Molecular mechanism for opioid dichotomy: bidirectional effect of μ-opioid receptors on P2X3 receptor currents in rat sensory neurones

Igor Chizhmakov, Vyacheslav Kulyk, Iryna Khasabova, Sergey Khasabov, Donald Simone, Georgy Bakalkin, Dmitri Gordienko, Alexei Verkhratsky, Oleg Krishtal

Research output: Contribution to journalArticle

5 Scopus citations

Abstract

Here, we describe a molecular switch associated with opioid receptors-linked signalling cascades that provides a dual opioid control over P2X3 purinoceptor in sensory neurones. Leu-enkephalin inhibited P2X3-mediated currents with IC50 ~10 nM in ~25 % of small nociceptive rat dorsal root ganglion (DRG) neurones. In contrast, in neurones pretreated with pertussis toxin leu-enkephalin produced stable and significant increase of P2X3 currents. All effects of opioid were abolished by selective μ-opioid receptor antagonist D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH2 (CTOP), nonselective inhibitor naloxone, and by PLC inhibitor U73122. Thus, we discovered a dual link between purinoceptors and μ-opioid receptors: the latter exert both inhibitory (pertussis toxin-sensitive) and stimulatory (pertussis toxin-insensitive) actions on P2X3 receptors through phospholipase C (PLC)-dependent pathways. This dual opioid control of P2X3 receptors may provide a molecular explanation for dichotomy of opioid therapy. Pharmacological control of this newly identified facilitation/inhibition switch may open new perspectives for the adequate medical use of opioids, the most powerful pain-killing agents known today.

Original languageEnglish (US)
Pages (from-to)171-181
Number of pages11
JournalPurinergic Signalling
Volume11
Issue number2
DOIs
StatePublished - Jun 1 2015

Keywords

  • Leu-enkephalin
  • Nociceptive neurones
  • Opioid receptors
  • P2X receptors
  • Pain
  • Sensory neurones

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