The Korean Journal of Physiology and Pharmacology

The Korean Society of Pharmacology (대한약리학회)
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Oxytocin produces thermal analgesia via vasopressin-1a receptor by modulating TRPV1 and potassium conductance in the dorsal root ganglion neurons

  • Han, Rafael Taeho (Neuroscience Research Institute and Department of Physiology, Korea University College of Medicine) ;
  • Kim, Han-Byul (Department of Brain and Cognitive Sciences, College of Natural Sciences, Seoul National University) ;
  • Kim, Young-Beom (Neuroscience Research Institute and Department of Physiology, Korea University College of Medicine) ;
  • Choi, Kyungmin (Neuroscience Research Institute and Department of Physiology, Korea University College of Medicine) ;
  • Park, Gi Yeon (Dental Research Institute and Department of Neurobiology & Physiology, School of Dentistry, Seoul National University) ;
  • Lee, Pa Reum (Department of Brain and Cognitive Sciences, College of Natural Sciences, Seoul National University) ;
  • Lee, JaeHee (Neuroscience Research Institute and Department of Physiology, Korea University College of Medicine) ;
  • Kim, Hye young (Neuroscience Research Institute and Department of Physiology, Korea University College of Medicine) ;
  • Park, Chul-Kyu (Department of Physiology, College of Medicine, Gachon University) ;
  • Kang, Youngnam (Department of Neuroscience and Oral Physiology, Osaka University Graduate School of Dentistry) ;
  • Oh, Seog Bae (Department of Brain and Cognitive Sciences, College of Natural Sciences, Seoul National University) ;
  • Na, Heung Sik (Neuroscience Research Institute and Department of Physiology, Korea University College of Medicine)
  • Received : 2017.09.29
  • Accepted : 2018.01.08
  • Published : 2018.03.01
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Abstract

Recent studies have provided several lines of evidence that peripheral administration of oxytocin induces analgesia in human and rodents. However, the exact underlying mechanism of analgesia still remains elusive. In the present study, we aimed to identify which receptor could mediate the analgesic effect of intraperitoneal injection of oxytocin and its cellular mechanisms in thermal pain behavior. We found that oxytocin-induced analgesia could be reversed by $d(CH_2)_5[Tyr(Me)^2,Dab^5]$ AVP, a vasopressin-1a (V1a) receptor antagonist, but not by $desGly-NH_2-d(CH_2)_5[D-Tyr^2,Thr^4]OVT$, an oxytocin receptor antagonist. Single cell RT-PCR analysis revealed that V1a receptor, compared to oxytocin, vasopressin-1b and vasopressin-2 receptors, was more profoundly expressed in dorsal root ganglion (DRG) neurons and the expression of V1a receptor was predominant in transient receptor potential vanilloid 1 (TRPV1)-expressing DRG neurons. Fura-2 based calcium imaging experiments showed that capsaicin-induced calcium transient was significantly inhibited by oxytocin and that such inhibition was reversed by V1a receptor antagonist. Additionally, whole cell patch clamp recording demonstrated that oxytocin significantly increased potassium conductance via V1a receptor in DRG neurons. Taken together, our findings suggest that analgesic effects produced by peripheral administration of oxytocin were attributable to the activation of V1a receptor, resulting in reduction of TRPV1 activity and enhancement of potassium conductance in DRG neurons.

Keywords

References

  1. Vrachnis N, Malamas FM, Sifakis S, Deligeoroglou E, Iliodromiti Z. The oxytocin-oxytocin receptor system and its antagonists as tocolytic agents. Int J Endocrinol. 2011;2011:350546.
  2. Gonzalez-Hernandez A, Rojas-Piloni G, Condes-Lara M. Oxytocin and analgesia: future trends. Trends Pharmacol Sci. 2014;35:549-551. https://doi.org/10.1016/j.tips.2014.09.004
  3. Yang J. Intrathecal administration of oxytocin induces analgesia in low back pain involving the endogenous opiate peptide system. Spine (Phila Pa 1976). 1994;19:867-871. https://doi.org/10.1097/00007632-199404150-00001
  4. Louvel D, Delvaux M, Felez A, Fioramonti J, Bueno L, Lazorthes Y, Frexinos J. Oxytocin increases thresholds of colonic visceral perception in patients with irritable bowel syndrome. Gut. 1996;39:741-747. https://doi.org/10.1136/gut.39.5.741
  5. Lundeberg T, Uvnas-Moberg K, Agren G, Bruzelius G. Anti-nociceptive effects of oxytocin in rats and mice. Neurosci Lett. 1994; 170:153-157. https://doi.org/10.1016/0304-3940(94)90262-3
  6. Kang YS, Park JH. Brain uptake and the analgesic effect of oxytocin-its usefulness as an analgesic agent. Arch Pharm Res. 2000;23:391-395. https://doi.org/10.1007/BF02975453
  7. Juif PE, Poisbeau P. Neurohormonal effects of oxytocin and vasopressin receptor agonists on spinal pain processing in male rats. Pain. 2013;154:1449-1456. https://doi.org/10.1016/j.pain.2013.05.003
  8. Breton JD, Veinante P, Uhl-Bronner S, Vergnano AM, Freund-Mercier MJ, Schlichter R, Poisbeau P. Oxytocin-induced antinociception in the spinal cord is mediated by a subpopulation of glutamatergic neurons in lamina I-II which amplify GABAergic inhibition. Mol Pain. 2008;4:19.
  9. Breton JD, Poisbeau P, Darbon P. Antinociceptive action of oxytocin involves inhibition of potassium channel currents in lamina II neurons of the rat spinal cord. Mol Pain. 2009;5:63.
  10. Wrobel L, Schorscher-Petcu A, Dupre A, Yoshida M, Nishimori K, Tribollet E. Distribution and identity of neurons expressing the oxytocin receptor in the mouse spinal cord. Neurosci Lett. 2011;495:49-54. https://doi.org/10.1016/j.neulet.2011.03.033
  11. Schorscher-Petcu A1, Sotocinal S, Ciura S, Dupre A, Ritchie J, Sorge RE, Crawley JN, Hu SB, Nishimori K, Young LJ, Tribollet E, Quirion R, Mogil JS. Oxytocin-induced analgesia and scratching are mediated by the vasopressin-1A receptor in the mouse. J Neurosci. 2010; 30:8274-8284. https://doi.org/10.1523/JNEUROSCI.1594-10.2010
  12. Hobo S, Hayashida K, Eisenach JC. Oxytocin inhibits the membrane depolarization-induced increase in intracellular calcium in capsaicin sensitive sensory neurons: a peripheral mechanism of analgesic action. Anesth Analg. 2012;114:442-449. https://doi.org/10.1213/ANE.0b013e31823b1bc8
  13. Qiu F, Qiu CY, Cai H, Liu TT, Qu ZW, Yang Z, Li JD, Zhou QY, Hu WP. Oxytocin inhibits the activity of acid-sensing ion channels through the vasopressin, V1A receptor in primary sensory neurons. Br J Pharmacol . 2014;171:3065-3076. https://doi.org/10.1111/bph.12635
  14. Hargreaves K, Dubner R, Brown F, Flores C, Joris J. A new and sensitive method for measuring thermal nociception in cutaneous hyperalgesia. Pain. 1988;32:77-88. https://doi.org/10.1016/0304-3959(88)90026-7
  15. Han RT, Lee H, Lee J, Lee SB, Kim HJ, Back SK, Na HS. Brief isolation changes nociceptive behaviors and compromises drug tests in mice. Pain Pract. 2016;16:749-757. https://doi.org/10.1111/papr.12325
  16. Kim YH, Park CK, Back SK, Lee CJ, Hwang SJ, Bae YC, Na HS, Kim JS, Jung SJ, Oh SB. Membrane-delimited coupling of TRPV1 and mGluR5 on presynaptic terminals of nociceptive neurons. J Neurosci. 2009;29:10000-10009. https://doi.org/10.1523/JNEUROSCI.5030-08.2009
  17. Kim YB, Kim YS, Kim WB, Shen FY, Lee SW, Chung HJ, Kim JS, Han HC, Colwell CS, Kim YI. GABAergic excitation of vasopressin neurons: possible mechanism underlying sodium-dependent hypertension. Circ Res. 2013;113:1296-1307. https://doi.org/10.1161/CIRCRESAHA.113.301814
  18. Achilles K, Okabe A, Ikeda M, Shimizu-Okabe C, Yamada J, Fukuda A, Luhmann HJ, Kilb W. Kinetic properties of Cl uptake mediated by $Na^+$-dependent $K^+$-$2Cl^{-}$ cotransport in immature rat neocortical neurons. J Neurosci. 2007;27:8616-8627. https://doi.org/10.1523/JNEUROSCI.5041-06.2007
  19. Diaz D, Bartolo R, Delgadillo DM, Higueldo F, Gomora JC. Contrasting effects of $Cd^{2+}$ and $Co^{2+}$ on the blocking/unblocking of human $Cav_3$ channels. J Membr Biol. 2005;207:91-105. https://doi.org/10.1007/s00232-005-0804-1
  20. Mandadi S, Numazaki M, Tominaga M, Bhat MB, Armati PJ, Roufogalis BD. Activation of protein kinase C reverses capsaicininduced calcium-dependent desensitization of TRPV1 ion channels. Cell Calcium. 2004;35:471-478. https://doi.org/10.1016/j.ceca.2003.11.003
  21. Caterina MJ, Leffler A, Malmberg AB, Martin WJ, Trafton J, Petersen-Zeitz KR, Koltzenburg M, Basbaum AI, Julius D. Impaired nociception and pain sensation in mice lacking the capsaicin receptor. Science. 2000;288:306-313. https://doi.org/10.1126/science.288.5464.306
  22. Manning M, Stoev S, Cheng LL, Wo NC, Chan WY. Design of oxytocin antagonists, which are more selective than atosiban. J Pept Sci. 2001;7:449-465. https://doi.org/10.1002/psc.339
  23. Eliava M, Melchior M, Knobloch-Bollmann HS, Wahis J, da Silva Gouveia M, Tang Y, Ciobanu AC, Triana Del Rio R, Roth LC, Althammer F, Chavant V, Goumon Y, Gruber T, Petit-Demouliere N, Busnelli M, Chini B, Tan LL, Mitre M, Froemke RC, Chao MV, Giese G, Sprengel R, Kuner R, Poisbeau P, Seeburg PH, Stoop R, Charlet A, Grinevich V. A new population of parvocellular oxytocin neurons controlling magnocellular neuron activity and inflammatory pain processing. Neuron. 2016;89:1291-1304. https://doi.org/10.1016/j.neuron.2016.01.041
  24. Chini B, Manning M. Agonist selectivity in the oxytocin/vasopressin receptor family: new insights and challenges. Biochem Soc Trans. 2007;35:737-741. https://doi.org/10.1042/BST0350737
  25. Dubin AE, Patapoutian A. Nociceptors: the sensors of the pain pathway. J Clin Invest. 2010;120:3760-3772. https://doi.org/10.1172/JCI42843
  26. Tan CH, McNaughton PA. The TRPM2 ion channel is required for sensitivity to warmth. Nature. 2016;536:460-463. https://doi.org/10.1038/nature19074
  27. Gonzalez-Hernandez A, Manzano-Garcia A, Martinez-Lorenzana G, Tello-Garcia IA, Carranza M, Aramburo C, Condes-Lara M. Peripheral oxytocin receptors inhibit the nociceptive input signal to spinal dorsal horn wide-dynamic-range neurons. Pain. 2017; 158:2117-2128. https://doi.org/10.1097/j.pain.0000000000001024
  28. Zhang H, Cang CL, Kawasaki Y, Liang LL, Zhang YQ, Ji RR, Zhao ZQ. Neurokinin-1 receptor enhances TRPV1 activity in primary sensory neurons via PKCepsilon: a novel pathway for heat hyperalgesia. J Neurosci. 2007;27:12067-12077. https://doi.org/10.1523/JNEUROSCI.0496-07.2007
  29. Moriyama T, Higashi T, Togashi K, Iida T, Segi E, Sugimoto Y, Tominaga T, Narumiya S, Tominaga M. Sensitization of TRPV1 by EP1 and IP reveals peripheral nociceptive mechanism of prostaglandins. Mol Pain. 2005;1:3.
  30. Premkumar LS, Ahern GP. Induction of vanilloid receptor channel activity by protein kinase C. Nature. 2000;408:985-990. https://doi.org/10.1038/35050121
  31. Bang S, Yoo S, Yang TJ, Cho H, Kim YG, Hwang SW. Resolvin D1 attenuates activation of sensory transient receptor potential channels leading to multiple anti-nociception. Br J Pharmacol. 2010; 161:707-720. https://doi.org/10.1111/j.1476-5381.2010.00909.x
  32. Caires R, Luis E, Taberner FJ, Fernandez-Ballester G, Ferrer-Montiel A, Balazs EA, Gomis A, Belmonte C, de la Pena E. Hyaluronan modulates TRPV1 channel opening, reducing peripheral nociceptor activity and pain. Nat Commun. 2015;6:8095. https://doi.org/10.1038/ncomms9095
  33. Neves SR, Ram PT, Iyengar R. G protein pathways. Science. 2002; 296:1636-1639. https://doi.org/10.1126/science.1071550
  34. Terrillon S, Barberis C, Bouvier M. Heterodimerization of V1a and V2 vasopressin receptors determines the interaction with betaarrestin and their trafficking patterns. Proc Natl Acad Sci U S A. 2004;101:1548-1553. https://doi.org/10.1073/pnas.0305322101
  35. Por ED, Bierbower SM, Berg KA, Gomez R, Akopian AN, Wetsel WC, Jeske NA. $\beta$-Arrestin-2 desensitizes the transient receptor potential vanilloid 1 (TRPV1) channel. J Biol Chem. 2012;287:37552-37563. https://doi.org/10.1074/jbc.M112.391847
  36. Gurevich VV. Arrestins-pharmacology and therapeutic potential. Heidelberg: Springer; 2014.
  37. Everill B, Rizzo MA, Kocsis JD. Morphologically identified cutaneous afferent DRG neurons express three different potassium currents in varying proportions. J Neurophysiol. 1998;79:1814-1824. https://doi.org/10.1152/jn.1998.79.4.1814
  38. Gold MS, Shuster MJ, Levine JD. Characterization of six voltagegated $K^+$ currents in adult rat sensory neurons. J Neurophysiol. 1996;75:2629-2646. https://doi.org/10.1152/jn.1996.75.6.2629
  39. Du X, Gamper N. Potassium channels in peripheral pain pathways: expression, function and therapeutic potential. Curr Neuropharmacol. 2013;11:621-640. https://doi.org/10.2174/1570159X113119990042
  40. Tsantoulas C, McMahon SB. Opening paths to novel analgesics: the role of potassium channels in chronic pain. Trends Neurosci. 2014;37:146-158. https://doi.org/10.1016/j.tins.2013.12.002
  41. Duan KZ, Xu Q, Zhang XM, Zhao ZQ, Mei YA, Zhang YQ. Targeting A-type $K^+$ channels in primary sensory neurons for bone cancer pain in a rat model. Pain. 2012;153:562-574. https://doi.org/10.1016/j.pain.2011.11.020

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