RT Journal Article
SR Electronic
T1 The cannabinoid CB2 agonist AM1710 differentially suppresses distinct pathological pain states and attenuates morphine tolerance and withdrawal
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP mol.118.113233
DO 10.1124/mol.118.113233
A1 Li, Ai-Ling
A1 Lin, Xiaoyan
A1 Dhopeshwarkar, Amey S
A1 Thomaz, Ana Carla
A1 Carey, Lawrence M
A1 Liu, Yingpeng
A1 Nikas, Spyros P
A1 Makriyannis, Alexandros
A1 Mackie, Ken
A1 Hohmann, Andrea G
YR 2018
UL http://molpharm.aspetjournals.org/content/early/2018/12/03/mol.118.113233.abstract
AB AM1710, a cannabilactone 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 ERK1/2 phosphorylation in HEK cells stably expressing mCB2. However, 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 chemotherapy-induced allodynia induced by paclitaxel. Prior history of AM1710 treatment (5 mg/kg/day x 12 day, i.p.) delayed the development of analgesic tolerance to morphine and attenuated morphine-induced physical dependence in paclitaxel-treated mice. However, AM1710 (10 mg/kg, i.p.) did not precipitate CB1-receptor mediated withdrawal in mice rendered tolerant to Δ9-tetrahydrocannabinol, suggesting AM1710 does not behave as 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 anti-allodynic 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.