CB1 Knockout Mice Unveil Sustained CB2-Mediated Anti-Allodynic Effects of the Mixed CB1/CB2 Agonist CP55,940 in a Mouse Model of Paclitaxel-Induced Neuropathic Pain.

Cannabinoids suppress neuropathic pain through activation of cannabinoid CB1 and/or CB2 receptors. However, unwanted CB1-mediated cannabimimetic effects limit clinical use. We asked whether CP55,940, a potent cannabinoid that binds with similar affinity to CB1 and CB2 in vitro, produces functionally separable CB1- and CB2-mediated pharmacological effects in vivo. We evaluated anti-allodynic effects, possible tolerance, and cannabimimetic effects (i.e., hypothermia, catalepsy, and CB1-dependent withdrawal signs) following systemic CP55,940 treatment in a mouse model of toxic neuropathy produced by a chemotherapeutic agent paclitaxel. The contribution of CB1 and CB2 receptors to in vivo actions of CP55,940 was evaluated using CB1 knockout (CB1KO), CB2 knockout (CB2KO), and wildtype (WT) mice. Low dose CP55,940 (0.3 mg/kg/day i.p.) suppressed paclitaxel-induced allodynia in WT and CB2KO, but not CB1KO mice. Low dose CP55,940 also produced hypothermia and rimonabant-precipitated withdrawal in WT, but not CB1KO mice. In WT mice, tolerance developed to CB1-mediated hypothermic effects of CP55,940 earlier than to anti-allodynic effects. High dose CP55,940 (10 mg/kg/day i.p.) produced catalepsy in WT mice, which precluded determination of anti-allodynic efficacy, but produced sustained CB2-mediated suppression of paclitaxel-induced allodynia in CB1KO mice; these anti-allodynic effects were blocked by the CB2 antagonist AM630. High dose CP55,940 did not produce hypothermia or rimonabant-precipitated withdrawal in CB1KO mice. Our results using the mixed CB1/CB2agonist CP55,940 document that CB1 and CB2 receptor activations produce mechanistically distinct suppression of neuropathic pain. Our study highlights the therapeutic potential of targeting cannabinoid CB2 receptors to bypass unwanted central effects associated with CB1receptor activation.
The American Society for Pharmacology and Experimental Therapeutics.