The cannabinoid agonist CB-13 produces peripherally mediated analgesia in mice but elicits tolerance and signs of central nervous system activity with repeated dosing.

Activation of cannabinoid receptor type 1 (CB 1 ) produces analgesia in a variety of preclinical models of pain; however, engagement of central CB 1 receptors is accompanied by unwanted side effects, such as psychoactivity, tolerance, and dependence. Therefore, some efforts to develop novel analgesics have focused on targeting peripheral CB 1 receptors to circumvent central CB 1 -related side effects. In the present study, we evaluated the effects of acute and repeated dosing with the peripherally selective CB 1 -preferring agonist CB-13 on nociception and central CB 1 -related phenotypes in a model of inflammatory pain in mice. We also evaluated cellular mechanisms underlying CB-13-induced antinociception in vitro using cultured mouse dorsal root ganglion neurons. CB-13 reduced inflammation-induced mechanical allodynia in male and female mice in a peripheral CB 1 -receptor-dependent manner and relieved inflammatory thermal hyperalgesia. In cultured mouse dorsal root ganglion neurons, CB-13 reduced TRPV1 sensitization and neuronal hyperexcitability induced by the inflammatory mediator prostaglandin E 2 , providing potential mechanistic explanations for the analgesic actions of peripheral CB 1 receptor activation. With acute dosing, phenotypes associated with central CB 1 receptor activation occurred only at a dose of CB-13 approximately 10-fold the ED 50 for reducing allodynia. Strikingly, repeated dosing resulted in both analgesic tolerance and CB 1 receptor dependence, even at a dose that did not produce central CB 1 -receptor-mediated phenotypes on acute dosing. This suggests that repeated CB-13 dosing leads to increased CNS exposure and unwanted engagement of central CB 1 receptors. Thus, caution is warranted regarding therapeutic use of CB-13 with the goal of avoiding CNS side effects. Nonetheless, the clear analgesic effect of acute peripheral CB 1 receptor activation suggests that peripherally restricted cannabinoids are a viable target for novel analgesic development.