A Regional and Projection-Specific Role of RGSz1 in the Ventrolateral Periaqueductal Grey in the Modulation of Morphine Reward.

Autor:	Sakloth F; Nash Family Department of Neuroscience, Friedman Brain Institute (F.S., A.R., A.N., R.A.S., K.D.P., F.B., A.T.-B., L.A.D., D.W., V.Z.) and Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, New York (O.B.S.R., I.G., L.A.D., D.W., V.Z.)., Sanchez-Reyes OB; Nash Family Department of Neuroscience, Friedman Brain Institute (F.S., A.R., A.N., R.A.S., K.D.P., F.B., A.T.-B., L.A.D., D.W., V.Z.) and Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, New York (O.B.S.R., I.G., L.A.D., D.W., V.Z.)., Ruiz A; Nash Family Department of Neuroscience, Friedman Brain Institute (F.S., A.R., A.N., R.A.S., K.D.P., F.B., A.T.-B., L.A.D., D.W., V.Z.) and Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, New York (O.B.S.R., I.G., L.A.D., D.W., V.Z.)., Nicolais A; Nash Family Department of Neuroscience, Friedman Brain Institute (F.S., A.R., A.N., R.A.S., K.D.P., F.B., A.T.-B., L.A.D., D.W., V.Z.) and Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, New York (O.B.S.R., I.G., L.A.D., D.W., V.Z.)., Serafini RA; Nash Family Department of Neuroscience, Friedman Brain Institute (F.S., A.R., A.N., R.A.S., K.D.P., F.B., A.T.-B., L.A.D., D.W., V.Z.) and Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, New York (O.B.S.R., I.G., L.A.D., D.W., V.Z.)., Pryce KD; Nash Family Department of Neuroscience, Friedman Brain Institute (F.S., A.R., A.N., R.A.S., K.D.P., F.B., A.T.-B., L.A.D., D.W., V.Z.) and Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, New York (O.B.S.R., I.G., L.A.D., D.W., V.Z.)., Bertherat F; Nash Family Department of Neuroscience, Friedman Brain Institute (F.S., A.R., A.N., R.A.S., K.D.P., F.B., A.T.-B., L.A.D., D.W., V.Z.) and Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, New York (O.B.S.R., I.G., L.A.D., D.W., V.Z.)., Torres-Berrío A; Nash Family Department of Neuroscience, Friedman Brain Institute (F.S., A.R., A.N., R.A.S., K.D.P., F.B., A.T.-B., L.A.D., D.W., V.Z.) and Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, New York (O.B.S.R., I.G., L.A.D., D.W., V.Z.)., Gomes I; Nash Family Department of Neuroscience, Friedman Brain Institute (F.S., A.R., A.N., R.A.S., K.D.P., F.B., A.T.-B., L.A.D., D.W., V.Z.) and Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, New York (O.B.S.R., I.G., L.A.D., D.W., V.Z.)., Devi LA; Nash Family Department of Neuroscience, Friedman Brain Institute (F.S., A.R., A.N., R.A.S., K.D.P., F.B., A.T.-B., L.A.D., D.W., V.Z.) and Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, New York (O.B.S.R., I.G., L.A.D., D.W., V.Z.)., Wacker D; Nash Family Department of Neuroscience, Friedman Brain Institute (F.S., A.R., A.N., R.A.S., K.D.P., F.B., A.T.-B., L.A.D., D.W., V.Z.) and Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, New York (O.B.S.R., I.G., L.A.D., D.W., V.Z.) daniel.wacker@mssm.edu venetia.zachariou@mssm.edu., Zachariou V; Nash Family Department of Neuroscience, Friedman Brain Institute (F.S., A.R., A.N., R.A.S., K.D.P., F.B., A.T.-B., L.A.D., D.W., V.Z.) and Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, New York (O.B.S.R., I.G., L.A.D., D.W., V.Z.) daniel.wacker@mssm.edu venetia.zachariou@mssm.edu.
Jazyk:	angličtina
Zdroj:	Molecular pharmacology [Mol Pharmacol] 2023 Jan; Vol. 103 (1), pp. 1-8. Date of Electronic Publication: 2022 Oct 30.
DOI:	10.1124/molpharm.122.000528
Abstrakt:	Opioid analgesics exert their therapeutic and adverse effects by activating μ opioid receptors (MOPR); however, functional responses to MOPR activation are modulated by distinct signal transduction complexes within the brain. The ventrolateral periaqueductal gray (vlPAG) plays a critical role in modulation of nociception and analgesia, but the exact intracellular pathways associated with opioid responses in this region are not fully understood. We previously showed that knockout of the signal transduction modulator Regulator of G protein Signaling z1 (RGSz1) enhanced analgesic responses to opioids, whereas it decreased the rewarding efficacy of morphine. Here, we applied viral mediated gene transfer methodology and delivered adeno-associated virus (AAV) expressing Cre recombinase to the vlPAG of RGSz1 fl\fl mice to demonstrate that downregulation of RGSz1 in this region decreases sensitivity to morphine in the place preference paradigm, under pain-free as well as neuropathic pain states. We also used retrograde viral vectors along with flippase-dependent Cre vectors to conditionally downregulate RGSz1 in vlPAG projections to the ventral tegmental area (VTA) and show that downregulation of RGSz1 prevents the development of place conditioning to low morphine doses. Consistent with the role for RGSz1 as a negative modulator of MOPR activity, RGSz1KO enhances opioid-induced cAMP inhibition in periaqueductal gray (PAG) membranes. Furthermore, using a new generation of bioluminescence resonance energy transfer (BRET) sensors, we demonstrate that RGSz1 modulates G α z but not other G α i family subunits and selectively impedes MOPR-mediated G α z signaling events invoked by morphine and other opioids. Our work highlights a regional and circuit-specific role of the G protein-signaling modulator RGSz1 in morphine reward, providing insights on midbrain intracellular pathways that control addiction-related behaviors. SIGNIFICANCE STATEMENT: This study used advanced genetic mouse models to highlight the role of the signal transduction modulator named RGSz1 in responses to clinically used opioid analgesics. We show that RGSz1 controls the rewarding efficacy of opioids by actions in ventrolateral periaqueductal gray projections to the ventral tegmental area, a key component of the midbrain dopamine pathway. These studies highlight novel mechanisms by which pain-modulating structures control the rewarding efficacy of opioids. (Copyright © 2022 by The American Society for Pharmacology and Experimental Therapeutics.)
Databáze:	MEDLINE
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