The Korean Journal of Physiology and Pharmacology

The Korean Society of Pharmacology (대한약리학회)
권호 표지
DOI QR코드

DOI QR Code

Rapamycin reduces orofacial nociceptive responses and microglial p38 mitogen-activated protein kinase phosphorylation in trigeminal nucleus caudalis in mouse orofacial formalin model

  • Yeo, Ji-Hee (Department of Oral Physiology, School of Dentistry, Kyung Hee University) ;
  • Kim, Sol-Ji (Department of Oral Physiology, School of Dentistry, Kyung Hee University) ;
  • Roh, Dae-Hyun (Department of Oral Physiology, School of Dentistry, Kyung Hee University)
  • Received : 2021.02.25
  • Accepted : 2021.05.21
  • Published : 2021.07.01
Download PDF
⟨ Previous Next ⟩

Abstract

The mammalian target of rapamycin (mTOR) plays a role in various cellular phenomena, including autophagy, cell proliferation, and differentiation. Although recent studies have reported its involvement in nociceptive responses in several pain models, whether mTOR is involved in orofacial pain processing is currently unexplored. This study determined whether rapamycin, an mTOR inhibitor, reduces nociceptive responses and the number of Fos-immunoreactive (Fos-ir) cells in the trigeminal nucleus caudalis (TNC) in a mouse orofacial formalin model. We also examined whether the glial cell expression and phosphorylated p38 (p-p38) mitogen-activated protein kinases (MAPKs) in the TNC are affected by rapamycin. Mice were intraperitoneally given rapamycin (0.1, 0.3, or 1.0 mg/kg); then, 30 min after, 5% formalin (10 μl) was subcutaneously injected into the right upper lip. The rubbing responses with the ipsilateral forepaw or hindpaw were counted for 45 min. High-dose rapamycin (1.0 mg/kg) produced significant antinociceptive effects in both the first and second phases of formalin test. The number of Fos-ir cells in the ipsilateral TNC was also reduced by high-dose rapamycin compared with vehicle-treated animals. Furthermore, the number of p-p38-ir cells the in ipsilateral TNC was significantly decreased in animals treated with high-dose rapamycin; p-p38 expression was co-localized in microglia, but not neurons and astrocytes. Therefore, the mTOR inhibitor, rapamycin, reduces orofacial nociception and Fos expression in the TNC, and its antinociceptive action on orofacial pain may be associated with the inhibition of p-p38 MAPK in the microglia.

Keywords

Acknowledgement

This study was supported by the National Research Foundation of Korea (NRF) grants funded by the Korea government (MSIP) (no. NRF-2019R1F1A1063430). This work was also supported by a grant from Kyung Hee University in 2018 (KHU-20181069).

References

  1. Raboisson P, Dallel R. The orofacial formalin test. Neurosci Biobehav Rev. 2004;28:219-226. https://doi.org/10.1016/j.neubiorev.2003.12.003
  2. Miranda HF, Sierralta F, Prieto JC. Synergism between NSAIDs in the orofacial formalin test in mice. Pharmacol Biochem Behav. 2009;92:314-318. https://doi.org/10.1016/j.pbb.2008.12.018
  3. Munoz J, Navarro C, Noriega V, Pinardi G, Sierralta F, Prieto JC, Miranda HF. Synergism between COX-3 inhibitors in two animal models of pain. Inflammopharmacology. 2010;18:65-71. https://doi.org/10.1007/s10787-009-0019-7
  4. Murakami M, Ichisaka T, Maeda M, Oshiro N, Hara K, Edenhofer F, Kiyama H, Yonezawa K, Yamanaka S. mTOR is essential for growth and proliferation in early mouse embryos and embryonic stem cells. Mol Cell Biol. 2004;24:6710-6718. https://doi.org/10.1128/MCB.24.15.6710-6718.2004
  5. Zoncu R, Efeyan A, Sabatini DM. mTOR: from growth signal integration to cancer, diabetes and ageing. Nat Rev Mol Cell Biol. 2011;12:21-35. https://doi.org/10.1038/nrm3025
  6. Altmann C, Hardt S, Fischer C, Heidler J, Lim HY, Haussler A, Albuquerque B, Zimmer B, Moser C, Behrends C, Koentgen F, Wittig I, Schmidt MHH, Clement AM, Deller T, Tegeder I. Progranulin overexpression in sensory neurons attenuates neuropathic pain in mice: role of autophagy. Neurobiol Dis. 2016;96:294-311. https://doi.org/10.1016/j.nbd.2016.09.010
  7. Guertin DA, Sabatini DM. An expanding role for mTOR in cancer. Trends Mol Med. 2005;11:353-361. https://doi.org/10.1016/j.molmed.2005.06.007
  8. Feng T, Yin Q, Weng ZL, Zhang JC, Wang KF, Yuan SY, Cheng W. Rapamycin ameliorates neuropathic pain by activating autophagy and inhibiting interleukin-1β in the rat spinal cord. J Huazhong Univ Sci Technolog Med Sci. 2014;34:830-837. https://doi.org/10.1007/s11596-014-1361-6
  9. Obara I, Medrano MC, Signoret-Genest J, Jimenez-Diaz L, Geranton SM, Hunt SP. Inhibition of the mammalian target of rapamycin complex 1 signaling pathway reduces itch behaviour in mice. Pain. 2015;156:1519-1529. https://doi.org/10.1097/j.pain.0000000000000197
  10. Xu Q, Fitzsimmons B, Steinauer J, O'Neill A, Newton AC, Hua XY, Yaksh TL. Spinal phosphinositide 3-kinase-Akt-mammalian target of rapamycin signaling cascades in inflammation-induced hyperalgesia. J Neurosci. 2011;31:2113-2124. https://doi.org/10.1523/JNEUROSCI.2139-10.2011
  11. Ji RR, Berta T, Nedergaard M. Glia and pain: is chronic pain a gliopathy? Pain. 2013;154 Suppl 1:S10-S28. https://doi.org/10.1016/j.pain.2013.06.022
  12. Kreutzberg GW. Microglia: a sensor for pathological events in the CNS. Trends Neurosci. 1996;19:312-318. https://doi.org/10.1016/0166-2236(96)10049-7
  13. Shinoda M, Hayashi Y, Kubo A, Iwata K. Pathophysiological mechanisms of persistent orofacial pain. J Oral Sci. 2020;62:131-135. https://doi.org/10.2334/josnusd.19-0373
  14. Ji RR, Woolf CJ. Neuronal plasticity and signal transduction in nociceptive neurons: implications for the initiation and maintenance of pathological pain. Neurobiol Dis. 2001;8:1-10. https://doi.org/10.1006/nbdi.2000.0360
  15. Ji RR, Samad TA, Jin SX, Schmoll R, Woolf CJ. p38 MAPK activation by NGF in primary sensory neurons after inflammation increases TRPV1 levels and maintains heat hyperalgesia. Neuron. 2002;36:57-68. https://doi.org/10.1016/S0896-6273(02)00908-X
  16. Sekiguchi A, Kanno H, Ozawa H, Yamaya S, Itoi E. Rapamycin promotes autophagy and reduces neural tissue damage and locomotor impairment after spinal cord injury in mice. J Neurotrauma. 2012; 29:946-956. https://doi.org/10.1089/neu.2011.1919
  17. Tateda S, Kanno H, Ozawa H, Sekiguchi A, Yahata K, Yamaya S, Itoi E. Rapamycin suppresses microglial activation and reduces the development of neuropathic pain after spinal cord injury. J Orthop Res. 2017;35:93-103. https://doi.org/10.1002/jor.23328
  18. Bornhof M, Ihmsen H, Schwilden H, Yeomans DC, Tzabazis A. The orofacial formalin test in mice revisited--effects of formalin concentration, age, morphine and analysis method. J Pain. 2011;12:633-639. https://doi.org/10.1016/j.jpain.2010.11.009
  19. Roh DH, Yoon SY. Sigma-1 receptor antagonist, BD1047 reduces nociceptive responses and phosphorylation of p38 MAPK in mice orofacial formalin model. Biol Pharm Bull. 2014;37:145-151. https://doi.org/10.1248/bpb.b13-00690
  20. Roh DH, Kim HW, Yoon SY, Kang SY, Kwon YB, Cho KH, Han HJ, Ryu YH, Choi SM, Lee HJ, Beitz AJ, Lee JH. Bee venom injection significantly reduces nociceptive behavior in the mouse formalin test via capsaicin-insensitive afferents. J Pain. 2006;7:500-512. https://doi.org/10.1016/j.jpain.2006.02.002
  21. Muller R, Bravo R, Burckhardt J, Curran T. Induction of c-fos gene and protein by growth factors precedes activation of c-myc. Nature. 1984;312:716-720. https://doi.org/10.1038/312716a0
  22. Williams S, Evan GI, Hunt SP. Changing patterns of c-fos induction in spinal neurons following thermal cutaneous stimulation in the rat. Neuroscience. 1990;36:73-81. https://doi.org/10.1016/0306-4522(90)90352-5
  23. Doyle T, Chen Z, Muscoli C, Obeid LM, Salvemini D. Intraplantar-injected ceramide in rats induces hyperalgesia through an NF-κB- and p38 kinase-dependent cyclooxygenase 2/prostaglandin E2 pathway. FASEB J. 2011;25:2782-2791. https://doi.org/10.1096/fj.10-178095
  24. Wang H, Tian J, Du F, Wang T. Effect of peritoneal transport characteristics on clinical outcome in nondiabetic and diabetic nephropathy patients with peritoneal dialysis. Iran J Kidney Dis. 2019;13:56-66.
  25. Choi SR, Beitz AJ, Lee JH. Inhibition of cytochrome P450c17 reduces spinal astrocyte activation in a mouse model of neuropathic pain via regulation of p38 MAPK phosphorylation. Biomed Pharmacother. 2019;118:109299. https://doi.org/10.1016/j.biopha.2019.109299
  26. Shillingford JM, Murcia NS, Larson CH, Low SH, Hedgepeth R, Brown N, Flask CA, Novick AC, Goldfarb DA, Kramer-Zucker A, Walz G, Piontek KB, Germino GG, Weimbs T. The mTOR pathway is regulated by polycystin-1, and its inhibition reverses renal cystogenesis in polycystic kidney disease. Proc Natl Acad Sci U S A. 2006; 103:5466-5471. https://doi.org/10.1073/pnas.0509694103
  27. Obara I, Hunt SP. Axonal protein synthesis and the regulation of primary afferent function. Dev Neurobiol. 2014;74:269-278. https://doi.org/10.1002/dneu.22133
  28. Asante CO, Wallace VC, Dickenson AH. Formalin-induced behavioural hypersensitivity and neuronal hyperexcitability are mediated by rapid protein synthesis at the spinal level. Mol Pain. 2009;5:27. https://doi.org/10.1186/1744-8069-5-27
  29. Geranton SM, Jimenez-Diaz L, Torsney C, Tochiki KK, Stuart SA, Leith JL, Lumb BM, Hunt SP. A rapamycin-sensitive signaling pathway is essential for the full expression of persistent pain states. J Neurosci. 2009;29:15017-15027. https://doi.org/10.1523/JNEUROSCI.3451-09.2009
  30. Ter Horst GJ, Meijler WJ, Korf J, Kemper RH. Trigeminal nociception-induced cerebral Fos expression in the conscious rat. Cephalalgia. 2001;21:963-975. https://doi.org/10.1046/j.1468-2982.2001.00285.x
  31. Mitsikostas DD, Sanchez del Rio M. Receptor systems mediating c-fos expression within trigeminal nucleus caudalis in animal models of migraine. Brain Res Brain Res Rev. 2001;35:20-35. https://doi.org/10.1016/S0165-0173(00)00048-5
  32. Bhatt DK, Gupta S, Ploug KB, Jansen-Olesen I, Olesen J. mRNA distribution of CGRP and its receptor components in the trigemino-vascular system and other pain related structures in rat brain, and effect of intracerebroventricular administration of CGRP on Fos expression in the TNC. Neurosci Lett. 2014;559:99-104. https://doi.org/10.1016/j.neulet.2013.11.057
  33. Beggs S, Salter MW. Stereological and somatotopic analysis of the spinal microglial response to peripheral nerve injury. Brain Behav Immun. 2007;21:624-633. https://doi.org/10.1016/j.bbi.2006.10.017
  34. Romero-Sandoval A, Chai N, Nutile-McMenemy N, Deleo JA. A comparison of spinal Iba1 and GFAP expression in rodent models of acute and chronic pain. Brain Res. 2008;1219:116-126. https://doi.org/10.1016/j.brainres.2008.05.004
  35. Tsuda M, Inoue K, Salter MW. Neuropathic pain and spinal microglia: a big problem from molecules in "small" glia. Trends Neurosci. 2005;28:101-107. https://doi.org/10.1016/j.tins.2004.12.002
  36. Chang YW, Tan A, Saab C, Waxman S. Unilateral focal burn injury is followed by long-lasting bilateral allodynia and neuronal hyperexcitability in spinal cord dorsal horn. J Pain. 2010;11:119-130. https://doi.org/10.1016/j.jpain.2009.06.009
  37. Guo W, Wang H, Watanabe M, Shimizu K, Zou S, LaGraize SC, Wei F, Dubner R, Ren K. Glial-cytokine-neuronal interactions underlying the mechanisms of persistent pain. J Neurosci. 2007;27:6006-6018. https://doi.org/10.1523/JNEUROSCI.0176-07.2007
  38. Piao ZG, Cho IH, Park CK, Hong JP, Choi SY, Lee SJ, Lee S, Park K, Kim JS, Oh SB. Activation of glia and microglial p38 MAPK in medullary dorsal horn contributes to tactile hypersensitivity following trigeminal sensory nerve injury. Pain. 2006;121:219-231. https://doi.org/10.1016/j.pain.2005.12.023
  39. Okada-Ogawa A, Suzuki I, Sessle BJ, Chiang CY, Salter MW, Dostrovsky JO, Tsuboi Y, Kondo M, Kitagawa J, Kobayashi A, Noma N, Imamura Y, Iwata K. Astroglia in medullary dorsal horn (trigeminal spinal subnucleus caudalis) are involved in trigeminal neuropathic pain mechanisms. J Neurosci. 2009;29:11161-11171. https://doi.org/10.1523/jneurosci.3365-09.2009
  40. Clark AK, Gentry C, Bradbury EJ, McMahon SB, Malcangio M. Role of spinal microglia in rat models of peripheral nerve injury and inflammation. Eur J Pain. 2007;11:223-230. https://doi.org/10.1016/j.ejpain.2006.02.003
  41. Fu KY, Light AR, Matsushima GK, Maixner W. Microglial reactions after subcutaneous formalin injection into the rat hind paw. Brain Res. 1999;825:59-67. https://doi.org/10.1016/S0006-8993(99)01186-5
  42. Dello Russo C, Lisi L, Tringali G, Navarra P. Involvement of mTOR kinase in cytokine-dependent microglial activation and cell proliferation. Biochem Pharmacol. 2009;78:1242-1251. https://doi.org/10.1016/j.bcp.2009.06.097
  43. Inyang KE, Szabo-Pardi T, Wentworth E, McDougal TA, Dussor G, Burton MD, Price TJ. The antidiabetic drug metformin prevents and reverses neuropathic pain and spinal cord microglial activation in male but not female mice. Pharmacol Res. 2019;139:1-16. https://doi.org/10.1016/j.phrs.2018.10.027
  44. Tozaki-Saitoh H, Masuda J, Kawada R, Kojima C, Yoneda S, Masuda T, Inoue K, Tsuda M. Transcription factor MafB contributes to the activation of spinal microglia underlying neuropathic pain development. Glia. 2019;67:729-740. https://doi.org/10.1002/glia.23570
  45. Lopes F, Vicentini FA, Cluny NL, Mathews AJ, Lee BH, Almishri WA, Griffin L, Goncalves W, Pinho V, McKay DM, Hirota SA, Swain MG, Pittman QJ, Sharkey KA. Brain TNF drives post-inflammation depression-like behavior and persistent pain in experimental arthritis. Brain Behav Immun. 2020;89:224-232. https://doi.org/10.1016/j.bbi.2020.06.023
  46. Ma W, Quirion R. Partial sciatic nerve ligation induces increase in the phosphorylation of extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK) in astrocytes in the lumbar spinal dorsal horn and the gracile nucleus. Pain. 2002;99:175-184. https://doi.org/10.1016/S0304-3959(02)00097-0
  47. Jin SX, Zhuang ZY, Woolf CJ, Ji RR. p38 mitogen-activated protein kinase is activated after a spinal nerve ligation in spinal cord microglia and dorsal root ganglion neurons and contributes to the generation of neuropathic pain. J Neurosci. 2003;23:4017-4022. https://doi.org/10.1523/jneurosci.23-10-04017.2003
  48. Hains BC, Waxman SG. Activated microglia contribute to the maintenance of chronic pain after spinal cord injury. J Neurosci. 2006;26:4308-4317. https://doi.org/10.1523/JNEUROSCI.0003-06.2006
  49. Wen YR, Suter MR, Ji RR, Yeh GC, Wu YS, Wang KC, Kohno T, Sun WZ, Wang CC. Activation of p38 mitogen-activated protein kinase in spinal microglia contributes to incision-induced mechanical allodynia. Anesthesiology. 2009;110:155-165. https://doi.org/10.1097/ALN.0b013e318190bc16
  50. Gu YW, Su DS, Tian J, Wang XR. Attenuating phosphorylation of p38 MAPK in the activated microglia: a new mechanism for intrathecal lidocaine reversing tactile allodynia following chronic constriction injury in rats. Neurosci Lett. 2008;431:129-134. https://doi.org/10.1016/j.neulet.2007.11.065
  51. Suter MR, Berta T, Gao YJ, Decosterd I, Ji RR. Large A-fiber activity is required for microglial proliferation and p38 MAPK activation in the spinal cord: different effects of resiniferatoxin and bupivacaine on spinal microglial changes after spared nerve injury. Mol Pain. 2009;5:53. https://doi.org/10.1186/1744-8069-5-53
  52. Svensson CI, Marsala M, Westerlund A, Calcutt NA, Campana WM, Freshwater JD, Catalano R, Feng Y, Protter AA, Scott B, Yaksh TL. Activation of p38 mitogen-activated protein kinase in spinal microglia is a critical link in inflammation-induced spinal pain processing. J Neurochem. 2003;86:1534-1544. https://doi.org/10.1046/j.1471-4159.2003.01969.x
  53. Cui XY, Dai Y, Wang SL, Yamanaka H, Kobayashi K, Obata K, Chen J, Noguchi K. Differential activation of p38 and extracellular signal-regulated kinase in spinal cord in a model of bee venom-induced inflammation and hyperalgesia. Mol Pain. 2008;4:17. https://doi.org/10.1186/1744-8069-4-17
  54. Nasseri B, Zaringhalam J, Daniali S, Manaheji H, Abbasnejad Z, Nazemian V. Thymulin treatment attenuates inflammatory pain by modulating spinal cellular and molecular signaling pathways. Int Immunopharmacol. 2019;70:225-234. https://doi.org/10.1016/j.intimp.2019.02.042
  55. Crown ED, Gwak YS, Ye Z, Johnson KM, Hulsebosch CE. Activation of p38 MAP kinase is involved in central neuropathic pain following spinal cord injury. Exp Neurol. 2008;213:257-267. https://doi.org/10.1016/j.expneurol.2008.05.025
  56. Tan YH, Li K, Chen XY, Cao Y, Light AR, Fu KY. Activation of Src family kinases in spinal microglia contributes to formalin-induced persistent pain state through p38 pathway. J Pain. 2012;13:1008-1015. https://doi.org/10.1016/j.jpain.2012.07.010
  57. Kumar S, Boehm J, Lee JC. p38 MAP kinases: key signalling molecules as therapeutic targets for inflammatory diseases. Nat Rev Drug Discov. 2003;2:717-726. https://doi.org/10.1038/nrd1177
  58. Obata K, Yamanaka H, Kobayashi K, Dai Y, Mizushima T, Katsura H, Fukuoka T, Tokunaga A, Noguchi K. Role of mitogen-activated protein kinase activation in injured and intact primary afferent neurons for mechanical and heat hypersensitivity after spinal nerve ligation. J Neurosci. 2004;24:10211-10222. https://doi.org/10.1523/JNEUROSCI.3388-04.2004
  59. Lim EJ, Jeon HJ, Yang GY, Lee MK, Ju JS, Han SR, Ahn DK. Intracisternal administration of mitogen-activated protein kinase inhibitors reduced mechanical allodynia following chronic constriction injury of infraorbital nerve in rats. Prog Neuropsychopharmacol Biol Psychiatry. 2007;31:1322-1329. https://doi.org/10.1016/j.pnpbp.2007.05.016