title: Molecular mechanism for opioid dichotomy: bidirectional effect of μ-opioid receptors on P2X₃ receptor currents in rat sensory neurones.
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.
authors.affiliation: State Key Laboratory for Molecular Biology, Bogomoletz Institute of Physiology, 4 Bogomoletz str., Kiev, 01024, Ukraine.
authors.forename: Igor
authors.initials: I
authors.lastname: Chizhmakov
authors.forename: Vyacheslav
authors.initials: V
authors.lastname: Kulyk
authors.forename: Iryna
authors.initials: I
authors.lastname: Khasabova
authors.forename: Sergey
authors.initials: S
authors.lastname: Khasabov
authors.forename: Donald
authors.initials: D
authors.lastname: Simone
authors.forename: Georgy
authors.initials: G
authors.lastname: Bakalkin
authors.forename: Dmitri
authors.initials: D
authors.lastname: Gordienko
authors.forename: Alexei
authors.initials: A
authors.lastname: Verkhratsky
authors.forename: Oleg
authors.initials: O
authors.lastname: Krishtal
mesh_terms: D000701:Analgesics, Opioid / Q000494:pharmacology; D000818:Animals; D004151:Dipeptides / Q000494:pharmacology; D009270:Naloxone / Q000494:pharmacology; D017208:Rats, Wistar; D017450:Receptors, Opioid, mu / Q000378:metabolism*; D058477:Receptors, Purinergic P2X3 / Q000378:metabolism*; D011984:Sensory Receptor Cells / Q000187:drug effects / Q000378:metabolism*
chemical_list: D000701:Analgesics, Opioid; D004151:Dipeptides; D017450:Receptors, Opioid, mu; D058477:Receptors, Purinergic P2X3; C072331:cysteinyltyrosine; D009270:Naloxone