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 A Simone, Georgy Bakalkin, Dmitri Gordienko, Alexei Verkhratsky, Oleg Krishtal

Research output: Contribution to journalArticle

5 Citations (Scopus)

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

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Purinergic P2X3 Receptors
Opioid Receptors
Sensory Receptor Cells
Opioid Analgesics
Pertussis Toxin
Leucine Enkephalin
Type C Phospholipases
Neurons
Purinergic Receptors
Narcotic Antagonists
Spinal Ganglia
Naloxone
Inhibitory Concentration 50
Pharmacology
Pain

Keywords

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

Cite this

Molecular mechanism for opioid dichotomy : bidirectional effect of μ-opioid receptors on P2X3 receptor currents in rat sensory neurones. / Chizhmakov, Igor; Kulyk, Vyacheslav; Khasabova, Iryna; Khasabov, Sergey; Simone, Donald A; Bakalkin, Georgy; Gordienko, Dmitri; Verkhratsky, Alexei; Krishtal, Oleg.

In: Purinergic Signalling, Vol. 11, No. 2, 01.06.2015, p. 171-181.

Research output: Contribution to journalArticle

Chizhmakov, Igor ; Kulyk, Vyacheslav ; Khasabova, Iryna ; Khasabov, Sergey ; Simone, Donald A ; Bakalkin, Georgy ; Gordienko, Dmitri ; Verkhratsky, Alexei ; Krishtal, Oleg. / Molecular mechanism for opioid dichotomy : bidirectional effect of μ-opioid receptors on P2X3 receptor currents in rat sensory neurones. In: Purinergic Signalling. 2015 ; Vol. 11, No. 2. pp. 171-181.
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