Role of signalling molecules in behaviours mediated by the δ opioid receptor agonist SNC80

  • Br J Pharmacol. 2018 Mar;175(6):891-901. doi: 10.1111/bph.14131.
Isaac J Dripps  1 ,  Brett T Boyer  1 ,  Richard R Neubig  2 ,  Kenner C Rice  3 ,  John R Traynor  1 ,  Emily M Jutkiewicz  1
Affiliations
  • 1. Department of Pharmacology, University of Michigan Medical School, Ann Arbor, MI, USA.
  • 2. Department of Pharmacology and Toxicology, Michigan State University, East Lansing, MI, USA.
  • 3. Drug Design and Synthesis Section, Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse, North Bethesda, MD, USA.
PMID: 29278419 DOI: 10.1111/bph.14131
Abstract

Background and purpose: GPCRs exist in multiple conformations that can engage distinct signalling mechanisms which in turn may lead to diverse behavioural outputs. In rodent models, activation of the δ Opioid Receptor (δ-receptor) has been shown to elicit antihyperalgesia, antidepressant-like effects and convulsions. We recently showed that these δ-receptor-mediated behaviours are differentially regulated by the GTPase-activating protein regulator of G protein signalling 4 (RGS4), which facilitates termination of G protein signalling. To further evaluate the signalling mechanisms underlying δ-receptor-mediated antihyperalgesia, antidepressant-like effects and convulsions, we observed how changes in Gαo or Arrestin proteins in vivo affected behaviours elicited by the δ-receptor agonist SNC80 in mice.

Experimental approach: Transgenic mice with altered expression of various signalling molecules were used in the current studies. Antihyperalgesia was measured in a nitroglycerin-induced thermal hyperalgesia assay. Antidepressant-like effects were evaluated in the forced swim test. Mice were also observed for convulsive activity following SNC80 treatment.

Key results: In Gαo RGS-insensitive heterozygous knock-in mice, the potency of SNC80 to produce antihyperalgesia and antidepressant-like effects was enhanced with no change in SNC80-induced convulsions. Conversely, in Gαo heterozygous knockout mice, SNC80-induced antihyperalgesia was abolished while antidepressant-like effects and convulsions were unaltered. No changes in SNC80-induced behaviours were observed in Arrestin 3 knockout mice. SNC80-induced convulsions were potentiated in Arrestin 2 knockout mice.

Conclusions and implications: Taken together, these findings suggest that different signalling molecules may underlie the convulsive effects of the δ-receptor relative to its antihyperalgesic and antidepressant-like effects.

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