Molecular mechanism for opioid dichotomy : bidirectional effect of mu-opioid receptors on P2X(3) receptor currents in rat sensory neurones

• 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.

Ämnesord

MEDICIN OCH HÄLSOVETENSKAP  -- Medicinska och farmaceutiska grundvetenskaper -- Farmaceutiska vetenskaper (hsv//swe)

MEDICAL AND HEALTH SCIENCES  -- Basic Medicine -- Pharmaceutical Sciences (hsv//eng)

Nyckelord

Pain

Sensory neurones

Nociceptive neurones

P2X(3) receptors

Opioid receptors

Leu-enkephalin

Publikations- och innehållstyp

ref (ämneskategori)

art (ämneskategori)