CB1 receptors mediate rimonabant-induced pruritic responses in mice: investigation of locus of action

Rationale Cannabinoids have recently been identified as potential neuronal modulators of pruritic response, representing a potential target in the treatment of itch associated with a variety of pathophysiologic conditions. While the selective CB1 receptor antagonist rimonabant is an established pruritic agent in both animal and clinical testing, its receptor mechanism of action and anatomical loci remain unclear. Objective The purpose of this study was to determine whether CB1 receptor blockade is critical to rimonabant-induced scratching and to identify differences in scratching response based on different routes of administration. Furthermore, experiments were designed to elucidate any evidence as to whether rimonabant elicits scratching behavior through common immunologic hypersensitivity mechanisms. Results Rimonabant was equally effective at producing scratching via intraperitoneal and local subcutaneous injection. This compound also produced an intense scratching response when administered intrathecally, but had no effects after intracerebroventricular administration. Repeated administration of rimonabant led to a decreased magnitude of scratching. While rimonabant-induced scratching was not attenuated either by pretreatment with the H-1 receptor antagonist loratadine or in mast cell-deficient mice, it lacked efficacy in CB1 (-/-) mice. Conclusions Rimonabant is a potent and fully effective pruritogen when administered spinally or systemically and requires CB1 receptors to induce scratching, suggesting an important spinal CB1 receptor component of action. The lack of responsiveness to H-1 antagonism or mast cell deficiency supports previous findings that cannabinoids modulate itch through neuronal mechanisms, and not by traditional hypersensitivity activation.