Українська Русский English

ISSN 2522-9028 (Print)
ISSN 2522-9036 (Online)
DOI: https://doi.org/10.15407/fz

Fiziologichnyi Zhurnal

is a scientific journal issued by the

Bogomoletz Institute of Physiology
National Academy of Sciences of Ukraine

Editor-in-chief: V.F. Sagach

The journal was founded in 1955 as
1955 – 1977 "Fiziolohichnyi zhurnal" (ISSN 0015 – 3311)
1978 – 1993 "Fiziologicheskii zhurnal" (ISSN 0201 – 8489)
1994 – 2016 "Fiziolohichnyi zhurnal" (ISSN 0201 – 8489)
2017 – "Fiziolohichnyi zhurnal" (ISSN 2522-9028)

Fiziol. Zh. 2015; 61(4): 22-29


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

  1. 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
  2.  
  3. 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  
  4. 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  
  5. 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
  6.  
  7. Thayer SA, Perney TM, Miller RJ. Regulation of calcium homeostasis in sensory neurons by bradykinin. J Neurosci. 1988; 8(11):4089-97.
  8.  
  9. 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.
  10.  
  11. 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  
  12. Stein C, Lang LJ. Peripheral mechanisms of opioid analgesia. Curr Opin Pharmacol. 2009; 9(1): 3-8. CrossRef PubMed
  13.  
  14. 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
  15.  
  16. Sverdlov Y. Modern pain problem. Medical scientific and educational - metodical journal. 2001; 1(3) : 31-40.
  17.  
  18. 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.
  19.  
  20. 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
  21.  
  22. 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.
  23.  
  24. 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
  25.  
  26. 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
  27.  
  28. 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
  29.  
  30. 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
  31.  
  32. 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  
  33. Rebecchi MJ, Pentyala SN. Structure, function, and control of phosphoinositide-specific phospholipase C. Physiol Rev. 2000; 80(4):1291-1335.
  34.  
  35. 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.
  36.  
  37. Delmas P, Crest M, Brown DA. Functional organization of PLC signaling microdomains in neurons. Trends Neurosci. 2004; 27(3):41-47. CrossRef PubMed
  38.  
  39. 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
  40.  
  41. 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
  42.  
  43. 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

© National Academy of Sciences of Ukraine, Bogomoletz Institute of Physiology, 2014-2019.