ATP-sensitive potassium channels alleviate postoperative pain through JNK-dependent MCP-1 expression in spinal cord

Zhu,Xiang; Liu,Jinqian; Gao,Yongjing; Cao,Su; Shen,Shiren

doi:10.3892/ijmm.2015.2143

ATP-sensitive potassium channels alleviate postoperative pain through JNK-dependent MCP-1 expression in spinal cord

Authors:
- Xiang Zhu
- Jinqian Liu
- Yongjing Gao
- Su Cao
- Shiren Shen
View Affiliations

Affiliations: Department of Anesthesiology, Affiliated Hospital of Nantong University, Nantong, Jiangsu 226001, P.R. China, Department of Anesthesiology, Binzhou Medical University Hospital, Binzhou, Shandong 256603, P.R. China, Institute of Nautical Medicine, Nantong University, Nantong, Jiangsu 226001, P.R. China
Published online on: March 17, 2015 https://doi.org/10.3892/ijmm.2015.2143
Pages: 1257-1265
Copyright: © Zhu et al. This is an open access article distributed under the terms of Creative Commons Attribution License [CC BY_NC 3.0].

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Although adenosine triphosphate-sensitive potassium (KATP) channels have been proven to be involved in regulating postoperative pain, the underlying mechanism remains to be investigated. In this study, we aimed to determine the role of spinal KATP channels in the control of mechanical hypersensitivity in a rat pain model, in which rats were subjected to skin/muscle incision and retraction (SMIR) surgery, as well as in LPS-stimulated astrocytes. The results showed that KATP channel subunits Kir6.1, SUR1 and SUR2 were normally expressed in the spinal cord and significantly downregulated after SMIR. SMIR caused a marked increase in monocyte chemoattractant protein-1 (MCP-1) mRNA expression and in the protein level of p-JNK in the spinal cord. Intrathecal administration of a KATP channel opener pinacidil (Pina) suppressed mechanical allodynia after SMIR and significantly downregulated the MCP-1 mRNA expression and the protein level of p-JNK induced by SMIR. Inverted fluorescence microscopy showed that Kir6.1 was co-localized with astrocytes only and SUR2 was co-localized primarily with neurons, in a small amount with astrocytes. Furthermore, in vitro studies showed that following incubation with LPS, the astrocytic MCP-1 mRNA expression and p-JNK content were markedly increased, whereas the mRNA levels of Kir6.1 and SUR2 were significantly downregulated in astrocytes. KATP channel opener pinacidil inhibited the LPS-triggered MCP-1 and p-JNK elevation in rat primary astrocytes. The results suggested that KATP channel opener treatment is an effective therapy for postoperative pain in animals, through the activation of the JNK/MCP-1 pathway in astrocytes.

View Figures

View References

1	Deumens R, Steyaert A, Forget P, et al: Prevention of chronic postoperative pain: cellular, molecular, and clinical insights for mechanism-based treatment approaches. Progress Neurobiol. 104:1–37. 2013. View Article : Google Scholar
2	Kehlet H, Jensen TS and Woolf CJ: Persistent postsurgical pain: risk factors and prevention. Lancet. 367:1618–1625. 2006. View Article : Google Scholar : PubMed/NCBI
3	Caffo O, Amichetti M, Ferro A, Lucenti A, Valduga F and Galligioni E: Pain and quality of life after surgery for breast cancer. Breast Cancer Res Treat. 80:39–48. 2003. View Article : Google Scholar : PubMed/NCBI
4	Zoga V, Kawano T, Liang MY, et al: KATP channel subunits in rat dorsal root ganglia: alterations by painful axotomy. Mol Pain. 6:62010. View Article : Google Scholar : PubMed/NCBI
5	Wu XF, Liu WT, Liu YP, Huang ZJ, Zhang YK and Song XJ: Reopening of ATP-sensitive potassium channels reduces neuropathic pain and regulates astroglial gap junctions in the rat spinal cord. Pain. 152:2605–2615. 2011. View Article : Google Scholar : PubMed/NCBI
6	Xia H, Zhang D, Yang S, et al: Role of ATP-sensitive potassium channels in modulating nociception in rat model of bone cancer pain. Brain Res. 1554:29–35. 2014. View Article : Google Scholar : PubMed/NCBI
7	Flatters SJ: Characterization of a model of persistent postoperative pain evoked by skin/muscle incision and retraction (SMIR). Pain. 135:119–130. 2008. View Article : Google Scholar
8	Zhang ZJ, Dong YL, Lu Y, Cao S, Zhao ZQ and Gao YJ: Chemokine CCL2 and its receptor CCR2 in the medullary dorsal horn are involved in trigeminal neuropathic pain. J Neuroinflammation. 9:1362012. View Article : Google Scholar : PubMed/NCBI
9	Guo W, Wang H, Zou S, Dubner R and Ren K: Chemokine signaling involving chemokine (CC motif) ligand 2 plays a role in descending pain facilitation. Neurosci Bull. 28:193–207. 2012. View Article : Google Scholar : PubMed/NCBI
10	Covino B, Dubner R, Gybels J, et al: Ethical standards for investigations of experimental pain in animals. Pain. 9:141–143. 1980. View Article : Google Scholar
11	Hylden JL and Wilcox GL: Intrathecal morphine in mice: a new technique. Eur J Pharmacol. 67:313–316. 1980. View Article : Google Scholar : PubMed/NCBI
12	Dixon WJ: Staircase bioassay: the up-and-down method. Neurosci Biobehav Rev. 15:47–50. 1991. View Article : Google Scholar : PubMed/NCBI
13	Scholz J and Yaksh TL: Preclinical research on persistent post-surgical pain: what we don’t know, but should start studying. Anesthesiology. 112:511–513. 2010. View Article : Google Scholar : PubMed/NCBI
14	Gao YJ, Zhang L, Samad OA, et al: JNK-induced MCP-1 production in spinal cord astrocytes contributes to central sensitization and neuropathic pain. J Neurosci. 29:4096–4108. 2009. View Article : Google Scholar : PubMed/NCBI
15	Tarassishin L, Suh HS and Lee SC: LPS and IL-1 differentially activate mouse and human astrocytes: Role of CD14. Glia. 62:999–1013. 2014. View Article : Google Scholar : PubMed/NCBI
16	Nomura J, Busso N, Ives A, et al: Febuxostat, an inhibitor of xanthine oxidase, suppresses lipopolysaccharide-induced MCP-1 production via MAPK phosphatase-1-mediated inactivation of JNK. PloS One. 8:e755272013. View Article : Google Scholar : PubMed/NCBI
17	Julius D and Basbaum AI: Molecular mechanisms of nociception. Nature. 413:203–210. 2001. View Article : Google Scholar : PubMed/NCBI
18	Woolf CJ and Ma Q: Nociceptors - noxious stimulus detectors. Neuron. 55:353–364. 2007. View Article : Google Scholar : PubMed/NCBI
19	Liu B, Linley JE, Du X, et al: The acute nociceptive signals induced by bradykinin in rat sensory neurons are mediated by inhibition of M-type K⁺ channels and activation of Ca²⁺-activated Cl⁻ channels. J Clin Invest. 120:1240–1252. 2010. View Article : Google Scholar : PubMed/NCBI
20	Ocaña M, Cendán CM, Cobos EJ, Entrena JM and Baeyens JM: Potassium channels and pain: present realities and future opportunities. Eur J Pharmacol. 500:203–219. 2004. View Article : Google Scholar : PubMed/NCBI
21	Delmas P and Brown DA: Pathways modulating neural KCNQ/M (Kv7) potassium channels. Nat Rev Neurosci. 6:850–862. 2005. View Article : Google Scholar : PubMed/NCBI
22	Liss B and Roeper J: Molecular physiology of neuronal K-ATP channels (Review). Mol Membr Biol. 18:117–127. 2001. View Article : Google Scholar : PubMed/NCBI
23	Inagaki N, Gonoi T, Clement JP IV, et al: Reconstitution of IKATP: an inward rectifier subunit plus the sulfonylurea receptor. Science. 270:1166–1170. 1995. View Article : Google Scholar : PubMed/NCBI
24	Inagaki N, Gonoi T, Clement JP, et al: A family of sulfonylurea receptors determines the pharmacological properties of ATP-sensitive K⁺ channels. Neuron. 16:1011–1017. 1996. View Article : Google Scholar : PubMed/NCBI
25	Kawano T, Zoga V, McCallum J, et al: ATP-sensitive potassium currents in rat primary afferent neurons: biophysical, pharmacological properties, and alterations by painful nerve injury. Neuroscience. 162:431–443. 2009. View Article : Google Scholar : PubMed/NCBI
26	Rodriguez AJ, Shenoy SM, Singer RH and Condeelis J: Visualization of mRNA translation in living cells. J Cell Biol. 175:67–76. 2006. View Article : Google Scholar : PubMed/NCBI
27	Vit JP, Jasmin L, Bhargava A and Ohara PT: Satellite glial cells in the trigeminal ganglion as a determinant of orofacial neuropathic pain. Neuron Glia Biol. 2:247–257. 2006. View Article : Google Scholar
28	Du X, Wang C and Zhang H: Activation of ATP-sensitive potassium channels antagonize nociceptive behavior and hyperexcitability of DRG neurons from rats. Mol Pain. 7:352011. View Article : Google Scholar : PubMed/NCBI
29	Obata H, Eisenach JC, Hussain H, Bynum T and Vincler M: Spinal glial activation contributes to postoperative mechanical hypersensitivity in the rat. J Pain. 7:816–822. 2006. View Article : Google Scholar : PubMed/NCBI
30	Ledeboer A, Sloane EM, Milligan ED, et al: Minocycline attenuates mechanical allodynia and proinflammatory cytokine expression in rat models of pain facilitation. Pain. 115:71–83. 2005. View Article : Google Scholar : PubMed/NCBI
31	Svensson CI, Fitzsimmons B, Azizi S, Powell HC, Hua XY and Yaksh TL: Spinal p38β isoform mediates tissue injury-induced hyperalgesia and spinal sensitization. J Neurochem. 92:1508–1520. 2005. View Article : Google Scholar : PubMed/NCBI
32	Gao YJ and Ji RR: Targeting astrocyte signaling for chronic pain. Neurotherapeutics. 7:482–493. 2010. View Article : Google Scholar : PubMed/NCBI
33	Gao YJ and Ji RR: Chemokines, neuronal-glial interactions, and central processing of neuropathic pain. Pharmacol Ther. 126:56–68. 2010. View Article : Google Scholar : PubMed/NCBI
34	Scholz J and Woolf CJ: The neuropathic pain triad: neurons, immune cells and glia. Nat neurosci. 10:1361–1368. 2007. View Article : Google Scholar : PubMed/NCBI
35	Rossi DJ, Brady JD and Mohr C: Astrocyte metabolism and signaling during brain ischemia. Nat Neurosci. 10:1377–1386. 2007. View Article : Google Scholar : PubMed/NCBI
36	Peters CM and Eisenach JC: Contribution of the chemokine (C-C motif) ligand 2 (CCL2) to mechanical hypersensitivity after surgical incision in rats. Anesthesiology. 112:1250–1258. 2010. View Article : Google Scholar : PubMed/NCBI
37	Figura M, Chilton L, Liacini A, et al: Blockade of K(ATP) channels reduces endothelial hyperpolarization and leukocyte recruitment upon reperfusion after hypoxia. Am J Transplant. 9:687–696. 2009. View Article : Google Scholar : PubMed/NCBI
38	Zhou F, Yao HH, Wu JY, Ding JH, Sun T and Hu G: Opening of microglial K(ATP) channels inhibits rotenone-induced neuroinflammation. J Cell Mol Med. 12:1559–1570. 2008. View Article : Google Scholar : PubMed/NCBI