Molecular mechanism for opioid dichotomy: bidirectional effect of mu-opioid receptors on P2X(3) receptor currents in rat sensory neurones
2015 (English)In: Purinergic Signalling Purinergic Signalling, ISSN 1573-9538, Vol. 11, no 2, 171-181 p.Article in journal (Refereed) Published
Here, we describe a molecular switch associated with opioid receptors-linked signalling cascades that provides a dual opioid control over P2X(3) purinoceptor in sensory neurones. Leu-enkephalin inhibited P2X(3)-mediated currents with IC50 similar to 10 nM in similar to 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 P2X(3) currents. All effects of opioid were abolished by selective mu-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 mu-opioid receptors: the latter exert both inhibitory (pertussis toxin-sensitive) and stimulatory (pertussis toxin-insensitive) actions on P2X(3) receptors through phospholipase C (PLC)-dependent pathways. This dual opioid control of P2X(3) 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.
Place, publisher, year, edition, pages
2015. Vol. 11, no 2, 171-181 p.
Pain, Sensory neurones, Nociceptive neurones, P2X(3) receptors, Opioid receptors, Leu-enkephalin
IdentifiersURN: urn:nbn:se:uu:diva-255060DOI: 10.1007/s11302-015-9443-xISI: 000354198200002PubMedID: 25592684OAI: oai:DiVA.org:uu-255060DiVA: diva2:824785