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

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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.

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Abbreviations

AC:

adenylate cyclase

[Ca2+]i :

free cytosolic Ca2+ concentration

cAMP:

cyclic adenosine monophosphate

DRG:

dorsal root ganglion

CTOP:

D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH2

DAG:

diacylglycerol

Enk:

leu-enkephalin

GPCRs:

G protein-coupled receptors

InsP3 :

inositol 1,4,5-trisphosphate

meATP:

α,β–methylene-ATP

MORs:

μ-opioid receptors

PKA:

protein kinase A

PKC:

protein kinase C

PLC:

phospholipase C

PTX:

pertussis toxin

TRPV1:

transient receptor potential vanilloid 1

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Acknowledgments

This work was supported by Ukrainian Fund for Fundamental Studies (grant DFFD F46.2/001) and by NIH (grant NIH 1R03TW008228-01A1).

Conflict of interest

The authors declare no conflict of interest.

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Authors and Affiliations

  1. State Key Laboratory for Molecular Biology, Bogomoletz Institute of Physiology, 4 Bogomoletz str., Kiev, 01024, Ukraine

    Igor Chizhmakov, Vyacheslav Kulyk, Dmitri Gordienko & Oleg Krishtal

  2. Department of Diagnostic and Biological Sciences, School of Dentistry, University of Minnesota, Minneapolis, MN, USA

    Iryna Khasabova, Sergey Khasabov & Donald Simone

  3. Deptartment of Pharmacological Bioscience, Uppsala University, Uppsala, Sweden

    Georgy Bakalkin

  4. Faculty of Life Sciences, The University of Manchester, Manchester, UK

    Alexei Verkhratsky

Authors
  1. Igor Chizhmakov
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  2. Vyacheslav Kulyk
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Correspondence to Alexei Verkhratsky or Oleg Krishtal.

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Chizhmakov, I., Kulyk, V., Khasabova, I. et al. Molecular mechanism for opioid dichotomy: bidirectional effect of μ-opioid receptors on P2X3 receptor currents in rat sensory neurones. Purinergic Signalling 11, 171–181 (2015). https://doi.org/10.1007/s11302-015-9443-x

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