Minocycline attenuates pain by inhibiting spinal microglia activation in diabetic rats

Sun,Jin‑Shan; Yang,Yu‑Jie; Zhang,Yong‑Zhen; Huang,Wen; Li,Zhao‑Shen; Zhang,Yong

doi:10.3892/mmr.2015.3735

Minocycline attenuates pain by inhibiting spinal microglia activation in diabetic rats

Authors:
- Jin‑Shan Sun
- Yu‑Jie Yang
- Yong‑Zhen Zhang
- Wen Huang
- Zhao‑Shen Li
- Yong Zhang
View Affiliations

Affiliations: Department of Gastroenterology, Changhai Hospital, The Second Military Medical University, Shanghai 200433, P.R. China, Department of Ophthalmology, No. 474 Hospital of Chinese People's Liberation Army, Urumqi, Xinjiang 830013, P.R. China, Department of Anatomy and K. K. Leung Brain Research Center, The Fourth Military Medical University, Xi'an, Shaanxi 710032, P.R. China
Published online on: May 6, 2015 https://doi.org/10.3892/mmr.2015.3735
Pages: 2677-2682

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

The mechanisms associated with diabetes‑induced neuropathic pain are complex and poorly understood. In order to understand the involvement of spinal microglia activity in diabetic pain, the present study investigated whether minocycline treatment is able to attenuate diabetic pain using a rat model. Diabetes was induced using a single intraperitoneal injection of streptozotocin (STZ). Minocycline was then intrathecally administered to the rats. Paw withdrawal threshold (PWT) and paw withdrawal latency (PWL) were tested weekly. The expression of OX‑42, Iba‑1, phospho‑p38 mitogen‑activated protein kinase (MAPK), tumor necrosis factor‑α (TNF‑α), interleukin‑1β (IL‑1β) and inducible nitric oxide synthase (iNOS), were examined in the spinal cord in order to evaluate the activation of microglia. The present study demonstrated that rats with STZ‑induced diabetes exhibited increased mean plasma glucose concentration, decreased mean body weight and significant pain hypersensitivity compared with control rats. PWT and PWL values of rats with STZ‑induced diabetes increased following treatment with minocycline. No differences were observed in expression levels of the microglial activity markers (OX‑42, Iba‑1 and phospho‑p38 MAPK) between rats with STZ‑induced diabetes and control rats. However, TNF‑α, IL‑1β and iNOS expression levels were higher in rats with STZ‑induced diabetes compared with control rats. Following treatment with minocycline markers of microglial activation, including cytokines and iNOS, were downregulated in rats with STZ‑induced diabetes. The results of the present study indicated that minocycline treatment may inhibit spinal microglial activation and attenuate diabetic pain in rats with STZ‑induced diabetes.

View Figures

View References

1	Yagihashi S, Yamagishi S and Wada R: Pathology and pathogenetic mechanisms of diabetic neuropathy: Correlation with clinical signs and symptoms. Diabetes Res Clin Pract. 77(Suppl 1): S184–S189. 2007. View Article : Google Scholar : PubMed/NCBI
2	Green CJ, Pedersen M, Pedersen BK and Scheele C: Elevated NF-κB activation is conserved in human myocytes cultured from obese type 2 diabetic patients and attenuated by AMP-activated protein kinase. Diabetes. 60:2810–2819. 2011. View Article : Google Scholar : PubMed/NCBI
3	Newsholme P, Gaudel C and Krause M: Mitochondria and diabetes. An intriguing pathogenetic role. Adv Exp Med Biol. 942:235–247. 2012.PubMed/NCBI
4	Zhang YL, Xu JM, Zhou P, Zhong XL and Dai RP: Distinct activation of tumor necrosis factor-α and interleukin-6 in the spinal cord after surgical incision in rats. Mol Med Rep. 5:1423–1427. 2012.PubMed/NCBI
5	Ren K and Dubner R: Interactions between the immune and nervous systems in pain. Nat Med. 16:1267–1276. 2010. View Article : Google Scholar : PubMed/NCBI
6	Jung WW, Kim HS, Shon JR, Lee M, Lee SH, Sul D, Na HS, Kim JH and Kim BJ: Intervertebral disc degeneration-induced expression of pain-related molecules: Glial cell-derived neurotropic factor as a key factor. J Neurosurg Anesthesiol. 23:329–334. 2011. View Article : Google Scholar : PubMed/NCBI
7	Prinz M, Tay TL, Wolf Y and Jung S: Microglia: Unique and common features with other tissue macrophages. Acta Neuropathol. 128:319–331. 2014. View Article : Google Scholar : PubMed/NCBI
8	Amin AR, Attur MG, Thakker GD, Patel PD, Vyas PR, Patel RN, Patel IR and Abramson SB: A novel mechanism of action of tetracyclines: Effects on nitric oxide synthases. Proc Natl Acad Sci USA. 93:14014–14019. 1996. View Article : Google Scholar : PubMed/NCBI
9	Leung L and Cahill CM: TNF-alpha and neuropathic pain - a review. J Neuroinflammation. 7:272010. View Article : Google Scholar
10	Naseri K, Saghaei E, Abbaszadeh F, Afhami M, Haeri A, Rahimi F and Jorjani M: Role of microglia and astrocyte in central pain syndrome following electrolytic lesion at the spinothalamic tract in rats. J Mol Neurosci. 49:470–479. 2013. View Article : Google Scholar
11	LoPachin RM, Rudy TA and Yaksh TL: An improved method for chronic catheterization of the rat spinal subarachnoid space. Physiol Behav. 27:559–561. 1981. View Article : Google Scholar : PubMed/NCBI
12	Ihara H, Yamamoto H, Ida T, Tsutsuki H, Sakamoto T, Fujita T, Okada T and Kozaki S: Inhibition of nitric oxide production and inducible nitric oxide synthase expression by a polymethoxyflavone from young fruits of Citrus unshiu in rat primary astrocytes. Biosci Biotechnol Biochem. 76:1843–1848. 2012. View Article : Google Scholar : PubMed/NCBI
13	Nikodemova M, Duncan ID and Watters JJ: Minocycline exerts inhibitory effects on multiple mitogen-activated protein kinases and IkappaBalpha degradation in a stimulus-specific manner in microglia. J Neurochem. 96:314–323. 2006. View Article : Google Scholar
14	Lim H, Kim D and Lee SJ: Toll-like receptor 2 mediates peripheral nerve injury-induced NADPH oxidase 2 expression in spinal cord microglia. J Biol Chem. 288:7572–7579. 2013. View Article : Google Scholar : PubMed/NCBI
15	Nikodemova M, Watters JJ, Jackson SJ, Yang SK and Duncan ID: Minocycline down-regulates MHC II expression in microglia and macrophages through inhibition of IRF-1 and protein kinase C (PKC)alpha/betaII. J Biol Chem. 282:15208–15216. 2007. View Article : Google Scholar : PubMed/NCBI
16	Gao YJ, Xu ZZ, Liu YC, Wen YR, Decosterd I and Ji RR: The c-Jun N-terminal kinase 1 (JNK1) in spinal astrocytes is required for the maintenance of bilateral mechanical allodynia under a persistent inflammatory pain condition. Pain. 148:309–319. 2010. View Article : Google Scholar :
17	Wei F, Guo W, Zou S, Ren K and Dubner R: Supraspinal glial-neuronal interactions contribute to descending pain facilitation. J Neurosci. 28:10482–10495. 2008. View Article : Google Scholar : PubMed/NCBI
18	Choi JI, Svensson CI, Koehrn FJ, Bhuskute A and Sorkin LS: Peripheral inflammation induces tumor necrosis factor dependent AMPA receptor trafficking and Akt phosphorylation in spinal cord in addition to pain behavior. Pain. 149:243–253. 2010. View Article : Google Scholar : PubMed/NCBI
19	Ren K: Emerging role of astroglia in pain hypersensitivity. Jpn Dent Sci Rev. 46:862010. View Article : Google Scholar : PubMed/NCBI
20	Weyerbacher AR, Xu Q, Tamasdan C, Shin SJ and Inturrisi CE: N-Methyl-D-aspartate receptor (NMDAR) independent maintenance of inflammatory pain. Pain. 148:237–246. 2010. View Article : Google Scholar :
21	Gao X, Kim HK, Chung JM and Chung K: Reactive oxygen species (ROS) are involved in enhancement of NMDA-receptor phosphorylation in animal models of pain. Pain. 131:262–271. 2007. View Article : Google Scholar : PubMed/NCBI
22	Yowtak J, Lee KY, Kim HY, Wang J, Kim HK, Chung K and Chung JM: Reactive oxygen species contribute to neuropathic pain by reducing spinal GABA release. Pain. 152:844–852. 2011. View Article : Google Scholar : PubMed/NCBI
23	Mollace V, Muscoli C, Rotiroti D and Nisticó G: Spontaneous induction of nitric oxide- and prostaglandin E2-release by hypoxic astroglial cells is modulated by interleukin 1 beta. Biochem Biophys Res Commun. 238:916–919. 1997. View Article : Google Scholar : PubMed/NCBI
24	Purwata TE: High TNF-alpha plasma levels and macrophages iNOS and TNF-alpha expression as risk factors for painful diabetic neuropathy. J Pain Res. 4:169–175. 2011. View Article : Google Scholar : PubMed/NCBI