Essential role for RGS9 in opiate action.
Regulators of G protein signaling (RGS) are a family of proteins known to accelerate termination of effector stimulation after G protein receptor activation. RGS9-2, a brain-specific splice variant of the RGS9 gene, is highly enriched in striatum and also expressed at much lower levels in periaqueductal gray and spinal cord, structures known to mediate various actions of morphine and other opiates. Morphine exerts its acute rewarding and analgesic effects by activation of inhibitory guanine nucleotide-binding regulatory protein-coupled opioid receptors, whereas chronic morphine causes addiction, tolerance to its acute analgesic effects, and profound physical dependence by sustained activation of these receptors. We show here that acute morphine administration increases expression of RGS9-2 in NAc and the other CNS regions, whereas chronic exposure decreases RGS9-2 levels. Mice lacking RGS9 show enhanced behavioral responses to acute and chronic morphine, including a dramatic increase in morphine reward, increased morphine analgesia with delayed tolerance, and exacerbated morphine physical dependence and withdrawal. These findings establish RGS9 as a potent negative modulator of opiate action in vivo, and suggest that opiate-induced changes in RGS9 levels contribute to the behavioral and neural plasticity associated with chronic opiate administration.
Zachariou
Venetia
V
Department of Psychiatry and Center for Basic Neuroscience, University of Texas Southwestern Medical Center, Dallas, TX 75390-9070, USA.
Georgescu
Dan
D
Sanchez
Nick
N
Rahman
Zia
Z
DiLeone
Ralph
R
Berton
Olivier
O
Neve
Rachael L
RL
Sim-Selley
Laura J
LJ
Selley
Dana E
DE
Gold
Stephen J
SJ
Nestler
Eric J
EJ
D017398:Alternative Splicing; D000701:Analgesics, Opioid / Q000494:pharmacology; D000818:Animals; D015153:Blotting, Western; D002490:Central Nervous System / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D018014:Gene Transfer Techniques; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009020:Morphine / Q000378:metabolism / Q000494:pharmacology; D009294:Narcotics / Q000378:metabolism*; D020710:RGS Proteins / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013116:Spinal Cord / Q000473:pathology; D013696:Temperature; D013997:Time Factors
D000701:Analgesics, Opioid; D009294:Narcotics; D020710:RGS Proteins; C116925:regulator of g-protein signaling 9; D009020:Morphine