Original Article

Neuropsychopharmacology (2017) 42, 1548–1556; doi:10.1038/npp.2017.4; published online 8 February 2017

RGS9-2 Modulates Responses to Oxycodone in Pain-Free and Chronic Pain States

Sevasti Gaspari1,2, Valeria Cogliani1, Lefteris Manouras2, Ethan M Anderson1, Vasiliki Mitsi1, Kleopatra Avrampou1, Fiona B Carr1 and Venetia Zachariou1

  1. 1Icahn School of Medicine at Mount Sinai, Fishberg Department of Neuroscience and Friedman Brain Institute, New York, NY, USA
  2. 2University of Crete Faculty of Medicine, Department of Basic Sciences, Heraklion, Greece

Correspondence: Dr V Zachariou, Icahn School of Medicine at Mount Sinai, Fishberg Department of Neuroscience and Friedman Brain Institute, One Gustave L. Levy Place, Box 1065, New York, NY 10029, USA, Tel: 212 659 8612, Fax: 212 659 8574, E-mail: venetia.zachariou@mssm.edu

Received 8 August 2016; Revised 28 November 2016; Accepted 23 December 2016
Accepted article preview online 11 January 2017; Advance online publication 8 February 2017



Regulator of G-protein signaling 9-2 (RGS9-2) is a striatal-enriched signal-transduction modulator known to have a critical role in the development of addiction-related behaviors following exposure to psychostimulants or opioids. RGS9-2 controls the function of several G-protein-coupled receptors, including dopamine receptor and mu opioid receptor (MOR). We previously showed that RGS9-2 complexes negatively control morphine analgesia, and promote the development of morphine tolerance. In contrast, RGS9-2 positively modulates the actions of other opioid analgesics, such as fentanyl and methadone. Here we investigate the role of RGS9-2 in regulating responses to oxycodone, an MOR agonist prescribed for the treatment of severe pain conditions that has addictive properties. Using mice lacking the Rgs9 gene (RGS9KO), we demonstrate that RGS9-2 positively regulates the rewarding effects of oxycodone in pain-free states, and in a model of neuropathic pain. Furthermore, although RGS9-2 does not affect the analgesic efficacy of oxycodone or the expression of physical withdrawal, it opposes the development of oxycodone tolerance, in both acute pain and chronic neuropathic pain models. Taken together, these data provide new information on the signal-transduction mechanisms that modulate the rewarding and analgesic actions of oxycodone.

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