PT  - JOURNAL ARTICLE
AU  - Lin, Xiaoyan
AU  - Dhopeshwarkar, Amey S.
AU  - Huibregtse, Megan
AU  - Mackie, Ken
AU  - Hohmann, Andrea G.
TI  - Slowly Signaling G Protein–Biased CB<sub>2</sub> Cannabinoid Receptor Agonist LY2828360 Suppresses Neuropathic Pain with Sustained Efficacy and Attenuates Morphine Tolerance and Dependence
AID  - 10.1124/mol.117.109355
DP  - 2018 Feb 01
TA  - Molecular Pharmacology
PG  - 49--62
VI  - 93
IP  - 2
4099  - http://molpharm.aspetjournals.org/content/93/2/49.short
4100  - http://molpharm.aspetjournals.org/content/93/2/49.full
SO  - Mol Pharmacol2018 Feb 01; 93
AB  - 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 extracellular signal-regulated kinase 1/2 signaling while failing to recruit arrestin, activate inositol phosphate signaling, or internalize CB2 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 CB2 knockout (KO) mice. Morphine (10 mg/kg per day i.p. × 12 days) tolerance developed in CB2KO 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 CB2KO 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 CB2KO mice. WT mice that received LY2828360 coadministered with morphine exhibited a trend (P = 0.055) toward fewer naloxone-precipitated jumps compared with 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.