Abstract
Recent studies have indicated that minocycline, a microglia inhibitor, could potentially be used as an antinociceptive agent in pain management, although the underlying mechanisms remain elusive. In this study, we investigated the extent to which minocycline could influence pain behavior in association with the expression of the N-methyl-d-aspartic acid receptor 1 (NMDAR1) in a rat L5 spinal nerve ligation (SNL) model. We observed that the intrathecal injection of minocycline significantly attenuated mechanical allodynia in a rat SNL model from day 1 postinjection and persisted for at least 18 days. We also observed that the expression of NMDAR1 was increased in the spinal dorsal horn at 8 days after SNL, which could be partly inhibited through the intrathecal injection of minocycline. These findings suggest that the attenuation of allodynia in the SNL model following minocycline administration might be associated with the inhibited expression of NMDAR1 and, therefore, might play an important role in the minocycline-mediated antinociception.
Similar content being viewed by others
References
Awad H, Hubert GW, Smith Y, Levey AI, Conn PJ (2000) Activation of metabotropic glutamate receptor 5 has direct excitatory effects and potentiates NMDA receptor currents in neurons of the subthalamic nucleus. J Neurosci 20(21):7871–7879
Benquet P, Gee CE, Gerber U (2002) Two distinct signaling pathways upregulate NMDA receptor responses via two distinct metabotropic glutamate receptor subtypes. J Neurosci 22(22):9679–9686
Bhat NR, Zhang P, Lee JC, Hogan EL (1998) Extracellular signal-regulated kinase and p38 subgroups of mitogen-activated protein kinases regulate inducible nitric oxide synthase and tumor necrosis factor-alpha gene expression in endotoxin-stimulated primary glial cultures. J Neurosci 18(5):1633–1641
Bhatt LK, Veeranjaneyulu A (2010) Minocycline with aspirin: a therapeutic approach in the treatment of diabetic neuropathy. Neurol Sci 31(6):705–716
Bonelli RM, Hodl AK, Hofmann P, Kapfhammer HP (2004) Neuroprotection in Huntington’s disease: a 2-year study on minocycline. Int Clin Psychopharmacol 19(6):337–342
Chao CC, Hu S, Ehrlich L, Peterson PK (1995) Interleukin-1 and tumor necrosis factor-alpha synergistically mediate neurotoxicity: involvement of nitric oxide and of N-methyl-d-aspartate receptors. Brain Behav Immun 9(4):355–365
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):55–63
Cheshire WP (2007) Trigeminal neuralgia: for one nerve a multitude of treatments. Expert Rev Neurother 7(11):1565–1579
Colburn RW, DeLeo JA, Rickman AJ, Yeager MP, Kwon P, Hickey WF (1997) Dissociation of microglial activation and neuropathic pain behaviors following peripheral nerve injury in the rat. J Neuroimmunol 79(2):163–175
Colburn RW, Rickman AJ, DeLeo JA (1999) The effect of site and type of nerve injury on spinal glial activation and neuropathic pain behavior. Exp Neurol 157(2):289–304
Coyle DE (1998) Partial peripheral nerve injury leads to activation of astroglia and microglia which parallels the development of allodynic behavior. Glia 23(1):75–83
DeGraba TJ, Pettigrew LC (2000) Why do neuroprotective drugs work in animals but not humans? Neurol Clin 18(2):475–493
Du Y, Ma Z, Lin S, Dodel RC, Gao F, Bales KR, Triarhou LC, Chernet E, Perry KW, Nelson DL, Luecke S, Phebus LA, Bymaster FP, Paul SM (2001) Minocycline prevents nigrostriatal dopaminergic neurodegeneration in the MPTP model of Parkinson’s disease. Proc Natl Acad Sci U S A 98(25):14669–14674
George A, Marziniak M, Schafers M, Toyka KV, Sommer C (2000) Thalidomide treatment in chronic constrictive neuropathy decreases endoneurial tumor necrosis factor-alpha, increases interleukin-10 and has long-term effects on spinal cord dorsal horn met-enkephalin. Pain 88(3):267–275
Gordon PH, Moore DH, Gelinas DF, Qualls C, Meister ME, Werner J, Mendoza M, Mass J, Kushner G, Miller RG (2004) Placebo-controlled phase I/II studies of minocycline in amyotrophic lateral sclerosis. Neurology 62(10):1845–1847
Gorkiewicz T, Szczuraszek K, Wyrembek P, Michaluk P, Kaczmarek L, Mozrzymas JW (2010) Matrix metalloproteinase-9 reversibly affects the time course of NMDA-induced currents in cultured rat hippocampal neurons. Hippocampus 20(10):1105–1108
Jander S, Schroeter M, Stoll G (2000) Role of NMDA receptor signaling in the regulation of inflammatory gene expression after focal brain ischemia. J Neuroimmunol 109(2):181–187
Ji RR, Strichartz G (2004) Cell signaling and the genesis of neuropathic pain. Sci STKE 2004(252):reE14
Jin SX, Zhuang ZY, Woolf CJ, Ji RR (2003) 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 23(10):4017–4022
Kim SH, Chung JM (1992) An experimental model for peripheral neuropathy produced by segmental spinal nerve ligation in the rat. Pain 50(3):355–363
Ledeboer A, Sloane EM, Milligan ED, Frank MG, Mahony JH, Maier SF, Watkins LR (2005) Minocycline attenuates mechanical allodynia and proinflammatory cytokine expression in rat models of pain facilitation. Pain 115(1–2):71–83
Lee SM, Yune TY, Kim SJ, Park DW, Lee YK, Kim YC, Oh YJ, Markelonis GJ, Oh TH (2003) Minocycline reduces cell death and improves functional recovery after traumatic spinal cord injury in the rat. J Neurotrauma 20(10):1017–1027
Machado LS, Kozak A, Ergul A, Hess DC, Borlongan CV, Fagan SC (2006) Delayed minocycline inhibits ischemia-activated matrix metalloproteinases 2 and 9 after experimental stroke. BMC Neurosci 7:56
Maier K, Merkler D, Gerber J, Taheri N, Kuhnert AV, Williams SK, Neusch C, Bahr M, Diem R (2007) Multiple neuroprotective mechanisms of minocycline in autoimmune CNS inflammation. Neurobiol Dis 25(3):514–525
Michaluk P, Mikasova L, Groc L, Frischknecht R, Choquet D, Kaczmarek L (2009) Matrix metalloproteinase-9 controls NMDA receptor surface diffusion through integrin beta1 signaling. J Neurosci 29(18):6007–6012
Nie H, Zhang H, Weng HR (2010) Minocycline prevents impaired glial glutamate uptake in the spinal sensory synapses of neuropathic rats. Neuroscience 170(3):901–912
Niederberger E, Kuhlein H, Geisslinger G (2008) Update on the pathobiology of neuropathic pain. Expert Rev Proteomics 5(6):799–818
Osikowicz M, Skup M, Mika J, Makuch W, Czarkowska-Bauch J, Przewlocka B (2009) Glial inhibitors influence the mRNA and protein levels of mGlu2/3, 5 and 7 receptors and potentiate the analgesic effects of their ligands in a mouse model of neuropathic pain. Pain 147(1–3):175–186
Roh DH, Kim HW, Yoon SY, Seo HS, Kwon YB, Han HJ, Beitz AJ, Lee JH (2008) Depletion of capsaicin-sensitive afferents prevents lamina-dependent increases in spinal N-methyl-d-aspartate receptor subunit 1 expression and phosphorylation associated with thermal hyperalgesia in neuropathic rats. Eur J Pain 12(5):552–563
Sadosky A, McDermott AM, Brandenburg NA, Strauss M (2008) A review of the epidemiology of painful diabetic peripheral neuropathy, postherpetic neuralgia, and less commonly studied neuropathic pain conditions. Pain Pract 8(1):45–56
Tanga FY, Raghavendra V, DeLeo JA (2004) Quantitative real-time RT-PCR assessment of spinal microglial and astrocytic activation markers in a rat model of neuropathic pain. Neurochem Int 45(2–3):397–407
Tilley BC, Alarcon GS, Heyse SP, Trentham DE, Neuner R, Kaplan DA, Clegg DO, Leisen JC, Buckley L, Cooper SM, Duncan H, Pillemer SR, Tuttleman M, Fowler SE (1995) Minocycline in rheumatoid arthritis. A 48-week, double-blind, placebo-controlled trial. MIRA Trial Group. Ann Intern Med 122(2):81–89
Watkins LR, Hutchinson MR, Ledeboer A, Wieseler-Frank J, Milligan ED, Maier SF (2007) Norman Cousins Lecture. Glia as the “bad guys”: implications for improving clinical pain control and the clinical utility of opioids. Brain Behav Immun 21(2):131–146
Wen Y-R, Tan P-H, Cheng J-K, Liu Y-C, Ji R-R (2011) Microglia: a promising target for treating neuropathic and postoperative pain, and morphine tolerance. J Formos Med Assoc 110(8):487–494
Yaksh TL, Rudy TA (1976) Chronic catheterization of the spinal subarachnoid space. Physiol Behav 17(6):1031–1036
Yrjanheikki J, Keinanen R, Pellikka M, Hokfelt T, Koistinaho J (1998) Tetracyclines inhibit microglial activation and are neuroprotective in global brain ischemia. Proc Natl Acad Sci U S A 95(26):15769–15774
Zhuo M, Wu G, Wu LJ (2011) Neuronal and microglial mechanisms of neuropathic pain. Mol Brain 4:31
Acknowledgments
This work was supported through a grant from the Science and Technology Commission of Shanghai Municipality. We would like to thank Chuanyao Tong for his comments on the manuscript. We also thank Gengcheng Wu and Yanqing Wang for their technical assistance.
Author information
Authors and Affiliations
Corresponding author
Additional information
Shaofeng Pu and Yongming Xu contributed equally to this work.
Rights and permissions
About this article
Cite this article
Pu, S., Xu, Y., Du, D. et al. Minocycline attenuates mechanical allodynia and expression of spinal NMDA receptor 1 subunit in rat neuropathic pain model. J Physiol Biochem 69, 349–357 (2013). https://doi.org/10.1007/s13105-012-0217-4
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s13105-012-0217-4