Ligand requirements for involvement of PKCε in synergistic analgesic interactions between spinal μ and δ opioid receptors

D. J. Schuster, M. D. Metcalf, K. F. Kitto, R. O. Messing, C. A. Fairbanks, George L. Wilcox

Research output: Contribution to journalArticlepeer-review

11 Scopus citations

Abstract

Background and Purpose We recently found that PKCε was required for spinal analgesic synergy between two GPCRs, δ opioid receptors and α2A adrenoceptors, co-located in the same cellular subpopulation. We sought to determine if co-delivery of μ and δ opioid receptor agonists would similarly result in synergy requiring PKCε.

Experimental Approach Combinations of μ and δ opioid receptor agonists were co-administered intrathecally by direct lumbar puncture to PKCε-wild-type (PKCε-WT) and -knockout (PKCε-KO) mice. Antinociception was assessed using the hot-water tail-flick assay. Drug interactions were evaluated by isobolographic analysis.

Key Results All agonists produced comparable antinociception in both PKCε-WT and PKCε-KO mice. Of 19 agonist combinations that produced analgesic synergy, only 3 required PKCε for a synergistic interaction. In these three combinations, one of the agonists was morphine, although not all combinations involving morphine required PKCε. Morphine + deltorphin II and morphine + deltorphin I required PKCε for synergy, whereas a similar combination, morphine + deltorphin, did not. Additionally, morphine + oxymorphindole required PKCε for synergy, whereas a similar combination, morphine + oxycodindole, did not.

Conclusions and Implications We discovered biased agonism for a specific signalling pathway at the level of spinally co-delivered opioid agonists. As the bias is only revealed by an appropriate ligand combination and cannot be accounted for by a single drug, it is likely that the receptors these agonists act on are interacting with each other. Our results support the existence of μ and δ opioid receptor heteromers at the spinal level in vivo.

Linked Articles This article is part of a themed section on Opioids: New Pathways to Functional Selectivity. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2015.172.issue-2.

Original languageEnglish (US)
Pages (from-to)642-653
Number of pages12
JournalBritish Journal of Pharmacology
Volume172
Issue number2
DOIs
StatePublished - Jan 2015

Bibliographical note

Publisher Copyright:
© 2014 The British Pharmacological Society.

Keywords

  • PKCε
  • biased agonism
  • heterodimer
  • heteromer
  • intrathecal
  • spinal
  • synergy
  • δ opioid receptor
  • μ opioid receptor

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