Evaluating the efficacy of cannabidiol to manage surgically induced neuropathic pain in a preclinical rat model: Are T cells a sexually dimorphic target?

Background: Considering the poorly understood etiology and complex symptoms of chronic neuropathic pain (NP), the lack of effective treatments, and sex-dependent differences in the neuroimmune system as well as in antinociceptive responses to existing pharmacological agents, the potential to therapeutically target the endocannabinoid system as a means of treating this type of intractable pain is clinically relevant and timely. Chronic NP may involve the utilization of distinct immune cell populations in males and females that differentially affect supraspinal and spinal neuromodulation. It is therefore important to investigate the effects of cannabidiol (CBD) on chronic NP-induced nociceptive responses in both sexes. Aims: Evaluating whether the expression of markers associated with CD4⁺ T cells are affected by CBD in a sexually dimorphic manner will provide key insights into the contribution of these adaptive immune cells to the onset and progression of NP. Methods: Future research will be directed toward examining the potential sex-dependent effects of this nonpsychotropic cannabinoid relative to vehicle in a preclinical model of chronic postsurgical NP. Specifically, (1) differences in nociceptive behavior, (2) chronic changes in neural firing patterns, and (3) up- or downregulation of markers associated with CD4⁺ T cells in relevant tissues will be evaluated to better understand CBD-mediated neuroimmune modulatory effects in males and females. Conclusions: Chronic postsurgical pain is a growing clinical problem. Current treatment strategies rely on opioid-based therapeutics, which affect patient quality of life and are associated with addiction and withdrawal. Treatment of nerve injuries with CBD could provide an effective alternative to manage NP. Understanding its mechanisms of action will provide important insights into the sex-dependent application of this nonpsychoactive cannabinoid, setting the groundwork for large-scale Canadian clinical trials in women and men presenting with chronic pain.