The role of regulator of G protein signaling 4 in delta-opioid receptor-mediated behaviors.
Regulator of G protein signaling (RGS) proteins act as negative modulators of G protein signaling. RGS4 has been shown to negatively modulate G protein signaling mediated by the delta opioid receptor (DOPr) in vitro. However, the role of RGS4 in modulating DOPr-mediated behaviors in vivo has not been elucidated.



The aim of this study was to compare the ability of the DOPr agonist SNC80 to induce DOPr-mediated antinociception, antihyperalgesia, antidepressant-like effects, and convulsions in wild-type and RGS4 knockout mice.



Antinociception was assessed in the acetic acid stretch assay. Antihyperalgesia was measured in a nitroglycerin-induced thermal hyperalgesia assay. Antidepressant-like effects were evaluated in the forced swim and tail suspension tests. Mice were also observed for convulsive activity post-SNC80 treatment. SNC80-induced phosphorylation of MAP kinase in striatal tissue from RGS4 wild-type and knockout mice was quantified by Western blot. DOPr number from forebrain tissue was measured using [3H]DPDPE saturation binding.



Elimination of RGS4 potentiated SNC80-induced antinociception and antihyperalgesia. SNC80-induced antidepressant-like effects were potentiated in RGS4 knockout mice in the forced swim test but not in the tail suspension test. Additionally, RGS4 knockout did not alter SNC80-induced convulsions. SNC80-induced phosphorylation of MAP kinase was potentiated in striatum from RGS4 knockout mice. Loss of RGS4 did not affect total DOPr number.



Overall, these findings demonstrate that reduction of RGS4 functionally may increase the therapeutic index of SNC80. These results provide the first evidence of differential regulation of DOPr-mediated behaviors by RGS proteins and G protein signaling pathways.
Department of Pharmacology, University of Michigan Medical School, Ann Arbor, MI, USA.
Isaac J
IJ
Dripps
Department of Pharmacology, University of Michigan Medical School, Ann Arbor, MI, USA.
Qin
Q
Wang
Department of Pharmacology and Toxicology, Michigan State University, East Lansing, MI, USA.
Richard R
RR
Neubig
Drug Design and Synthesis Section, Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse, Rockville, MD, USA.
Kenner C
KC
Rice
Department of Pharmacology, University of Michigan Medical School, Ann Arbor, MI, USA.
John R
JR
Traynor
Department of Pharmacology, University of Michigan Medical School, Ann Arbor, MI, USA. ejutkiew@umich.edu.
Emily M
EM
Jutkiewicz
D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology / Q000627:therapeutic use; D001549:Benzamides / Q000494:pharmacology* / Q000627:therapeutic use; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D006930:Hyperalgesia / Q000188:drug therapy; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D010766:Phosphorylation / Q000187:drug effects; D010879:Piperazines / Q000494:pharmacology* / Q000627:therapeutic use; D020710:RGS Proteins / Q000235:genetics / Q000378:metabolism*; D017465:Receptors, Opioid, delta / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D013550:Swimming
D000928:Antidepressive Agents; D001549:Benzamides; D010879:Piperazines; D020710:RGS Proteins; D017465:Receptors, Opioid, delta; C088464:4-(alpha-(4-allyl-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl)-N,N-diethylbenzamide; C098799:RGS4 protein
Antidepressant; Antinociception; Convulsion; Delta opioid receptor; Mice; Regulator of G protein signaling 4