Tetracyclines and pain

Naunyn-Schmiedeberg's Archives of Pharmacology

Volumn 385, Issue 3, 2012, Pages 225-241

  Bastos, Leandro F S ^a   De Oliveira, Antônio C P ^a   Watkins, Linda R ^b   Moraes, Márcio F D ^a   Coelho, Márcio M ^a  

^a FEDERAL UNIVERSITY OF MINAS GERAIS   (Brazil)

^b UNIVERSITY OF COLORADO   (United States)

Author keywords

Chemically modified tetracyclines; Drug repositioning; Inflammation; Microglia; Minocycline; Nociception

Indexed keywords

6 DEOXY 6 DEMETHYLTETRACYCLINE; BRAIN DERIVED NEUROTROPHIC FACTOR; CHLORTETRACYCLINE; DEMECLOCYCLINE; DOXYCYCLINE; HYDROXY 1,12 PYRAZOLINOMINOCYCLINE; INCYCLINIDE; INTERLEUKIN 1BETA; LYMECYCLINE; MINOCYCLINE; MORPHINE; PROSTAGLANDIN E2; ROLITETRACYCLINE; SECONDARY LYMPHOID TISSUE CHEMOKINE; TETRACYCLINE; TETRACYCLINE DERIVATIVE; TIGECYCLINE; TUMOR NECROSIS FACTOR ALPHA; UNCLASSIFIED DRUG;

ANTIBACTERIAL ACTIVITY; APOPTOSIS; ARTERIAL PRESSURE; BODY MASS; CELL ACTIVATION; DRUG ABSORPTION; DRUG ELIMINATION; HUMAN; INTRACELLULAR SIGNALING; LIPOPHILICITY; MICROGLIA; NOCICEPTION; NONHUMAN; PAIN; PERIPHERAL NERVOUS SYSTEM; PROTEIN EXPRESSION; RESPIRATION DEPRESSION; REVIEW; SIDE EFFECT; SKIN IRRITATION; STREPTOMYCES;

ANALGESICS; ANIMALS; HUMANS; PAIN; TETRACYCLINES;

EID: 84862833900     PISSN: 00281298     EISSN: 14321912     Source Type: Journal    
DOI: 10.1007/s00210-012-0727-1     Document Type: Review

References (139)

1. (2009) Deal watch: Novartis acquires marketing rights for novel broad-spectrum antibiotic. Nat Rev Drug Discov 8: 922
2. Alano CC, Kauppinen TM, Valls AV, Swanson RA (2006) Minocycline inhibits poly(ADP-ribose) polymerase-1 at nanomolar concentra-tions. Proc Natl Acad Sci USA 103:9685-9690 (Pubitemid 43955885)
3. Amin AR, Attur MG, Thakker GD, Patel PD, Vyas PR, Patel RN, Patel IR, Abramson SB (1996) A novel mechanism of action of tetracyclines: effects on nitric oxide synthases. Proc Natl Acad Sci USA 93:14014-14019 (Pubitemid 26424237)
4. Aronson AL (1980) Pharmacotherapeutics of the newer tetracyclines. J Am Vet Med Assoc 176:1061-1068 (Pubitemid 11133171)
5. Ashburn TT, Thor KB (2004) Drug repositioning: identifying and developing new uses for existing drugs. Nat Rev Drug Discov 3:673-683 (Pubitemid 39173508)
6. Bastos LFS, Merlo LA, Rocha LTS, Coelho MM (2007) Characterization of the antinociceptive and anti-inflammatory activities of doxycycline and minocycline in different experimental models. Eur J Pharmacol 576:171-179 (Pubitemid 47588248)
7. Bastos LFS, Angusti A, Vilaca MC, Merlo LA, Nascimento EB, Rocha LT, Godin AM, Solano AGR, Jarussophon S, Nunan EA, Konishi Y, Coelho MM (2008) A novel non-antibacterial, non-chelating hydroxypyrazoline derivative of minocycline inhibits nociception and oedema in mice. Br J Pharmacol 155:714-721
8. Bastos LFS, de Oliveira ACP, Schlachetzki JCM, Fiebich BL (2011) Minocycline reduces prostaglandin E synthase expression and 8-isoprostane formation in LPS-activated primary rat microglia. Immunopharmacol Immunotoxicol 33:576-580
9. Beggs S, Salter MW (2010) Microglia-neuronal signalling in neuro-pathic pain hypersensitivity 2.0. Curr Opin Neurobiol20:474-480
10. Bernardino AL, Kaushal D, Philipp MT (2009) The antibiotics doxy-cycline and minocycline inhibit the inflammatory responses to the Lyme disease spirochete Borrelia burgdorferi. J Infect Dis 199:1379-1388
11. Blum D, Chtarto A, Tenenbaum L, Brotchi J, Levivier M (2004) Clinical potential ofminocycline for neurodegenerative disorders. Neurobiol Dis 17:359-366 (Pubitemid 39574870)
12. Bocker R, Estler CJ, Ludewig-Sandig D (1991) Evaluation of the hepa-totoxic potential of minocycline. Antimicrob Agents Chemother 35:1434-1436
13. Bouhassira D, Lanteri-Minet M, Attal N, Laurent B, Touboul C (2008) Prevalence of chronic pain with neuropathic characteristics in the general population. Pain 136:380-387 (Pubitemid 351680253)
14. Bradesi S, Svensson CI, Steinauer J, Pothoulakis C, Yaksh TL, Mayer EA (2009) Role of spinal microglia in visceral hyperalgesia and NK1R up-regulation in a rat model of chronic stress. Gastroenterology 136:1339-1348
15. Brown EM, Gamba G, Riccardi D, Lombardi M, Butters R, Kifor O, Sun A, Hediger MA, Lytton J, Hebert SC (1993) Cloning and characterization of an extracellular Ca(2+)-sensing receptor from bovine parathyroid. Nature 366:575-580 (Pubitemid 24035999)
16. Brundula V Rewcastle NB, Metz LM, Bernard CC, Yong VW (2002) Targeting leukocyte MMPs and transmigration: minocycline as a potential therapy for multiple sclerosis. Brain 125:1297-1308 (Pubitemid 34587139)
17. Chacur M, Lambertz D, Hoheisel U, Mense S (2009) Role of spinal microglia in myositis-induced central sensitisation: an immunohis-tochemical and behavioural study in rats. Eur J Pain 13:915-923
18. Chang YW, Waxman SG (2010) Minocycline attenuates mechanical allodynia and central sensitization following peripheral second-degree burn injury. J Pain 11:1146-1154
19. Chen Y, Sommer C (2009) The role of mitogen-activated protein kinase (MAPK) in morphine tolerance and dependence. Mol Neurobiol 40:101-107
20. Chen M, Ona VO, Li M, Ferrante RJ, Fink KB, Zhu S, Bian J, Guo L, Farrell LA, Hersch SM, Hobbs W, Vonsattel JP, Cha JH, Friedlander RM (2000) Minocycline inhibits caspase-1 and caspase-3 expres-sion and delays mortality in a transgenic mouse model of Hunting-ton disease. Nat Med 6:797-801 (Pubitemid 30469429)
21. Chen S, Hui H, Zhang D, Xue Y (2010) The combination of morphine and minocycline may be a good treatment for intractable post-herpetic neuralgia. Med Hypotheses 75:663-665
22. Cho IH, Chung YM, Park CK, Park SH, Li HY, Kim D, Piao ZG, Choi SY, Lee SJ, Park K, Kim JS, Jung SJ, Oh SB (2006) Systemic administration of minocycline inhibits formalin-induced inflam-matory pain in rat. Brain Res 1072:208-214 (Pubitemid 43255466)
23. Chong CR, Chen X, Shi L, Liu JO, Sullivan DJ Jr (2006) A clinical drug library screen identifies astemizole as an antimalarial agent. Nat Chem Biol 2:415-416 (Pubitemid 44114918)
24. Chopra I, Roberts M (2001) Tetracycline antibiotics: mode of action, applications, molecular biology, and epidemiology of bacterial resistance. Microbiol Mol Biol Rev 65:232-260 (Pubitemid 32538179)
25. Chow AK, Cena J, Schulz R (2007) Acute actions and novel targets of matrix metalloproteinases in the heart and vasculature. Br J Phar-macol 152:189-205 (Pubitemid 47517601)
26. Colovic M, Caccia S (2003) Liquid chromatographic determination of minocycline in brain-to-plasma distribution studies in the rat J Chromatogr B Anal Technol Biomed Life Sci 791:337-343 (Pubitemid 36638766)
27. Costigan M, Scholz J, Woolf CJ (2009) Neuropathic pain: a maladaptive response of the nervous system to damage. Annu Rev Neurosci 32:1-32
28. Coull JA, Beggs S, Boudreau D, Boivin D, Tsuda M, Inoue K, Gravel C, Salter MW, De Koninck Y (2005) BDNF from microglia causes the shift in neuronal anion gradient underlying neuropathic pain. Nature 438:1017-1021 (Pubitemid 43093974)
29. Cui Y Liao XX, Liu W, Guo RX, Wu ZZ, Zhao CM, Chen PX, Feng JQ (2008) A novel role of minocycline: attenuating morphine antinociceptive tolerance by inhibition of p38 MAPK in the activated spinal microglia. Brain Behav Immun 22:114-123 (Pubitemid 350216368)
30. Cuzzocrea S, Costantino G, Zingarelli B, Caputi AP (1999) Protective effects of poly (ADP-ribose) synthase inhibitors in zymosan-activated plasma induced paw edema. Life Sci 65:957-964 (Pubitemid 29400595)
31. Cuzzocrea S, Chatterjee PK, Mazzon E, Dugo L, Serraino I, Britti D, Mazzullo G, Caputi AP, Thiemermann C (2002) Pyrrolidine di-thiocarbamate attenuates the development of acute and chronic inflammation. Br J Pharmacol 135:496-510 (Pubitemid 34151183)
32. Dray A (2008) Neuropathic pain: emerging treatments. Br J Anaesth 101:48-58 (Pubitemid 351881912)
33. 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 USA 98:14669-14674 (Pubitemid 33121449)
34. Fagan SC, Edwards DJ, Borlongan CV, Xu L, Arora A, Feuerstein G, Hess DC (2004) Optimal delivery of minocycline to the brain: implication for human studies ofacute neuroprotection. Exp Neurol 186:248-251 (Pubitemid 38333198)
35. Gabler WL, Creamer HR (1991) Suppression of human neutrophil functions by tetracyclines. J Periodontal Res 26:52-58
36. Golub LM, McNamara TF, DAngelo G, Greenwald RA, Ramamurthy NS (1987) A non-antibacterial chemically-modified tetracycline inhibits mammalian collagenase activity. J Dent Res 66:1310-1314 (Pubitemid 17127109)
37. Golub LM, Lee HM, Ryan ME, Giannobile WV, Payne J, Sorsa T(1998) Tetracyclines inhibit connective tissue breakdown by multiple non-antimicrobial mechanisms. Adv Dent Res 12:12-26
38. Gonzalez JC, Egea J, Del Carmen GM, Fernandez-Gomez FJ, Sanchez-Prieto J, Gandia L, Garcia AG, Jordan J, Hernandez-Guijo JM (2007) Neuroprotectant minocycline depresses gluta-matergic neurotransmission and Ca(2+) signalling in hippocampal neurons. Eur J Neurosci 26:2481-2495 (Pubitemid 350050444)
39. Goulden V, Glass D, Cunliffe WJ (1996) Safety of long-term high-dose minocycline in the treatment ofacne. Br J Dermatol 134:693-695 (Pubitemid 26120737)
40. Habibi-Asl B, Hassanzadeh K, Charkhpour M (2009) Central admin-istration of minocycline and riluzole prevents morphine-induced tolerance in rats. Anesth Analg 109:936-942
41. Hains BC, Waxman SG (2006) Activated microglia contribute to the maintenance of chronic pain after spinal cord injury. J Neurosci 26:4308-4317 (Pubitemid 44315390)
42. Hamann S, Sloan P (2007) Oral naltrexone to enhance analgesia in patients receiving continuous intrathecal morphine for chronic pain: a ran-domized, double-blind, prospective pilot study. J Opioid Manag 3:137-144
43. Hashimoto K, Ishima T (2010) A novel target of action ofminocycline in NGF-induced neurite outgrowth in PC12 cells: translation initiation factor eIF4AI. PLoS One 5:e15430
44. Hassanzadeh K, Habibi-asl B, Farajnia S, Roshangar L (2011) Minocycline prevents morphine-induced apoptosis in rat cerebral cortex and lum-bar spinal cord: a possible mechanism for attenuating morphine tolerance. Neurotox Res 19:649-659
45. Hu P, McLachlan EM (2002) Macrophage and lymphocyte invasion of dorsal root ganglia after peripheral nerve lesions in the rat Neu-roscience 112:23-38 (Pubitemid 34603495)
46. Hu J, Van den Steen PE, Sang QX, Opdenakker G (2007a) Matrix metalloproteinase inhibitors as therapy for inflammatory and vas-cular diseases. Nat Rev Drug Discov 6:480-498 (Pubitemid 47064570)
47. Hu P, Bembrick AL, Keay KA, McLachlan EM (2007b) Immune cell involvement in dorsal root ganglia and spinal cord after chronic constriction or transection of the rat sciatic nerve. Brain Behav Immun 21:599-616 (Pubitemid 46830961)
48. Hua XY, Svensson CI, Matsui T, Fitzsimmons B, Yaksh TL, Webb M (2005) Intrathecal minocycline attenuates peripheral inflammation-induced hyperalgesia by inhibiting p38 MAPK in spinal microglia. Eur J Neurosci 22:2431-2440 (Pubitemid 41758986)
49. Huang WC, Qiao Y, Xu L, Kacimi R, Sun X, Giffard RG, Yenari MA (2010) Direct protection of cultured neurons from ischemia-like injury by minocycline. Anat Cell Biol 43:325-331
50. Hunskaar S, Hole K (1987) The formalin test in mice: dissociation between inflammatory and non-inflammatory pain. Pain 30:103-114 (Pubitemid 17094194)
51. Hutchinson MR, Northcutt AL, Chao LW, Kearney JJ, Zhang Y Berkelhammer DL, Loram LC, Rozeske RR, Bland ST, Maier SF, Gleeson TT, Watkins LR (2008a) Minocycline suppresses morphine-induced respiratory depression, suppresses morphine-induced reward, and enhances systemic morphine-induced anal-gesia. Brain Behav Immun 22:1248-1256
52. Hutchinson MR, Zhang Y, Brown K, Coats BD, Shridhar M, Sholar PW, Patel SJ, Crysdale NY, Harrison JA, Maier SF, Rice KC, Watkins LR (2008b) Non-stereoselective reversal of neuropathic pain by naloxone and naltrexone: involvement of toll-like recep-tor 4 (TLR4). Eur J Neurosci 28:20-29
53. Hutchinson MR, Lewis SS, Coats BD, Skyba DA, Crysdale NY Berkelhammer DL, Brzeski A, Northcutt A, Vietz CM, Judd CM, Maier SF, Watkins LR, Johnson KW (2009) Reduction of opioid withdrawal and potentiation of acute opioid analgesia by systemic AV411 (ibudilast). Brain Behav Immun 23:240-250
54. Hutchinson MR, Zhang Y, Shridhar M, Evans JH, Buchanan MM, Zhao TX, Slivka PF, Coats BD, Rezvani N, Wieseler J, Hughes TS, LandgrafKE, Chan S, Fong S, Phipps S, Falke JJ, Leinwand LA, Maier SF, Yin H, Rice KC, Watkins LR (2010) Evidence that opioids may have toll-like receptor 4 and MD-2 effects. Brain Behav Immun 24:83-95
55. Ito N, Obata H, Saito S (2009) Spinal microglial expression and mechanical hypersensitivity in a postoperative pain model: com-parison with a neuropathic pain model. Anesthesiology 111:640-648
56. 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 ofneuropathic pain. J Neurosci 23:4017-4022 (Pubitemid 36958419)
57. Kim HS, Suh YH (2009) Minocycline and neurodegenerative diseases. Behav Brain Res 196:168-179
58. 2 in BV2 microglial cells. Arch Pharm Res 27:314-318 (Pubitemid 43073754)
59. Kim TH, Kim HI, Kim J, Park M, Song JH (2011) Effects ofminocy-cline on Na(+) currents in rat dorsal root ganglion neurons. Brain Res 1370:34-42
60. Kwon BK, Sekhon LH, Fehlings MG (2010) Emerging repair, regen-eration, and translational research advances for spinal cord injury. Spine 35:S263-S270
61. Leblanc BW, Zerah ML, Kadasi LM, Chai N, Saab CY (2011) Mino-cycline injection in the ventral posterolateral thalamus reverses microglial reactivity and thermal hyperalgesia secondary to sciatic neuropathy. Neurosci Lett 498:138-142
62. Ledeboer A, Sloane EM, Milligan ED, Frank MG, Mahony JH, Maier SF, Watkins LR (2005) Minocycline attenuates mechanical allo-dynia and proinflammatory cytokine expression in rat models of pain facilitation. Pain 115:71-83
63. Lertvorachon J, Kim JP, Soldatov DV, Boyd J, Roman G, Cho SJ, Popek T, Jung YS, Lau PC, Konishi Y (2005) 1,12-Substituted tetracy-clines as antioxidant agents. Bioorg Med Chem 13:4627-4637
64. Lewis SS, Hutchinson MR, Rezvani N, Loram LC, Zhang Y, Maier SF, Rice KC, Watkins LR (2010) Evidence that intrathecal morphine-3-glucuronide may cause pain enhancement via toll-like receptor 4/MD-2 and interleukin-1beta. Neuroscience 165:569-583
65. Light RW, Wang NS, Sassoon CS, Gruer SE, Vargas FS (1994) Com-parison of the effectiveness of tetracycline and minocycline as pleural sclerosing agents in rabbits. Chest 106:577-582 (Pubitemid 24252063)
66. Ma L, Nagai J, Ueda H (2010) Microglial activation mediates de novo lysophosphatidic acid production in a model ofneuropathic pain. JNeurochem 115:643-653
67. Mao J, Price DD, Mayer DJ (1994) Thermal hyperalgesia in associa-tion with the development ofmorphine tolerance in rats: roles of excitatory amino acid receptors and protein kinase C. J Neurosci 14:2301-2312 (Pubitemid 24108135)
68. Mao J, Sung B, Ji RR, Lim G (2002) Neuronal apoptosis associated with morphine tolerance: evidence for an opioid-induced neuro-toxic mechanism. J Neurosci 22:7650-7661 (Pubitemid 35386364)
69. Marchand F, Tsantoulas C, Singh D, Grist J, Clark AK, Bradbury EJ, McMahon SB (2009) Effects of Etanercept and Minocycline in a rat model of spinal cord injury. Eur J Pain 13:673-681
70. Matsumura T, Sakai A, Nagano M, Sawada M, Suzuki H, Umino M (2008) Increase in hemokinin-1 mRNA in the spinal cord during the early phase of a neuropathic pain state. Br J Pharmacol 155:767-774
71. Mattioli TA, Milne B, Cahill CM (2010) Ultra-low dose naltrexone attenuates chronic morphine-induced gliosis in rats. Mol Pain 6:22
72. McKenna JE, Melzack R (2001) Blocking NMDA receptors in the hippocampal dentate gyrus with AP5 produces analgesia in the formalin pain test. Exp Neurol 172:92-99 (Pubitemid 33141157)
73. Mei XP, Xu H, Xie C, Ren J, Zhou Y, Zhang H, Xu LX (2011) Post-injury administration of minocycline: an effective treatment for nerve-injury induced neuropathic pain. Neurosci Res 70:305-312
74. Melnikova I (2010) Pain market. Nat Rev Drug Discov 9:589-590
75. Mika J, Wawrzczak-Bargiela A, Osikowicz M, Makuch W, Przewlocka B (2009) Attenuation of morphine tolerance by minocycline and pentoxifylline in naive and neuropathic mice. Brain Behav Immun 23:75-84
76. Mika J, Rojewska E, Makuch W, Przewlocka B (2010) Minocycline reduces the injury-induced expression of prodynorphin and pro-nociceptin in the dorsal root ganglion in a rat model of neuro-pathic pain. Neuroscience 165:1420-1428
77. Milligan ED, Watkins LR (2009) Pathological and protective roles of glia in chronic pain. Nat Rev Neurosci 10:23-36
78. Milligan ED, Mehmert KK, Hinde JL, Harvey LO, Martin D, Tracey KJ, Maier SF, Watkins LR (2000) Thermal hyperalgesia and mechanical allodynia produced by intrathecal administration of the human immunodeficiency virus-1 (HIV-1) envelope glycopro-tein, gp120. Brain Res 861:105-116 (Pubitemid 30177288)
79. Milligan ED, Zapata V, Chacur M, Schoeniger D, Biedenkapp J, O'Connor KA, Verge GM, Chapman G, Green P, Foster AC, Naeve GS, Maier SF, Watkins LR (2004) Evidence that exoge-nous and endogenous fractalkine can induce spinal nociceptive facilitation in rats. Eur J Neurosci 20:2294-2302 (Pubitemid 39472392)
80. Milligan E, Zapata V, Schoeniger D, Chacur M, Green P, Poole S, Martin D, Maier SF, Watkins LR (2005) An initial investigation of spinal mechanisms underlying pain enhancement induced by fractalkine, a neuronally released chemokine. Eur J Neurosci 22:2775-2782 (Pubitemid 41811274)
81. Morgado C, Pereira-Terra P, Cruz CD, Tavares I (2011) Minocycline completely reverses mechanical hyperalgesia in diabetic rats through microglia-induced changes in the expression of the po-tassium chloride co-transporter 2 (KCC2) at the spinal cord. Diabetes Obes Metab 13:150-159
82. Morin N, Owolabi SA, Harty MW, Papa EF, Tracy TF Jr, Shaw SK, Kim M, Saab CY (2007) Neutrophils invade lumbar dorsal root ganglia after chronic constriction injury of the sciatic nerve. J Neuroimmunol 184:164-171 (Pubitemid 46365998)
83. Mullard A (2011) 2010 FDA drug approvals. Nat Rev Drug Discov 10:82-85
84. Nikodemova M, Duncan ID, Watters JJ (2006) 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
85. Nikodemova M, Watters JJ, Jackson SJ, Yang SK, Duncan ID (2007) 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 (Pubitemid 47093379)
86. Noble JF, Kanegis LA, Hallesy DW (1967) Short-term toxicity and observations on certain aspects of the pharmacology of a unique tetracycline\-minocycline. Toxicol Appl Pharmacol 11:128-149
87. Padi SS, Kulkarni SK (2008) Minocycline prevents the development of neuropathic pain, but not acute pain: possible anti-inflammatory and antioxidant mechanisms. Eur J Pharmacol 601:79-87
88. 2 production. J Immunol 163:3459-3467 (Pubitemid 29431850)
89. Pi R, Li W, Lee NT, Chan HH, Pu Y, Chan LN, Sucher NJ, Chang DC, Li M, Han Y (2004) Minocycline prevents glutamate-induced apoptosis of cerebellar granule neurons by differential regulation of p38 and Akt pathways. J Neurochem 91:1219-1230 (Pubitemid 39587460)
90. Piao ZG, Cho IH, Park CK, Hong JP, Choi SY, Lee SJ, Lee S, Park K, Kim JS, Oh SB (2006) Activation of glia and microglial p38 MAPK in medullary dorsal horn contributes to tactile hypersensitivity follow-ing trigeminal sensory nerve injury. Pain 121:219-231
91. Poiger H, Schlatter C (1979) Interaction ofcations and chelators with the intestinal absorption of tetracycline. Naunyn Schmiedebergs Arch Pharmacol 306:89-92 (Pubitemid 10164002)
92. Prado WA (2001) Involvement ofcalcium in pain and antinociception. Braz J Med Biol Res 34:449-461
93. Pruzanski W, Greenwald RA, Street IP, Laliberte F, Stefanski E, Vadas P (1992) Inhibition ofenzymatic activity ofphospholipases A2 by minocycline and doxycycline. Biochem Pharmacol 44:1165-1170
94. Pruzanski W, Stefanski E, Vadas P, McNamara TF, Ramamurthy N, Golub LM (1998) Chemically modified non-antimicrobial tetra-cyclines inhibit activity of phospholipases A2. J Rheumatol 25:1807-1812 (Pubitemid 28439277)
95. Raghavendra V, Tanga F, DeLeo JA (2003) Inhibition of microglial activation attenuates the development but not existing hypersen-sitivity in a rat model of neuropathy. J Pharmacol Exp Ther 306:624-630 (Pubitemid 36886161)
96. Rivera C, Voipio J, Thomas-Crusells J, Li H, Emri Z, Sipila S, Payne JA, Minichiello L, Saarma M, Kaila K (2004) Mechanism of activity-dependent downregulation of the neuron-specific K-Cl cotransporter KCC2. J Neurosci 24:4683-4691 (Pubitemid 38656623)
97. Roberts J, Ossipov MH, Porreca F (2009) Glial activation in the rostro-ventromedial medulla promotes descending facilitation to mediate inflammatory hypersensitivity. Eur J Neurosci 30:229-241
98. Saito O, Svensson CI, Buczynski MW, Wegner K, Hua XY, Codeluppi S, Schaloske RH, Deems RA, Dennis EA, Yaksh TL (2010) Spinal glial TLR4-mediated nociception and production of pros-taglandin E(2) and TNF. Br J Pharmacol 160:1754-1764
99. Saliba R, Paasch L, El Solh A (2009) Tigecycline attenuates staphylo-coccal superantigen-induced T-cell proliferation and production ofcytokines and chemokines. Immunopharmacol Immunotoxicol 31:583-588
100. Salvatore CM, Techasaensiri C, Tagliabue C, Katz K, Leos N, Gomez AM, McCracken GH, Hardy RD (2009) Tigecycline therapy significantly reduces the concentrations of inflammatory pulmo-nary cytokines and chemokines in a murine model ofMycoplasma pneumoniae pneumonia. Antimicrob Agents Chemother 53:1546-1551
101. Sanchez AR, Rogers RS 3rd, Sheridan PJ (2004) Tetracycline and other tetracycline-derivative staining of the teeth and oral cavity. Int J Dermatol 43:709-715 (Pubitemid 39405851)
102. Sandler C, Ekokoski E, Lindstedt KA, Vainio PJ, Finel M, Sorsa T, Kovanen PT, Golub LM, Eklund KK (2005) Chemically modified tetracycline (CMT)-3 inhibits histamine release and cytokine pro-duction in mast cells: possible involvement of protein kinase C. Inflamm Res 54:304-312 (Pubitemid 41185492)
103. Seabrook TJ, Jiang L, Maier M, Lemere CA (2006) Minocycline affects microglia activation, Abeta deposition, and behavior in APP-tg mice. Glia 53:776-782
104. Shan S, Qi-Liang MY, Hong C, Tingting L, Mei H, Haili P, Yan-Qing W, Zhi-Qi Z, Yu-Qiu Z (2007) Is functional state of spinal micro-glia involved in the anti-allodynic and anti-hyperalgesic effects of electroacupuncture in rat model of monoarthritis? Neurobiol Dis 26:558-568 (Pubitemid 46756323)
105. Shimizu K, Guo W, Wang H, Zou S, LaGraize SC, Iwata K, Wei F, Dubner R, Ren K (2009) Differential involvement of trigeminal transition zone and laminated subnucleus caudalis in orofacial deep and cutaneous hyperalgesia: the effects of interleukin-10 and glial inhibitors. Mol Pain 5:75
106. Si Q, Cosenza M, Kim MO, Zhao ML, Brownlee M, Goldstein H, Lee S (2004) A novel action of minocycline: inhibition of human immunodeficiency virus type 1 infection in microglia. J Neuro-virol 10:284-292 (Pubitemid 39429939)
107. Skidmore R, Kovach R, Walker C, Thomas J, Bradshaw M, Leyden J, Powala C, Ashley R (2003) Effects of subantimicrobial-dose doxycycline in the treatment of moderate acne. Arch Dermatol 139:459-464 (Pubitemid 36427610)
108. Smith DL, Woodman B, Mahal A, Sathasivam K, Ghazi-Noori S, Lowden PA, Bates GP, Hockly E (2003) Minocycline and doxy-cycline are not beneficial in a model ofHuntington's disease. Ann Neurol 54:186-196 (Pubitemid 36909617)
109. Soleimannejad E, Naghdi N, Semnanian S, Fathollahi Y, Kazemnejad A (2007) Antinociceptive effect of intra-hippocampal CA1 and dentate gyrus injection ofMK801 and AP5 in the formalin test in adult male rats. Eur J Pharmacol 562:39-46 (Pubitemid 46476788)
110. Sorkin LS, Schäfers M (2007) Immune cells in peripheral nerve. In: DeLeo JA, Sorkin LS, Watkins LR (eds) Immune and glial regu-lation ofpain, 1st edn. IASP Press, Seattle, WA, pp 3-19
111. Svensson CI, Marsala M, Westerlund A, Calcutt NA, Campana WM, Freshwater JD, Catalano R, Feng Y, Protter AA, Scott B, Yaksh TL (2003) Activation of p38 mitogen-activated protein kinase in spinal microglia is a critical link in inflammation-induced spinal pain processing. J Neurochem 86:1534-1544 (Pubitemid 37174270)
112. Szeto GL, Pomerantz JL, Graham DR, Clements JE (2011) Minocy-cline suppresses activation ofnuclear factor ofactivated T cells 1 (NFAT1) inhuman CD4+ T Cells. JBiol Chem286:11275-11282
113. Tajima K, Miyagawa J, Nakajima H, Shimizu M, Katayama S, Mashita K, Tarui S (1985) Morphological and biochemical studies on minocycline-induced black thyroid in rats. Toxicol Appl Pharma-col 81:393-400 (Pubitemid 16185188)
114. Talbot S, Chahmi E, Dias JP, Couture R (2010) Key role for spinal dorsal horn microglial kinin B1 receptor in early diabetic pain neuropathy. J Neuroinflammation 7:36
115. Tobinick EL (2009) The value of drug repositioning in the current pharmaceutical market. Drug News Perspect 22:119-125
116. Torrance N, Smith BH, Bennett MI, Lee AJ (2006) The epidemiology ofchronic pain ofpredominantly neuropathic origin. Results from a general population survey. J Pain 7:281-289
117. Trang T, Beggs S, Wan X, Salter MW (2009) P2X4-receptor-mediated synthesis and release of brain-derived neurotrophic factor in microglia is dependent on calcium and p38-mitogen-activated protein kinase activation. J Neurosci 29:3518-3528
118. Trujillo KA, Akil H (1991) Inhibition of morphine tolerance and dependence by the NMDA receptor antagonist MK-801. Science 251:85-87 (Pubitemid 21916858)
119. Tsuda M, Shigemoto-Mogami Y, Koizumi S, Mizokoshi A, Kohsaka S, Salter MW, Inoue K (2003) P2X4 receptors induced in spinal micro-glia gate tactile allodynia after nerve injury. Nature 424:778-783 (Pubitemid 37021707)
120. Vale ML, Benevides VM, Sachs D, Brito GA, da Rocha FA, Poole S, Ferreira SH, Cunha FQ, Ribeiro RA (2004) Antihyperalgesic effect of pentoxifylline on experimental inflammatory pain. Br J Pharmacol 143:833-844 (Pubitemid 39664842)
121. Verge GM, Milligan ED, Maier SF, Watkins LR, Naeve GS, Foster AC (2004) Fractalkine (CX3CL1) and fractalkine re-ceptor (CX3CR1) distribution in spinal cord and dorsal root ganglia under basal and neuropathic pain conditions. Eur J Neurosci 20:1150-1160 (Pubitemid 39233569)
122. Wang LN, Yang JP, Zhan Y, Ji FH, Wang XY, Zuo JL, Xu QN (2011) Minocycline-induced reduction ofbrain-derived neurotrophic fac-tor expression in relation to cancer-induced bone pain in rats. J Neurosci Res. doi:10.1002/jnr.22788
123. Wardle RA, Poo MM (2003) Brain-derived neurotrophic factor mod-ulation of GABAergic synapses by postsynaptic regulation of chloride transport. J Neurosci 23:8722-8732 (Pubitemid 37176653)
124. Watkins LR, Maier SF (2003) Glia: a novel drug discovery target for clinical pain. Nat Rev Drug Discov 2:973-985 (Pubitemid 37540579)
125. Webster GF, Toso SM, Hegemann L (1994) Inhibition of a model of in vitro granuloma formation by tetracyclines and ciprofloxacin. Involvement of protein kinase C. Arch Dermatol 130:748-752 (Pubitemid 24182684)
126. White JP, Cantor CR (1971) Role of magnesium in the binding of tetracycline to Escherichia coli ribosomes. J Mol Biol 58:397-400
127. WHO (2009) World Health Organization Model List of Essential Medicines. Available on: http://www.who.int/medicines/publica tions/essentialmedicines/en. Accessed 30 November 2011
128. Willemen HL, Eijkelkamp N, Wang H, Dantzer R, Dorn GW 2nd, Kelley KW, Heijnen CJ, Kavelaars A (2010) Microglial/macro-phage GRK2 determines duration ofperipheral IL-1beta-induced hyperalgesia: contribution of spinal cord CX3CR1, p38 and IL-1 signaling. Pain 150:550-560
129. Woodcock J (2009) A difficult balance\-pain management, drug safety, and the FDA. N Engl J Med 361:2105-2107
130. Wu DC, Jackson-Lewis V, Vila M, Tieu K, Teismann P, Vadseth C, Choi DK, Ischiropoulos H, Przedborski S (2002) Blockade of microglial activation is neuroprotective in the 1-methyl-4-phenyl-1,2,3,6-tetra-hydropyridine mouse model of Parkinson disease. J Neurosci 22:1763-1771 (Pubitemid 35386294)
131. Younger J, Mackey S (2009) Fibromyalgia symptoms are reduced by low-dose naltrexone: a pilot study. Pain Med 10:663-672
132. 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 USA 95:15769-15774 (Pubitemid 29018775)
133. Yrjanheikki J, Tikka T, Keinanen R, Goldsteins G, Chan PH, Koistinaho J (1999) A tetracycline derivative, minocycline, reduces inflammation and protects against focal cerebral is-chemia with a wide therapeutic window. Proc Natl Acad Sci USA 96:13496-13500
134. Zanjani TM, Sabetkasaei M, Mosaffa N, Manaheji H, Labibi F, Farokhi B (2006) Suppression ofinterleukin-6 by minocycline in a rat model of neuropathic pain. Eur J Pharmacol 538:66-72
135. 2 contributes to pain after spinal cord injury. JNeurosci 27:2357-2368 (Pubitemid 46340975)
136. Zhao P, Waxman SG, Hains BC (2007b) Modulation of thalamic nociceptive processing after spinal cord injury through remote activation of thalamic microglia by cysteine-cysteine chemokine ligand 21. J Neurosci 27:8893-8902 (Pubitemid 47292772)
137. Zhou LJ, Zhong Y, Ren WJ, Li YY, Zhang T, Liu XG (2008) BDNF induces late-phase LTP of C-fiber evoked field potentials in rat spinal dorsal horn. Exp Neurol 212:507-514
138. Zhou LJ, Yang T, Wei X, Liu Y, Xin WJ, Chen Y, Pang RP, Zang Y, Li YY Liu XG (2011) Brain-derived neurotrophic factor contributes to spinal long-term potentiation and mechanical hypersensitivity by activation ofspinal microglia in rat Brain Behav Immun 25:322-334
139. Zhu S, Stavrovskaya IG, Drozda M, Kim BY, Ona V, Li M, Sarang S, Liu AS, Hartley DM, Wu DC, Gullans S, Ferrante RJ, Przedborski S, Kristal BS, Friedlander RM (2002) Minocycline inhibits cyto-chrome c release and delays progression of amyotrophic lateral sclerosis in mice. Nature 417:74-78 (Pubitemid 34498818)