex-specific strategies in the development of future CIPN therapeutics.
Work supported by DA047858 (to AGH and KM).

References: -

Presenting Author: Laura Boullon
Submitting Author: Laura Boullon

Senior Author: Andrea G Hohmann

IASP 2026 Global Year theme of Neuropathic Pain: Yes

• Ananya Balaji - Indiana University
• Richard A. Slivicki: PhD - Washington University in St. Louis
• Sonali Mali - Indiana University
• Ken Mackie: PhD - Indiana University
• Andrea G Hohmann: PhD - Indiana University