Sex-related differences in cannabidiol's antinociceptive efficacy in a trigeminal neuralgia rodent model

Trigeminal neuralgia (TN) is a severe orofacial pain condition with sex-specific differences in pain responses. Standard treatments offer limited efficacy and significant side effects. We hypothesized that cannabidiol (CBD) alleviates TN-induced allodynia more effectively than carbamazepine in a sex- and dose-dependent manner through neuroimmune mechanisms, including modulation of glia, Fos protein expression, and oxidative stress in the ventrolateral periaqueductal gray (vlPAG) and spinal trigeminal nucleus caudalis (Sp5c). In an infraorbital nerve constriction model, mechanical allodynia was evaluated in male and female Wistar-Hannover rats. Our study demonstrates the potent antinociceptive effects of CBD in reducing mechanical allodynia in both male and female models of trigeminal neuralgia, without affecting locomotor activity, unlike carbamazepine. Although CBD's analgesic effects were consistent across sexes, carbamazepine showed sex-dependent efficacy. Cannabidiol's effects on Fos-B were region- and sex-dependent: it inhibited Fos-B in the Sp5c in both sexes but only in males in the vlPAG, suggesting sexually dimorphic activation of descendent pain circuits. Cannabidiol prevented superoxide oxidation in the vlPAG in both sexes, with effects on microglia and astrocytes at similar doses, suggesting that glial cells produce the oxidative stress inhibited by CBD. In the Sp5c, CBD modulated Fos-B, superoxide oxidation, microglia, and astrocytes in both sexes, indicating a possible lack of sexual dimorphism in this region. These results highlight CBD's efficacy in managing TN by modulating ascending and descending nociceptive pathways. Beyond its neuronal effects, CBD's analgesic actions in TN may also involve significant modulation of glial cell activity, underscoring the complexity of its therapeutic mechanisms.