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 and/or 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 1/2 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 mg/kg per day × 12 day, i.p.) delayed the development of antinociceptive tolerance to
morphine and attenuated
morphine-induced physical dependence.
AM1710 (10 mg/kg, i.p.) did not precipitate
CB1 receptor-mediated withdrawal in mice rendered tolerant to Δ9-tetrahydrocannabinol, suggesting that
AM1710 is not a functional CB1 antagonist in vivo. Furthermore,
AM1710 (1, 3, 10 mg/kg, i.p.) did not suppress established
mechanical allodynia induced by complete
Freund's adjuvant (CFA) or by partial sciatic nerve
ligation (PSNL). Similarly, prophylactic and chronic dosing with
AM1710 (10 mg/kg, i.p.) did not produce antiallodynic efficacy in the CFA model. By contrast,
gabapentin suppressed
allodynia in both CFA and PSNL models. Our results indicate that
AM1710 is not a broad-spectrum
analgesic agent in mice and suggest the need to identify signaling pathways underlying CB2 therapeutic efficacy to identify appropriate indications for clinical translation.