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Gα o Proteins Mediate the Antihyperalgesic and Antidepressant‐like Effects, but not the Convulsive Effects, Produced by Delta Opioid Receptor Activation
Author(s) -
Dripps Isaac,
Neubig Richard,
Rice Kenner,
Jutkiewicz Emily
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.926.4
Subject(s) - g protein coupled receptor , agonist , potency , receptor , knockout mouse , opioid , pharmacology , δ opioid receptor , regulator of g protein signaling , chemistry , antidepressant , medicine , g protein , endocrinology , in vitro , biochemistry , gtpase activating protein , hippocampus
The delta opioid receptor (DOPr) is a member of the opioid receptor family of G protein‐coupled receptors (GPCRs). Activation of DOPr induces antihyperalgesia and antidepressant‐like effects in animal models. However, some DOPr agonists cause convulsions, hindering their development as therapeutics in humans. Regulator of G protein signaling (RGS) proteins act as negative modulators of GPCR signaling. Our lab has previously demonstrated that RGS4 acts as a negatively modulator of DOPr‐mediated antihyperalgesia and antidepressant‐like effects without impacting convulsions. These findings indicate that the antihyperalgesic and antidepressant‐like effects of DOPr are G protein‐mediated. However, DOPr is known to couple to multiple G i/o proteins. Therefore, we sought to determine which G protein mediates these behaviors and whether that G protein also plays a role in generating DOPr‐mediated convulsions. To this end, we compared behaviors induced by the DOPr agonist SNC80 in Gα o RGS‐insensitive (RGSi) knock‐in, and Gα o heterozygote knockout mice. DOPr‐mediated antihyperalgesia was evaluated using a CNS‐mediated nitroglycerin‐induced thermal hyperalgesia assay. Antidepressant‐like effects were measured using the forced swim test. The potency of SNC80 to produce antihyperalgesia was significantly increased in the Gα o RGSi mice. SNC80 also produced antidepressant‐like effects in the Gα o RGSi mice with enhanced potency and efficacy. In the Gα o heterozygote knockout mice, SNC80‐induced antihyperalgesia was completely abolished while antidepressant‐like effects in the forced swim test were unaltered. There were no changes in the frequency, duration, or time of onset of SNC80‐induced convulsions in either mouse strain. Taken together, our data demonstrate that DOPr‐mediated antihyperalgesia and antidepressant‐like effects require Gα o . A 50% loss in Gα o was sufficient to abolish the antihyperalgesic, but not the antidepressant‐like effects of DOPr, indicating that DOPr‐mediated antidepressant‐like effects had a lower efficacy requirement than the antihyperalgesic effects. Ostensibly, DOPr‐mediated convulsions are not regulated by Gα o . However, it is possible that the efficacy requirement for convulsions is low enough that they are unaffected by loss of RGS regulation or a 50% reduction in Gα o . DOPr‐mediated convulsions may also be generated by a G protein‐independent signaling mechanism such as the β‐arrestin pathway. Future studies will focus on investigating the efficacy requirements of DOPr‐mediated behaviors and characterizing these behaviors in β‐arrestin2 knockout mice. Support or Funding Information Research support was provided by start‐up funds to EMJ.