Advertisement

Journal of Molecular Neuroscience

, Volume 68, Issue 1, pp 19–28 | Cite as

MicroRNA-211-5p Enhances Analgesic Effect of Dexmedetomidine on Inflammatory Visceral Pain in Rats by Suppressing ERK Signaling

  • Li Sun
  • Jinjun Zhou
  • Chaohui SunEmail author
Article
  • 64 Downloads

Abstract

Dexmedetomidine (DEX) is a high-selectivity α2 adrenergic receptor agonist. The present study aimed to characterize the analgesic effects of DEX on TNBS-induced chronic inflammatory visceral pain (CIVP) in rats and to evaluate whether its antinociceptive effect is regulated by microRNAs (miRNAs) and the ERK pathway. TNBS with or without DEX was administered to 60 male Sprague-Dawley rats. These rats were randomly classified into four groups: control, TNBS, vehicle, and DEX groups. Pain behaviors were assessed by the abdominal withdrawal reflex (AWR), thermal withdrawal latency (TWL), and mechanical withdrawal threshold (MWT). qPCR, ELISA, and western blotting results showed increased serum IL-1β, TNF-α, and IL-6 levels. RNA microarray and qPCR results indicated that miR-211 was downregulated by CIVP induction but upregulated by DEX administration. ERK signaling was decreased in the TNBS+miR-211 group and increased in the DEX + miR-211 group, indicating that miR-211 targeted the 3′-UTR of the ERK gene. Moreover, ectopic expression of miR-211 in these two groups ameliorated pain behaviors and reduced proinflammatory cytokine production. Therefore, DEX exhibited an analgesic effect on CIVP in rats through a miR-211-mediated MEK/ERK/CREB pathway, suppressing visceral hypersensitivity.

Keywords

Dexmedetomidine Chronic inflammatory visceral pain Inflammation MEK/ERK/CREB signal pathway 

Notes

Funding information

This work was supported by Beijing Science and Technology Commission Fund [Z171100000417035].

Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no conflict of interest.

References

  1. Al-Chaer ED, Kawasaki M, Pasricha PJ (2000) A new model of chronic visceral hypersensitivity in adult rats induced by colon irritation during postnatal development. Gastroenterology 119(5):1276–1285CrossRefGoogle Scholar
  2. Cervero F, Laird JM (1999) Visceral pain. Lancet 353(9170):2145–2148CrossRefGoogle Scholar
  3. Chaplan SR, Bach FW, Pogrel JW, Chung JM, Yaksh TL (1994) Quantitative assessment of tactile allodynia in the rat paw. J Neurosci Methods 53(1):55–63CrossRefGoogle Scholar
  4. Clarke KW, Hall LW (1969) “Xylazine”—a new sedative for horses and cattle. Vet Rec 85(19):512–517CrossRefGoogle Scholar
  5. Davis MP (2012) Drug management of visceral pain: concepts from basic research. Pain Res Treat 2012:265605Google Scholar
  6. Elvan EG, Oc B, Uzun S, Karabulut E, Coskun F, Aypar U (2008) Dexmedetomidine and postoperative shivering in patients undergoing elective abdominal hysterectomy. Eur J Anaesthesiol 25(5):357–364CrossRefGoogle Scholar
  7. Galan A, Cervero F, Laird JM (2003) Extracellular signaling-regulated kinase-1 and -2 (ERK 1/2) mediate referred hyperalgesia in a murine model of visceral pain. Brain Res Mol Brain Res 116(1–2):126–134CrossRefGoogle Scholar
  8. Hargreaves K, Dubner R, Brown F, Flores C, Joris J (1988) A new and sensitive method for measuring thermal nociception in cutaneous hyperalgesia. Pain 32(1):77–88CrossRefGoogle Scholar
  9. Hu XD, Liu YN, Zhang ZY, Ma ZA, Suo ZW, Yang X (2015) Spinophilin-targeted protein phosphatase-1 alleviated inflammatory pain by negative control of MEK/ERK signaling in spinal cord dorsal horn of rats. J Neurosci 35(41):13989–14001CrossRefGoogle Scholar
  10. Huang R, Zhao J, Wu L, Dou C, Liu H, Weng Z et al (2014) Mechanisms underlying the analgesic effect of moxibustion on visceral pain in irritable bowel syndrome: a review. Evid Based Complement Alternat Med 2014:895914Google Scholar
  11. Ji RR, Baba H, Brenner GJ, Woolf CJ (1999) Nociceptive-specific activation of ERK in spinal neurons contributes to pain hypersensitivity. Nat Neurosci 2(12):1114–1119CrossRefGoogle Scholar
  12. Ji RR, Befort K, Brenner GJ, Woolf CJ (2002) ERK MAP kinase activation in superficial spinal cord neurons induces prodynorphin and NK-1 upregulation and contributes to persistent inflammatory pain hypersensitivity. J Neurosci 22(2):478–485CrossRefGoogle Scholar
  13. Karim F, Wang CC, Gereau RWt (2001) Metabotropic glutamate receptor subtypes 1 and 5 are activators of extracellular signal-regulated kinase signaling required for inflammatory pain in mice. J Neurosci 21(11):3771–3779CrossRefGoogle Scholar
  14. Kim Y, Kwon SY, Jung HS, Park YJ, Kim YS, In JH, Choi JW, Kim JA, Joo JD (2019) Amitriptyline inhibits MAPK/ERK, CREB pathway and proinflammatory cytokines through A3AR activation in rat neuropathic pain models. Korean J Anesthesiol 72(1):60–67Google Scholar
  15. Kwiecien JM, Jarosz B, Urdzikova LM, Rola R, Dabrowski W (2015) Subdural infusion of dexamethasone inhibits leukomyelitis after acute spinal cord injury in a rat model. Folia Neuropathol 53(1):41–51CrossRefGoogle Scholar
  16. Lai HH, Qiu CS, Crock LW, Morales ME, Ness TJ, Gereau RWt, Gereau RWt (2011) Activation of spinal extracellular signal-regulated kinases (ERK) 1/2 is associated with the development of visceral hyperalgesia of the bladder. Pain 152(9):2117–2124CrossRefGoogle Scholar
  17. Li ZY, Huang Y, Yang YT, Zhang D, Zhao Y, Hong J, Liu J, Wu LJ, Zhang CH, Wu HG, Zhang J, Ma XP (2017) Moxibustion eases chronic inflammatory visceral pain through regulating MEK, ERK and CREB in rats. World J Gastroenterol 23(34):6220–6230CrossRefGoogle Scholar
  18. Lin J-P, Chen C-Q, Huang L-E, Li N-N, Yang Y, Zhu S-M, Yao YX (2018) Dexmedetomidine attenuates neuropathic pain by inhibiting P2X7R expression and ERK phosphorylation in rats. Exp Neurobiol 27(4):267–276CrossRefGoogle Scholar
  19. Liu Y, Liu W, Wang X, Wan Z, Liu Y, Leng Y (2018) Dexmedetomidine relieves acute inflammatory visceral pain in rats through the ERK pathway, toll-like receptor signaling, and TRPV1 channel. J Mol Neurosci 66(2):279–290CrossRefGoogle Scholar
  20. Million M, Wang L, Wang Y, Adelson DW, Yuan PQ, Maillot C, Coutinho SV, Mcroberts JA, Bayati A, Mattsson H, Wu V, Wei JY, Rivier J, Vale W, Mayer EA, Taché Y (2006) CRF2 receptor activation prevents colorectal distension induced visceral pain and spinal ERK1/2 phosphorylation in rats. Gut 55(2):172–181CrossRefGoogle Scholar
  21. Nag S, Mokha SS (2014) Activation of a Gq-coupled membrane estrogen receptor rapidly attenuates α2-adrenoceptor-induced antinociception via an ERK I/II-dependent, non-genomic mechanism in the female rat. Neuroscience 267:122–134CrossRefGoogle Scholar
  22. Pereira Do Carmo G, Stevenson GW, Carlezon WA, Negus SS (2009) Effects of pain- and analgesia-related manipulations on intracranial self-stimulation in rats: further studies on pain-depressed behavior. Pain 144(1–2):170–177CrossRefGoogle Scholar
  23. Sakurai J, Obata K, Ozaki N, Tokunaga A, Kobayashi K, Yamanaka H, Dai Y, Kondo T, Miyoshi K, Sugiura Y, Matsumoto T, Miwa H, Noguchi K (2008) Activation of extracellular signal-regulated protein kinase in sensory neurons after noxious gastric distention and its involvement in acute visceral pain in rats. Gastroenterology 134(4):1094–1103CrossRefGoogle Scholar
  24. Sato N, Kamino K, Tateishi K, Satoh T, Nishiwaki Y, Yoshiiwa A, Miki T, Ogihara T (1997) Elevated amyloid beta protein(1-40) level induces CREB phosphorylation at serine-133 via p44/42 MAP kinase (Erk1/2)-dependent pathway in rat pheochromocytoma PC12 cells. Biochem Biophys Res Commun 232(3):637–642CrossRefGoogle Scholar
  25. Song XS, Cao JL, Xu YB, He JH, Zhang LC, Zeng YM (2005) Activation of ERK/CREB pathway in spinal cord contributes to chronic constrictive injury-induced neuropathic pain in rats. Acta Pharmacol Sin 26(7):789–798CrossRefGoogle Scholar
  26. Stirling DP, Koochesfahani KM, Steeves JD, Tetzlaff W (2005) Minocycline as a neuroprotective agent. Neuroscientist 11(4):308–322CrossRefGoogle Scholar
  27. Tu L, Chen J, Xu D, Xie Z, Yu B, Tao Y, Shi G, Duan L (2017) IL-33-induced alternatively activated macrophage attenuates the development of TNBS-induced colitis. Oncotarget 8(17):27704–27714CrossRefGoogle Scholar
  28. Tufanogullari B, White PF, Peixoto MP, Kianpour D, Lacour T, Griffin J, Skrivanek G, Macaluso A, Shah M, Provost DA (2008) Dexmedetomidine infusion during laparoscopic bariatric surgery: the effect on recovery outcome variables. Anesth Analg 106(6):1741–1748CrossRefGoogle Scholar
  29. Wang B, Liu S, Fan B, Xu X, Chen Y, Lu R, Xu Z, Liu X (2018) PKM2 is involved in neuropathic pain by regulating ERK and STAT3 activation in rat spinal cord. J Headache Pain 19(1):7CrossRefGoogle Scholar
  30. Whyte E, Lauder G (2012) Intrathecal infusion of bupivacaine and clonidine provides effective analgesia in a terminally ill child. Paediatr Anaesth 22(2):173–175CrossRefGoogle Scholar
  31. Xu Y, Wang X, Zhang Z, Suo Z, Yang X, Hu X (2015) Noradrenergic α2 receptor attenuated inflammatory pain through STEP 61/ERK signalling. Eur J Pain 19(9):1298–1307CrossRefGoogle Scholar
  32. Yang J, Chen L, Yang J, Ding J, Li S, Wu H, Zhang J, Fan Z, Dong W, Li X (2014) MicroRNA-22 targeting CBP protects against myocardial ischemia-reperfusion injury through anti-apoptosis in rats. Mol Biol Rep 41(1):555–561CrossRefGoogle Scholar
  33. Yang F, Sun W, Yang Y, Wang Y, Li CL, Fu H, Wang XL, Yang F, He T, Chen J (2015) SDF1-CXCR4 signaling contributes to persistent pain and hypersensitivity via regulating excitability of primary nociceptive neurons: involvement of ERK-dependent Nav1.8 up-regulation. J Neuroinflammation 12:219CrossRefGoogle Scholar
  34. Yu CG, Yezierski RP (2005) Activation of the ERK1/2 signaling cascade by excitotoxic spinal cord injury. Brain Res Mol Brain Res 138(2):244–255CrossRefGoogle Scholar
  35. Zhang YB, Guo ZD, Li MY, Fong P, Zhang JG, Zhang CW, Gong KR, Yang MF, Niu JZ, Ji XM, Lv GW (2015) Gabapentin effects on PKC-ERK1/2 signaling in the spinal cord of rats with formalin-induced visceral inflammatory pain. PLoS One 10(10):e0141142CrossRefGoogle Scholar
  36. Zhang H, Yan X, Wang DG, Leng YF, Wan ZH, Liu YQ, Zhang Y (2017) Dexmedetomidine relieves formaldehyde-induced pain in rats through both alpha2 adrenoceptor and imidazoline receptor. Biomed Pharmacother 90:914–920CrossRefGoogle Scholar
  37. Zhou Q, Price DD, Caudle RM, Verne GN (2008) Visceral and somatic hypersensitivity in TNBS-induced colitis in rats. Dig Dis Sci 53(2):429–435CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of AnesthesiologyThe Seventh Medical Center of PLA General HospitalBeijingChina
  2. 2.Department of AnesthesiologyEzhou Women and Children Health HospitalEzhouChina
  3. 3.Department of AnesthesiologyAffiliated Huxi Hospital of Jining Medical College, Shanxian Central HospitalHezeChina

Personalised recommendations