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 (CB1) produces analgesia in a variety of preclinical models of pain; however, engagement of central CB1 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 CB1 receptors to circumvent central CB1-related side effects. In the present study, we evaluated the effects of acute and repeated dosing with the peripherally selective CB1-preferring agonist CB-13 on nociception and central CB1-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 CB1-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 CB1 receptor activation. With acute dosing, phenotypes associated with central CB1 receptor activation occurred only at a dose of CB-13 approximately 10-fold the ED50 for reducing allodynia. Strikingly, repeated dosing resulted in both analgesic tolerance and CB1 receptor dependence, even at a dose that did not produce central CB1-receptor-mediated phenotypes on acute dosing. This suggests that repeated CB-13 dosing leads to increased CNS exposure and unwanted engagement of central CB1 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 CB1 receptor activation suggests that peripherally restricted cannabinoids are a viable target for novel analgesic development.

Automated summary

The study found that CB-13 can alleviate pain induced by inflammation in a peripheral CB1 receptor-dependent manner, but repeated dosing may lead to analgesic tolerance and unwanted central nervous system effects.