Slowly Signaling G Protein–Biased CB$_2$ Cannabinoid Receptor Agonist LY2828360 Suppresses Neuropathic Pain with Sustained Efficacy and Attenuates Morphine Tolerance and Dependence

Abstract

The CB$_2$ 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 CB$_2$ agonist, inhibiting cAMP accumulation and activating extracellular signal-regulated kinase 1/2 signaling while failing to recruit arrestin, activate inositol phosphate signaling, or internalize CB$_2$ receptors. In wild-type (WT) mice, LY2828360 (3 mg/kg per day i.p. × 12 days) suppressed chemotherapy-induced neuropathic pain produced by paclitaxel without producing tolerance. Antiallodynic efficacy of LY2828360 was absent in CB$_2$ knockout (KO) mice. Morphine (10 mg/kg per day i.p. × 12 days) tolerance developed in CB$_2$KO mice but not in WT mice with a history of LY2828360 treatment (3 mg/kg per day i.p. × 12 days). LY2828360-induced antiallodynic efficacy was preserved in WT mice previously rendered tolerant to morphine (10 mg/kg per day i.p. × 12 days), but it was absent in morphine-tolerant CB$_2$KO mice. Coadministration of LY2828360 (0.1 mg/kg per day i.p. × 12 days) with morphine (10 mg/kg per day × 12 days) blocked morphine tolerance in WT but not in CB$_2$KO mice. WT mice that received LY2828360 coadministered with morphine exhibited a trend ($P$ = 0.055) toward fewer naloxone-precipitated jumps compared with CB$_2$KO mice. In conclusion, LY2828360 is a slowly signaling, G protein–biased CB$_2$ 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.