Brain region specific actions of regulator of G protein signaling 4 oppose morphine reward and dependence but promote analgesia.
BACKGROUND
Regulator of G protein signaling 4 (RGS4) is one of the smaller members of the RGS family of proteins, which are known to control signaling amplitude and duration via interactions with G protein alpha subunits or other signaling molecules. Earlier evidence suggests dynamic regulation of RGS4 levels in neuronal networks mediating actions of opiates and other drugs of abuse, but the consequences of RGS4 actions in vivo are largely unknown.


METHODS
In this study, we use constitutive and nucleus accumbens-inducible RGS4 knockout mice as well as mice overexpressing RGS4 in the nucleus accumbens via viral mediated gene transfer, to examine the influence of RGS4 on behavioral responses to opiates. We also use electrophysiology and immunoprecipitation assays to further understand the mechanisms underlying the tissue-specific actions of RGS4.


RESULTS
Inducible knockout or selective overexpression of RGS4 in the nucleus accumbens reveals that, in this brain region, RGS4 acts as a negative regulator of morphine reward, whereas in the locus coeruleus RGS4 opposes morphine physical dependence. In contrast, we show that RGS4 does not affect morphine analgesia or tolerance but is a positive modulator of certain opiate analgesics, such as methadone and fentanyl.


CONCLUSIONS
These findings provide fundamentally novel information concerning the role of RGS4 in the cellular mechanisms underlying the diverse actions of opiate drugs in the nervous system.
Han
Ming-Hi
MH
Department of Psychiatry, UT Southwestern Medical Center, Dallas, Texas, USA.
Renthal
Willam
W
Ring
Robert H
RH
Rahman
Zia
Z
Psifogeorgou
Kassi
K
Howland
David
D
Birnbaum
Shari
S
Young
Kathleen
K
Neve
Rachael
R
Nestler
Eric J
EJ
Zachariou
Venetia
V
D000256:Adenoviridae / Q000235:genetics; D000701:Analgesics, Opioid / Q000494:pharmacology*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D015153:Blotting, Western; D003216:Conditioning, Operant / Q000187:drug effects; D004594:Electrophysiology; D018014:Gene Transfer Techniques; D047468:Immunoprecipitation; D008125:Locus Coeruleus / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009020:Morphine / Q000494:pharmacology*; D009021:Morphine Dependence / Q000503:physiopathology*; D009154:Mutation / Q000502:physiology; D010147:Pain Measurement / Q000187:drug effects; D020710:RGS Proteins / Q000235:genetics / Q000502:physiology*; D011930:Reaction Time / Q000187:drug effects; D017450:Receptors, Opioid, mu / Q000819:agonists; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012201:Reward; D015398:Signal Transduction / Q000187:drug effects
D000701:Analgesics, Opioid; D020710:RGS Proteins; D017450:Receptors, Opioid, mu; C098799:RGS4 protein; D009020:Morphine