Chronic Administration of Cannabinoid Agonists ACEA, AM1241, and CP55,940 Induce Sex-Specific Differences in Tolerance and Sex Hormone Changes in a Chemotherapy-Induced Peripheral Neuropathy.

Chemotherapy-induced peripheral neuropathy (CIPN) is a common side effect of chemotherapy treatment, routinely manifesting as increased pain sensitivity (allodynia) in distal extremities. Despite its prevalence, effective treatment options are limited. Cannabinoids are increasingly being evaluated for their ability to treat chronic pain conditions, including CIPN. While previous studies have revealed sex differences in cannabinoid-mediated antinociception in acute and chronic pain models, there is a paucity of studies addressing potential sex differences in the response of CIPN to cannabinoid treatment. Therefore, we evaluated the long-term antiallodynic efficacy of cannabinoid receptor type 1 (CB(1))-selective, cannabinoid receptor type 2 (CB(2))-selective, and CB(1)/CB(2) mixed agonists in the cisplatin CIPN model, using both male and female mice. CB(1) selective agonism was observed to have sex differences in the development of tolerance to antiallodynic effects, with females developing tolerance more rapidly than males, while the antiallodynic effects of selective CB(2) agonism lacked tolerance development. Compound-specific changes to the female estrous cycle and female plasma estradiol levels were noted, with CB(1) selective agonism decreasing plasma estradiol while CB(2) selective agonism increased plasma estradiol. Chronic administration of a mixed CB(1)/CB(2) agonist resulted in increased mRNA expression of proinflammatory cytokines and endocannabinoid regulatory enzymes in female spinal cord tissue. Ovarian tissue was noted to have proinflammatory cytokine mRNA expression following administration of a CB(2) acting compound while selective CB(1) agonism resulted in decreased proinflammatory cytokines and endocannabinoid regulatory enzymes in testes. These results support the need for further investigation into the role of sex and sex hormones signaling in pain and cannabinoid-mediated antinociceptive effects. SIGNIFICANCE STATEMENT: CIPN is a common side effect of chemotherapy. We have found that both CB(1) and CB(2) receptor agonism produce antinociceptive effects in a cisplatin CIPN model. We observed that tolerance to CB(1)-mediated antinociception developed faster in females and did not develop for CB(2)-mediated antinociception. Additionally, we found contrasting roles for CB(1)/CB(2) receptors in the regulation of plasma estradiol in females, with CB(1) agonism attenuating estradiol and CB(2) agonism enhancing estradiol. These findings support the exploration of cannabinoid agonists for CIPN.