Hostname: page-component-745bb68f8f-grxwn Total loading time: 0 Render date: 2025-01-14T19:42:42.211Z Has data issue: false hasContentIssue false
  • English
  • Français

Melanocortin 4 Receptor Mediates Neuropathic Pain Through p38MAPK in Spinal Cord

Published online by Cambridge University Press:  02 December 2014

Haichen Chu ,
Jiangling Xia ,
Hongmei Xu ,
Zhao Yang ,
Jie Gao  and
Shihai Liu
Haichen Chu*
Affiliation:
Department of Anesthesiology, Affiliate Hospital of Qingdao University Medical College, Qingdao, Shandong Province, China
Jiangling Xia
Affiliation:
Department of Anesthesiology, Affiliate Hospital of Qingdao University Medical College, Qingdao, Shandong Province, China
Hongmei Xu
Affiliation:
Department of Anesthesiology, Affiliate Hospital of Qingdao University Medical College, Qingdao, Shandong Province, China
Zhao Yang
Affiliation:
Qingdao Institute for Drug Control, Affiliate Hospital of Qingdao University Medical College, Qingdao, Shandong Province, China
Jie Gao
Affiliation:
Department of Anesthesiology, Affiliate Hospital of Qingdao University Medical College, Qingdao, Shandong Province, China
Shihai Liu
Affiliation:
Central Laboratory, Affiliate Hospital of Qingdao University Medical College, Qingdao, Shandong Province, China
*
Department of Anesthesiology, Affiliate Hospital of Qingdao University Medical College, Qingdao 266003, Shandong Province, China. email: haichen0312@yahoo.com.cn
Rights & Permissions [Opens in a new window]

Abstract

Core share and HTML view are not available for this content. However, as you have access to this content, a full PDF is available via the ‘Save PDF’ action button.
Background:

Neuropathic pain is characterised by spontaneous ongoing or shooting pain and evoked amplified pain responses after noxious or non-noxious stimuli. Neuropathic pain develops as a result of lesions or disease affecting the somatosensory nervous system either in the periphery or centrally. Melanocortin 4 receptor (MC4R) plays an important role in the initiation of neuropathic pain but the underlying mechanisms are still unclear.

Methods:

Adult male Wistar rats were given chronic constriction injury (CCI) or sham operations. Part of CCI rats were intrathecally treated with HS014 (MC4R antagonist) or SB203580 (p38MAPK inhibitor). On the third, seventh and fourteenth day, the thermal threshold of operated paws was tested. In addition, the MC4R or phosphorylated p38MAPK (p-p38MAPK) levels of lumbar spinal cord were tested with ELISA (enzyme-linked immunosorbent assay), western blot and immunohistochemistry.

Results:

Here we demonstrate that (1) both HS014 and SB203580 reduced CCI reduced hyperalgesia (2) p-p38MAPK was increased after CCI with a time course parallel to that of the MC4R change, (3) The p38 activation was prevented by blocking MC4R with an antagonist HS014, but MC4R-IR was not prevented by SB203580. (4) MC4R and p-p38MAPK were located in the same cells.

Conclusion:

The mechanisms of neuropathic pain mediated by MC4R is related to the inhibition of p38MAPK activation. P38MAPK may be a downstream of MC4R.

Type
Original Article
Information
Canadian Journal of Neurological Sciences , Volume 39 , Issue 4 , July 2012 , pp. 458 - 464
Copyright
Copyright © The Canadian Journal of Neurological 2012

References

1.Tsuda, M, Mizokashi, A, Shigemoto-Mogami, Y, et a1.Activation of P38 mitogen·activated protein kinase in spinal hyperactive microglia contributes to pain hypersensitivity following peripheral nerve injury. Glia. 2004;45:89–95.CrossRefGoogle ScholarPubMed
2.Starowicz, K, Mousa, SA, Obara1, I, et al.Peripheral antinociceptive effects of MC4receptor antagonists in a rat model of neuropathicpain - a biochemical and behavioral study. J Pharmacol rep. 2009;61:1086–95.CrossRefGoogle Scholar
3.Starowicz, K, Bilecki, W, Sieja, A, Przewlocka, B, Przewlocki, R.Melanocortin 4 receptor is expressed in the dorsal root ganglions and down-regulated in neuropathic rats. Neurosc Lett. 2004;358:79–82.CrossRefGoogle ScholarPubMed
4.Wen, YR, Suter, MR, Ji, RR, et al.Activation of p38 mitogen-activated protein kinase in spinal microglia contributes to incision-induced mechanical allodynia. Anesthesiology. 2009;110:155–65.Google Scholar
5.Milligan, ED, Twining, C, Chacur, M, et al.Spinal glia and proinflammatory cytokines mediate mirror-image neuropathic pain in rats. J Neurosci. 2003;23:1026–40.CrossRefGoogle ScholarPubMed
6.Ji, R, Samad, T, Jin, S, Schmoll, R, Woolf, C.p38 MAPK activation by NGF in primary sensory neurons after inflammation increases TRPV1 levels and maintains heat hyperalgesia. Neuron. 2002;36:57–68.CrossRefGoogle ScholarPubMed
7.Kim, SY, Bae, JC, Kim, JY, et al.Activation of p38 MAP kinase in the rat dorsal root ganglia and spinal cord following peripheral inflammation and nerve injury. Neuroreport. 2002;13:2483–6.CrossRefGoogle ScholarPubMed
8.Jin, SX, Zhuang, ZY, Woolf, CJ, Ji, RR.p3 8 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;23:4017–22.CrossRefGoogle Scholar
9.Obata, K, Yamanaka, H, Kobayashi, K, et al.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;24:10211–22.CrossRefGoogle ScholarPubMed
10.Lim, EJ, Jeon, HJ, Yang, GY, et al.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;31:1322–9.Google Scholar
11.Vongs, A, Lynn, NM, Rosenblum, CI.Activation of MAP kinaseby MC4-R through PI3 kinase. Regul Pept. 2004;120:113–18.CrossRefGoogle Scholar
12.Daniels, D, Patten, CS, Roth, JD, Yee, DK, Fluharty, SJ.Melanocortin receptor signaling through mitogen-activated protein kinase in vitro and in rat hypothalamus. Brain Res. 2003;986:1–911.CrossRefGoogle ScholarPubMed
13.Bennett, GJ, Xie, YK.A peripheral mononeuropathy in rat that produces disorders of pain sensation like those seen in man. Pain. 1998;33:87–107.Google Scholar
14.Yaksh, TL.Chronic catheterisation of the spinal subaraehnoid space. Physiol Behav. 1976;17:1031–6.CrossRefGoogle Scholar
15.Mountjoy, KG, Mortrud, MT, Low, MJ, Simerly, RB, Cone, RD.Localization of the melanocortin-4 receptor (MC4-R) in neuroendocrine and autonomic control circuits in the brain. Mol Endocrino. 1994;l8: 1298–308.Google Scholar
16.Kraan, M, Tatro, JB, Entwistle, ML, et al.Expression of melanocortin receptors and pro-opiomelanocortin in the rat spinal cord in relation to neurotrophic effects of melanocortins. Brain Res Mol Brain Res. 1999;63:276–86.CrossRefGoogle ScholarPubMed
17.Kishi, T, Aschkenasi, CJ, Lee, CE, Mountjoy, KG, Saper, CB, Elmquist, JK.Expression of melanocortin 4 receptor mRNA in the central nervous system of the rat. J Comp Neurol. 2003;457:213–35.CrossRefGoogle ScholarPubMed
18.Spencer, JD, Schallreuter, KU.Regulation of pigmentation in human epidermal melanocytes by functional high affinity-β-melanocyte-stimulating hormone/melanocortin-4 receptor signaling. Endocrinology. 2009;150:1250–8.Google Scholar
19.Tao, YX.The melanocortin-4 receptor: physiology, pharmacology, and pathophysiology. Endocr Rev. 2010;31(4):1–38.CrossRefGoogle ScholarPubMed
20.Selkirk, JV, Nottebaum, LM, Lee, J, Yang, W, Foster, AC, Lechner, SM.Identification of differential melanocortin 4 receptor agonist profiles at natively expressed receptors in rat cortical astrocytes and recombinantly expressed receptors in human embryonic kidney cells. Neuropharmacology. 2007;52:459–66.CrossRefGoogle ScholarPubMed
21.Caruso, C, Durand, D, Schioth, HB, Rey, R, Seilicovich, A, Lasaga, M M.Activation of melanocortin 4 receptors reduces the inflammatory response and prevents apoptosis induced by lipopolysaccharide and interferon in astrocytes. Endocrinology. 2009;148:4918–26.CrossRefGoogle Scholar
22.Kalange, AS, Kokare, DM, Singru, PS, Upadhya, MA, Chopde, CT, Subhedar, NK.Central administration of selective melanocortin 4 receptor antagonist HS014 prevents morphine tolerance and withdrawal hyperalgesia. Brain Res. 2007;1181:10–20.Google Scholar
23.Vrinten, DH, Adan, RA, Groen, Gj, et al.Chronic blockade of melanocotin receptors alleviates allodynia in rats with neuropathic pain. Anesth Analg. 2001;93:1572–7.CrossRefGoogle ScholarPubMed
24.Bertorelli, R, Fredduzzi, S, Tarozzo, G, et al.Endogenous and exogenous melanocortin antagonists induce antiallodynic effects in a model of rat neuropathic pain. Behav Brain Res. 2005;157:55–62.Google Scholar
25.Schafers, M, Svensson, C.I, Sommer, C, Sorkin, LS.Tumor necrosis factor-alpha induces mechanical allodynia after spinal nerve ligation by activation of p38 MAPK in primary sensory neurons. J Neurosci. 2003;23:2517–21.Google Scholar
26.Xu, L, Huang, YG.The influence of p38 mitogen-activated protein kinase inhibitor on synthesis of inflammatory cytokine tumor necrosis factor Alpha in spinal cord of rats with chronic constriction injury. Int Anesth Res Soc. 2007;105(6):1838–44.Google ScholarPubMed
27.Zhang, FE, Cao, JL.Activation of p38 mitogen-activated protein kinase in spinal cord contributes to chronic constriction injury-induced neuropathic pain. Acta Physiologica Sinica. 2005;57(5):545–51.Google ScholarPubMed
28.Lee, KM, Jeon, SM, Cho, HJ.Interleukin-6 induces microglial CX3CR1 expression in the spinal cord after peripheral nerve injury through the activation of p38 MAPK. Euro J Pain. 2010;14(7):682.e1–12.CrossRefGoogle ScholarPubMed
29.Wen, YR, Suter, MR, Kawasaki, Y, et al.Nerve conduction blockade in the sciatic nerve prevents but does not reverse the activation of p38 mitogen-activated protein kinase in spinal microglia in the rat spared nerve injury model. Anesthesiology. 2007;107:312–21.Google Scholar
30.Chai, BX, Li, JY.Melanocortin-4 receptor-mediated inhibition of apoptosis in immortalized hypothalamic neurons via mitogen-activated protein kinase. Peptides. 2006;27:2846–57.CrossRefGoogle ScholarPubMed
31.Chu, HC, Luo, YJ, Sun, XP.Role of melanocortin receptor 4 in excitatory amino acid release from rat astrocytes in spinal cord. Chinese J Anesth. 2010;30(5):569–74.Google Scholar