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  • Addiction, Drugs
  • Information from Lay-Language Summaries is Embargoed Until the Conclusion of the Scientific Presentation

    257—Opioids: Neural Mechanisms of Addiction

    Sunday, November 10, 2013, 1:00 pm - 5:00 pm

    257.07: A role of Regulator of G protein signaling 9-2 (RGS9-2) in the Nucleus Accumbens in opiate addiction and analgesia

    Location: Halls B-H

    1Dept. of Basic sciences, Univ. of Crete, Heraklion, Greece; 2Dept. of Bioengineering, Stanford Univ., Stanford, CA; 3Anat. and Neurobio., Univ. of Maryland, Baltimore, MD; 4Neurosci. and Pharmacol. and Systems Therapeut., Icahn Sch. of Med. at Mount Sinai, New York, NY

    Abstract Body: Regulator of G Protein Signaling 9-2 (RGS9-2) is a multifunctional signal transduction protein with high levels of expression in the striatum. RGS9-2 plays a major role in the modulation of several GPCR responses in the striatum, and has been shown to potently modulate dopaminergic and opioidergic transmission. We recently identified RGS9-2 complexes in the striatum associated with the acute and chronic actions of different mu opioid receptor agonists. We have also developed viral mediated gene transfer approaches to investigate the actions of RGS9-2 in particular brain regions of adult animals. Using adenoassociated viruses (AAV) expressing RGS9-2 or a dominant negative form of the protein (DEPless RGS9-2) we explored the brain specific actions of this molecule in a series of behavioral paradigms for opiate reward and analgesia. Our studies reveal that RGS9-2 actions in the nucleus accumbens (NAc) negatively regulate the rewarding actions of morphine and they also affect the development of physical dependence. In addition, RGS9-2 in the NAc plays a key role in morphine analgesia and tolerance in paradigms of acute and chronic pain. These findings are further supported by optogenetic studies, in which subpopulations of dopamine D1 or dopamine D2 receptor enriched neurons were activated following morphine administration. Activation of D1 receptor enriched neurons leads to an increase in RGS9-2 levels and accelerates the development of analgesic tolerance. These findings point to RGS9-2 complexes in the NAc as novel targets for the treatment of addiction and reveal the influence of RGS9-2 in the NAc in morphine analgesia and tolerance.

    Lay Language Summary: Morphine, and other opiates are clinically used for the treatment of some types of chronic pain, but their use is limited by the numerous side effects, including the risk of respiratory depression, the development of addiction and analgesic tolerance. Understanding the mechanism underlying the analgesic actions of opiates and the development of tolerance may lead to the development of new pharmacological strategies which permit the use of much lower drug doses, limit the side effects and delay the development of tolerance. Over the last few years, evidence from biochemical studies shed light onto the mechanism via which morphine exerts its actions in neurons, and it became clear that while this drug acts via binding to mu opioid receptors in varous brain regions, the actions of morphine in each of these brain regions involves distinct cellular mechanisms. Therefore, it is important to understand the specific cellular mechanisms of morphine actions in neuronal pathways mediating addiction and analgesia. Our goa lis to understand the key determinants of analgesic efficacy and to identify the cellular adaptations associated with analgesic tolerance. Our earlier work revealed that the protein names RGS9-2 (regulator of G protein signaling), which controls the function of many G protein coupled receptors, including the mu opioid receptor, plays a key role in analgesic responses to morphine, as well as in morphine addiction. Interestingly, RGS9-2 does not affect morphine actions in all brain regions, as it is localized only in the striatum, which is part of the brain reward center. Our findings suggest that protein complexes within the brain reward center affect the analgesic responses to morphine, as well as the development of morphine tolerance. To further understand the function of such complexes, we developed genetic tools for gene transfer studies, and we overexpressed RGS9-2, or mutant forms of the protein in the brain reward center. We then performed a series of behavioural studies, to show that changes in RGS9-2 gene expression in the nucleus accumbens, affect not only morphine reward and dependence, but also analgesia and analgesic tolerance. Using elaborate genetic tools, we were able to provide the first evidence about the specific cell populations in the brain reward centre mediating analgesic tolerance or dependence. Another important piece of information was obtained from optogenetic studies, which permitted selective activation of neuronal subpopulations of the nucleus accumbens, and provided evidence for a role of dopamine D1-enriched medium spiny neurons in morphine tolerance. This work provides important information about the brain region and cell type specific mechanisms underlying morphine actions.