ROLE PHOSPHOINOSITID SIGNALING PATHWAY IN OPIOIDS CONTROL OF Р2Х3 RECEPTORS IN THE PRIMARY SENSORY NEURONS
V.B.Kulyk, I.V.Chizhmakov, T.M. Volkova, O.P. Maximyuk, O.A.Krishtal
O.O. Bogomoletz Institute of Physiology National Academy
of Sciences of Ukraine, Kyiv
DOI: https://doi.org/10.15407/fz61.04.022

Abstract
Homomeriс P2X3 receptors expressed in primary nociceptive
neurons are crucial elements in the pain signal generation. In
turn, opioid system regulates the intensity of this signal in
both CNS and PNS. Here we describe the effects of opioids on
P2X3 receptors in DRG neurons studied by using patch clamp
technique. Activation of G-protein coupled opioid receptors
by endogenous opioid Leu-enkephalin (Leu), resulted in the
two opposite effects on P2X3 receptor-mediated currents
(P2X3 currents). In particular, application of 1 µM Leu lead
to the complete inhibition of P2X3 currents. However, after
pretreatment of the neurons with a Gi/o‑protein inhibitor
pertussis toxin (PT), the same concentration of Leu caused
facilitation of P2X3 currents. PLC inhibitor U-73122 at concentration
of 1 µM completely eliminated both facilitating
and inhibitory effects of Leu on P2X3 currents. Thus, opioid
receptor agonists cause two oppositely directed effects on
P2X3 receptors in DRG neurons of rats and both of them are
mediated through PLC signaling pathway. Our results point
to a possible molecular basis of the mechanism for the wellknown
transition inhibitory action of opioids (analgesia) to
facilitating (hyperalgesia).
Keywords:
P2X3-receptors; opioid receptors; Leu-enkephalin; phospholipase C; pertussis toxin; G-proteins.
References
- Ueno S, Tsuda M, Iwanaga T, Inoue K. Cell type-specific ATP-activated responses in rat dorsal root ganglion neurons. Br J Pharmacol. 1999;126(2): 429-36.
CrossRef
PubMed PubMedCentral
- Xiang Z, Bo X, Burnstock G. Localization of ATP-gated P2X receptor immunoreactivity in rat sensory and sympathetic ganglia. Neurosci Lett. 1998; 256(2):105-8.
CrossRef
- Steranka LR, Manning DC, DeHaas CJ, Ferkany JW, Borosky SA, Connor JR, Vavrek RJ, Stewart JM, Snyder SH. Bradykinin as a pain mediator: receptors are localized to sensory neurons, and antagonists have analgesic actions. Proc Natl Acad Sci USA. 1998;85(9):3245-9.
CrossRef
- Prado FC, Araldi D, Vieira AS, Oliveira-Fusaro MC, Tambeli CH, Parada CA. Neuronal P2X3 receptor activation is essential to the hyperalgesia induced by prostaglandins and sympathomimetic amines released during inflammation. Neuropharmacology. 2013; 67 (8): 252-8.
CrossRef
PubMed
- Thayer SA, Perney TM, Miller RJ. Regulation of calcium homeostasis in sensory neurons by bradykinin. J Neurosci. 1988; 8(11):4089-97.
- Reichert JA, Daughters RS, Rivard R, Simone DA. Peripheral and preemptive opioid antinociception in a mouse visceral pain model. Pain. 2001;89(2-3): 221-27.
- Shannon HE, Lutz EA. Comparison of the peripheral and central effects of the opioid agonists loperamide and morphine in the formalin test in rats. Neuropharmacology. 2002; 42(2):253-61.
CrossRef
- Stein C, Lang LJ. Peripheral mechanisms of opioid analgesia. Curr Opin Pharmacol. 2009; 9(1): 3-8.
CrossRef
PubMed
- Chizhmakov I, Yudin Y, Mamenko N, Prudnikov I, Tamarova Z, Krishtal O. Opioids inhibit purinergic nociceptors in the sensory neurons and fibres of rat via a G protein-dependent mechanism. Neuropharmacology. 2005; 48(5): 639-47.
CrossRef
PubMed
- Sverdlov Y. Modern pain problem. Medical scientific and educational - metodical journal. 2001; 1(3) : 31-40.
- Crain SM, Shen KF. Antagonists of excitatory opioid receptor functions enhance morphine's analgesic potency and attenuate opioid tolerance/dependence liability. Pain. 2000; 84(2-3):121-31.
- Sharma SK, Klee WA, Nirenberg M. Opiate-dependent modulation of adenylate cyclase. Proc Natl Acad Sci USA. 1977; 74(8): 3365-9.
CrossRef
PubMed PubMedCentral
- Mo G, Bernier LP, Zhao Q, Chabot-Dore AJ, Ase AR, Logothetis D, Cao CQ, Seguela P. Subtypespecific regulation of P2X3 and P2X2/3 receptors by phosphoinositides in peripheral nociceptors. Mol Pain. 2009; 5 (2): 47-56.
- Xie W, Samoriski GM, McLaughlin JP, Romoser VA, Smrcka A, Hinkle PM, Bidlack JM, Gross RA, Jiang H, Wu D. Genetic alteration of phospholipase C beta3 expression modulates behavioral and cellular responses to mu opioids. Proc Natl Acad Sci USA. 1999; 96(18):10385-90.
CrossRef
PubMed PubMedCentral
- Mo G, Peleshok JC, Cao CQ, Ribeiro-da-Silva A, Seguela P. Control of P2X3 channel function by metabotropic P2Y2 utp receptors in primary sensory neurons. Mol Pharmacol. 2013; 83(3):640-47.
CrossRef
PubMed
- Park CK, Bae JH, Kim HY, Jo HJ, Kim YH, Jung SJ, Kim JS. Substance P sensitizes P2X3 in nociceptive trigeminal neurons. J Dent Res. 2010; 89 (5):1154-59.
CrossRef
PubMed
- Paukert M, Osteroth R, Geisler HS, Brandle U, Glowatzki E, Ruppersberg JP, Grunder S. Inflammatory mediators potentiate ATP-gated channels through the P2X(3) subunit. J Biol Chem. 2001;276 (6): 21077-82.
CrossRef
PubMed
- Rubovitch V, Gafni M, Sarne Y. The mu opioid agonist DAMGO stimulates cAMP production in SK-N-SH cells through a PLC-PKC-Ca++ pathway. Brain Res Mol Brain Res. 2003; 110(2): 261-6.
CrossRef
- Rebecchi MJ, Pentyala SN. Structure, function, and control of phosphoinositide-specific phospholipase C. Physiol Rev. 2000; 80(4):1291-1335.
- Brown DA, Yule DI. Protein kinase C regulation of P2X3 receptors is unlikely to involve direct receptor phosphorylation. Biochim Biophys Acta. 2007;173(9):166-75.
- Delmas P, Crest M, Brown DA. Functional organization of PLC signaling microdomains in neurons. Trends Neurosci. 2004; 27(3):41-47.
CrossRef
PubMed
- Fujita A, Chend J, Tauchi–Sato K. A distinct pool of phosphatidylinositol 4,5 – bisphosphate in caveolae revealed by a nanoscale labeling technique. Proc Natl Acad Sci USA. 2009;106(2): 9256-61.
CrossRef
PubMed PubMedCentral
- Newton PM, Kim JA, McGeehan AJ, Paredes JP, Messing RO. Increased response to morphine in mice lacking protein kinase C epsilon. Genes Brain Behav. 2007;6(4):329-38.
CrossRef
PubMed PubMedCentral
- Galeotti N, Stefano GB, Guarna M, Bianchi E, Ghelardini C. Signaling pathway of morphine indused acute thermal hyperalgesia in mice. Pain. 2006;123(3):294 -305.
CrossRef
PubMed
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