Cannabinoid CB2 Agonist AM1710 Differentially Suppresses Distinct Pathological Pain States and Attenuates Morphine Tolerance and Withdrawal.
AM1710 (3-(1,1-dimethyl-heptyl)-1-hydroxy-9-methoxy-benzo(c) chromen-6-one), a cannabilactone cannabinoid receptor 2 (CB2) agonist, suppresses chemotherapy-induced neuropathic pain in rodents without producing tolerance or unwanted side effects associated with CB1 receptors however, the signaling profile of AM1710 remains incompletely characterized. It is not known whether AM1710 behaves as a broad-spectrum analgesic andor suppresses the development of opioid tolerance and physical dependence. In vitro, AM1710 inhibited forskolin-stimulated cAMP production and produced enduring activation of extracellular signal-regulated kinases 12 phosphorylation in human embryonic kidney (HEK) cells stably expressing mCB2. Only modest species differences in the signaling profile of AM1710 were observed between HEK cells stably expressing mCB2 and hCB2. In vivo, AM1710 produced a sustained inhibition of paclitaxel-induced allodynia in mice. In paclitaxel-treated mice, a history of AM1710 treatment (5 mgkg per day × 12 day, i.p.) delayed the development of antinociceptive tolerance to morphine and attenuated morphine-induced physical dependence. AM1710 (10 mgkg, i.p.) did not precipitate CB1 receptor-mediated withdrawal in mice rendered tolerant to Δ