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The slowly signaling G protein-biased CB2 cannabinoid receptor agonist LY2828360 suppresses neuropathic pain with sustained efficacy and attenuates morphine tolerance and dependence.

The slowly signaling G protein-biased CB2 cannabinoid receptor agonist LY2828360 suppresses neuropathic pain with sustained efficacy and attenuates morphine tolerance and dependence.
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Lin X, Dhopeshwarkar AS, Huibregtse M, Mackie K, Hohmann AG,


Lin X, Dhopeshwarkar AS, Huibregtse M, Mackie K, Hohmann AG, (click to view)

Lin X, Dhopeshwarkar AS, Huibregtse M, Mackie K, Hohmann AG,

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Molecular pharmacology 2017 11 30() pii mol.117.109355
Abstract

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.

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