Abstract

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 [(−)-3-[2-hydroxy-4-(1,1-dimethylheptyl)phenyl]-4-(3-hydroxypropyl)cyclohexanol], 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 antiallodynic effects, possible tolerance, and cannabimimetic effects (e.g., hypothermia, catalepsy, CB₁-dependent withdrawal signs) after 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 (KO), CB₂KO, and wild-type (WT) mice. Low-dose CP55,940 (0.3 mg/kg daily, i.p. ) suppressed paclitaxel-induced allodynia in WT and CB₂KO mice, 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 antiallodynic effects. High-dose CP55,940 (10 mg/kg daily, i.p.) produced catalepsy in WT mice, which precluded determination of antiallodynic efficacy but produced sustained CB₂-mediated suppression of paclitaxel-induced allodynia in CB₁KO mice; these antiallodynic effects were blocked by the CB₂ antagonist 6-iodopravadoline (AM630). High-dose CP55,940 did not produce hypothermia or rimonabant-precipitated withdrawal in CB₁KO mice. Our results using the mixed CB₁/CB₂ agonist 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 CB₁ receptor activation.