TY - JOUR T1 - The slowly signaling G protein-biased CB2 cannabinoid receptor agonist LY2828360 suppresses neuropathic pain with sustained efficacy and attenuates morphine tolerance and dependence JF - Molecular Pharmacology JO - Mol Pharmacol DO - 10.1124/mol.117.109355 SP - mol.117.109355 AU - Xiaoyan Lin AU - Amey S. Dhopeshwarkar AU - Megan Huibregtse AU - Ken Mackie AU - Andrea G. Hohmann Y1 - 2017/01/01 UR - http://molpharm.aspetjournals.org/content/early/2017/11/30/mol.117.109355.abstract N2 - The CB2 cannabinoid agonist LY2828360 lacked both toxicity and efficacy in a clinical trial for osteoarthritis. Whether LY2828360 suppresses neuropathic pain has not been reported and its signaling profile is unknown. In vitro, LY2828360 was a slowly acting but efficacious G protein-biased CB2 agonist, inhibiting cAMP accumulation and activating ERK1/2 signaling while failing to recruit arrestin, activate inositol phosphate signaling or internalize CB2 receptors. In wildtype (WT) mice, LY2828360 (3 mg/kg/day i.p. x 12 days) suppressed chemotherapy-induced neuropathic pain produced by paclitaxel without producing tolerance. Anti-allodynic efficacy of LY2828360 was absent in CB2KO mice. Morphine (10 mg/kg/day i.p. x 12 days) tolerance developed in CB2KO mice but not in WT mice with a history of LY2828360 treatment (3 mg/kg/day i.p. x 12 days). LY2828360-induced anti-allodynic efficacy was preserved in WT mice previously rendered tolerant to morphine (10 mg/kg/day i.p. x 12 days) but absent in morphine-tolerant CB2KO mice. Coadministration of LY2828360 (0.1 mg/kg/day i.p. x 12 days) with morphine (10 mg/kg/day x 12 days) blocked morphine tolerance in WT but not CB2KO mice. WT mice that received LY2828360 coadministered with morphine exhibited a trend (p=0.055) towards fewer naloxone-precipitated jumps compared to CB2KO mice. In conclusion, LY2828360 is a slowly signaling, G protein-biased CB2 agonist that attenuates chemotherapy-induced neuropathic pain without producing tolerance, and may prolong effective opioid analgesia while reducing opioid dependence. LY2828360 may be useful as a first line treatment in chemotherapy-induced neuropathic pain and may be highly efficacious in neuropathic pain states that are refractive to opioid analgesics. ER -