title: Differential control of opioid antinociception to thermal stimuli in a knock-in mouse expressing regulator of G-protein signaling-insensitive Gαo protein.
abstract: Regulator of G-protein signaling (RGS) proteins classically function as negative modulators of G-protein-coupled receptor signaling. In vitro, RGS proteins have been shown to inhibit signaling by agonists at the μ-opioid receptor, including morphine. The goal of the present study was to evaluate the contribution of endogenous RGS proteins to the antinociceptive effects of morphine and other opioid agonists. To do this, a knock-in mouse that expresses an RGS-insensitive (RGSi) mutant Gαo protein, Gαo(G184S) (Gαo RGSi), was evaluated for morphine or methadone antinociception in response to noxious thermal stimuli. Mice expressing Gαo RGSi subunits exhibited a naltrexone-sensitive enhancement of baseline latency in both the hot-plate and warm-water tail-withdrawal tests. In the hot-plate test, a measure of supraspinal nociception, morphine antinociception was increased, and this was associated with an increased ability of opioids to inhibit presynaptic GABA neurotransmission in the periaqueductal gray. In contrast, antinociception produced by either morphine or methadone was reduced in the tail-withdrawal test, a measure of spinal nociception. In whole-brain and spinal cord homogenates from mice expressing Gαo RGSi subunits, there was a small loss of Gαo expression and an accompanying decrease in basal G-protein activity. Our results strongly support a role for RGS proteins as negative regulators of opioid supraspinal antinociception and also reveal a potential novel function of RGS proteins as positive regulators of opioid spinal antinociceptive pathways.
authors: Department of Pharmacology, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA.
authors: Jennifer T
authors: JT
authors: Lamberts
authors: Chelsea E
authors: CE
authors: Smith
authors: Ming-Hua
authors: MH
authors: Li
authors: Susan L
authors: SL
authors: Ingram
authors: Richard R
authors: RR
authors: Neubig
authors: John R
authors: JR
authors: Traynor
mesh_terms: D000701:Analgesics, Opioid / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D004174:Diprenorphine / Q000493:pharmacokinetics; D004305:Dose-Response Relationship, Drug; D004558:Electric Stimulation; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)- / Q000493:pharmacokinetics; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005260:Female; D018756:GABA Antagonists / Q000494:pharmacology; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000493:pharmacokinetics; D006358:Hot Temperature / Q000009:adverse effects; D006801:Humans; D006930:Hyperalgesia / Q000188:drug therapy* / Q000235:genetics; D053444:Inhibitory Postsynaptic Potentials / Q000187:drug effects / Q000235:genetics; D007554:Isotopes / Q000493:pharmacokinetics; D008297:Male; D008691:Methadone / Q000494:pharmacology / Q000627:therapeutic use; D051379:Mice; D008822:Mice, Transgenic; D009020:Morphine / Q000494:pharmacology / Q000627:therapeutic use*; D009154:Mutation; D009270:Naloxone / Q000494:pharmacology; D009271:Naltrexone / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D009842:Oligopeptides / Q000494:pharmacology; D010147:Pain Measurement / Q000187:drug effects; D018408:Patch-Clamp Techniques; D037342:Pertussis Toxin / Q000494:pharmacology; D011485:Protein Binding / Q000187:drug effects / Q000235:genetics; D020710:RGS Proteins / Q000235:genetics / Q000378:metabolism*; D011930:Reaction Time / Q000187:drug effects / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
chemical_list: D000701:Analgesics, Opioid; D018691:Excitatory Amino Acid Antagonists; D018756:GABA Antagonists; D007554:Isotopes; D009292:Narcotic Antagonists; D009842:Oligopeptides; D020710:RGS Proteins; C089773:phenylalanyl--cysteinyl-tyrosyl-tryptophyl-arginyl-penicillaminyl-threoninamide; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D004174:Diprenorphine; D009270:Naloxone; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D005680:gamma-Aminobutyric Acid; D009271:Naltrexone; D009020:Morphine; D037342:Pertussis Toxin; D019206:GTP-Binding Protein alpha Subunits, Gi-Go; D008691:Methadone