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Molecular Pharmacology

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Research ArticleArticle

Slowly Signaling G Protein–Biased CB2 Cannabinoid Receptor Agonist LY2828360 Suppresses Neuropathic Pain with Sustained Efficacy and Attenuates Morphine Tolerance and Dependence

Xiaoyan Lin, Amey S. Dhopeshwarkar, Megan Huibregtse, Ken Mackie and Andrea G. Hohmann
Molecular Pharmacology February 2018, 93 (2) 49-62; DOI: https://doi.org/10.1124/mol.117.109355
Xiaoyan Lin
Psychological and Brain Sciences (X.L., A.S.D., M.H., K.M., A.G.H.), Program in Neuroscience (K.M., A.G.H.), and Gill Center for Biomolecular Science (K.M., A.G.H.), Indiana University, Bloomington, Indiana
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Amey S. Dhopeshwarkar
Psychological and Brain Sciences (X.L., A.S.D., M.H., K.M., A.G.H.), Program in Neuroscience (K.M., A.G.H.), and Gill Center for Biomolecular Science (K.M., A.G.H.), Indiana University, Bloomington, Indiana
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Megan Huibregtse
Psychological and Brain Sciences (X.L., A.S.D., M.H., K.M., A.G.H.), Program in Neuroscience (K.M., A.G.H.), and Gill Center for Biomolecular Science (K.M., A.G.H.), Indiana University, Bloomington, Indiana
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Ken Mackie
Psychological and Brain Sciences (X.L., A.S.D., M.H., K.M., A.G.H.), Program in Neuroscience (K.M., A.G.H.), and Gill Center for Biomolecular Science (K.M., A.G.H.), Indiana University, Bloomington, Indiana
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Andrea G. Hohmann
Psychological and Brain Sciences (X.L., A.S.D., M.H., K.M., A.G.H.), Program in Neuroscience (K.M., A.G.H.), and Gill Center for Biomolecular Science (K.M., A.G.H.), Indiana University, Bloomington, Indiana
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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 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.

Footnotes

    • Received May 5, 2017.
    • Accepted November 6, 2017.
  • This research was supported by the National Institutes of Health National Institute on Drug Abuse [Grants DA041229, DA009158, and DA021696] and National Cancer Institute [Grant CA200417].

  • https://doi.org/10.1124/mol.117.109355.

  • ↵Embedded ImageThis article has supplemental material available at molpharm.aspetjournals.org.

  • Copyright © 2017 by The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 93 (2)
Molecular Pharmacology
Vol. 93, Issue 2
1 Feb 2018
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Research ArticleArticle

Role of CB2 in Morphine Tolerance and Dependence

Xiaoyan Lin, Amey S. Dhopeshwarkar, Megan Huibregtse, Ken Mackie and Andrea G. Hohmann
Molecular Pharmacology February 1, 2018, 93 (2) 49-62; DOI: https://doi.org/10.1124/mol.117.109355

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Research ArticleArticle

Role of CB2 in Morphine Tolerance and Dependence

Xiaoyan Lin, Amey S. Dhopeshwarkar, Megan Huibregtse, Ken Mackie and Andrea G. Hohmann
Molecular Pharmacology February 1, 2018, 93 (2) 49-62; DOI: https://doi.org/10.1124/mol.117.109355
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