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

Purinergic Signalling

Sergey Khasabov¹  Igor Chizhmakov⁴  Vyacheslav Kulyk⁴  Donald Simone¹  Alexei Verkhratsky²  Georgy Bakalkin³  Iryna Khasabova¹  Dmitri Gordienko⁴  Oleg Krishtal⁴ 

[1] University of Minnesota$$;The University of Manchester$$;Uppsala University$$;Bogomoletz Institute of Physiology$$

关键词: Leu-enkephalin;   

DOI  :  10.1007/s11302-015-9443-x

学科分类：分子生物学，细胞生物学和基因

来源: Springer

【 摘 要 】

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.

【 授权许可】

Unknown