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Tetracyclines and pain

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Abstract

Tetracyclines are natural or semi-synthetic bacteriostatic agents which have been used since late 1940s against a wide range of gram-positive and gram-negative bacteria and atypical organisms such as chlamydia, mycoplasmas, rickettsia, and protozoan parasites. After the discovery of the first tetracyclines, a second generation of compounds was sought in order to improve water solubility for parenteral administration or to enhance bioavailability after oral administration. This approach resulted in the development of doxycycline and minocycline in the 1970s. Doxycycline was included in the World Health Organization Model List of Essential Medicines either as antibacterial or to prevent malaria or to treat patients with this disease. Additional development led to the third generation of tetracyclines, being tigecycline the only medicine of this class to date. Besides antibacterial activities, the anti-inflammatory, antihypernociceptive and neuroprotective activities of tetracyclines began to be widely studied in the late 1990s. Indeed, there has been an increasing interest in investigating the effects induced by minocycline as this liposoluble derivative is known to cross the blood–brain barrier to the greatest extent. Minocycline induces antihypernociceptive effects in a wide range of animal models of nociceptive, inflammatory and neuropathic pain. In this study, we discuss the antihypernociceptive activity of tetracyclines and summarise its underlying cellular and molecular mechanisms.

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Abbreviations

BDNF:

Brain-derived neurotrophic factor

CCL21:

Chemokine (C–C motif) ligand 21

CFA:

Complete Freund’s adjuvant

CMT:

Chemically modified tetracycline

COX:

Cyclooxygenase

CX3CL1:

Fractalkine

CX3CR1:

Fractalkine receptor

GABA:

Gamma-amino butyric acid

HIV-1:

Human immunodeficiency virus-1

IL:

Interleukin

JNK:

c-Jun-N-terminal

KCC2:

K+-Cl− co-transporter 2

LPS:

Lipopolysaccharide

MAPK:

Mitogen-activated protein kinase

MHCII:

Major histocompatibility complex class II

MMP:

Matrix metalloproteinase

NFAT1:

Nuclear factor of activated T-cells 1

NF-κB:

Nuclear factor-kappa B

NGF:

Nerve growth factor

NMDA:

N-Methyl-d-aspartate

PARP-1:

Poly(ADP-ribose) polymerase-1

PG:

Prostaglandin

PKC:

Protein kinase C

PLA2 :

Phospholipase A2

PMIN:

12S-Hydroxy-1,12-pyrazolinominocycline

TLR4:

Toll-like receptor-4

TNF-α:

Tumour-necrosis factor-alpha

WHO:

World Health Organization

References

  • (2009) Deal watch: Novartis acquires marketing rights for novel broad-spectrum antibiotic. Nat Rev Drug Discov 8: 922

  • Alano CC, Kauppinen TM, Valls AV, Swanson RA (2006) Minocycline inhibits poly(ADP-ribose) polymerase-1 at nanomolar concentrations. Proc Natl Acad Sci USA 103:9685–9690

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • Aronson AL (1980) Pharmacotherapeutics of the newer tetracyclines. J Am Vet Med Assoc 176:1061–1068

    PubMed  CAS  Google Scholar 

  • Ashburn TT, Thor KB (2004) Drug repositioning: identifying and developing new uses for existing drugs. Nat Rev Drug Discov 3:673–683

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  CAS  Google Scholar 

  • Beggs S, Salter MW (2010) Microglia-neuronal signalling in neuropathic pain hypersensitivity 2.0. Curr Opin Neurobiol 20:474–480

    Article  PubMed  CAS  Google Scholar 

  • Bernardino AL, Kaushal D, Philipp MT (2009) The antibiotics doxycycline and minocycline inhibit the inflammatory responses to the Lyme disease spirochete Borrelia burgdorferi. J Infect Dis 199:1379–1388

    Article  PubMed  CAS  Google Scholar 

  • Blum D, Chtarto A, Tenenbaum L, Brotchi J, Levivier M (2004) Clinical potential of minocycline for neurodegenerative disorders. Neurobiol Dis 17:359–366

    Article  PubMed  CAS  Google Scholar 

  • Bocker R, Estler CJ, Ludewig-Sandig D (1991) Evaluation of the hepatotoxic potential of minocycline. Antimicrob Agents Chemother 35:1434–1436

    PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  Google Scholar 

  • Chacur M, Lambertz D, Hoheisel U, Mense S (2009) Role of spinal microglia in myositis-induced central sensitisation: an immunohistochemical and behavioural study in rats. Eur J Pain 13:915–923

    Article  PubMed  Google Scholar 

  • Chang YW, Waxman SG (2010) Minocycline attenuates mechanical allodynia and central sensitization following peripheral second-degree burn injury. J Pain 11:1146–1154

    PubMed  CAS  Google Scholar 

  • Chen Y, Sommer C (2009) The role of mitogen-activated protein kinase (MAPK) in morphine tolerance and dependence. Mol Neurobiol 40:101–107

    Article  PubMed  CAS  Google Scholar 

  • 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 expression and delays mortality in a transgenic mouse model of Huntington disease. Nat Med 6:797–801

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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 inflammatory pain in rat. Brain Res 1072:208–214

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • Chow AK, Cena J, Schulz R (2007) Acute actions and novel targets of matrix metalloproteinases in the heart and vasculature. Br J Pharmacol 152:189–205

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  CAS  Google Scholar 

  • Costigan M, Scholz J, Woolf CJ (2009) Neuropathic pain: a maladaptive response of the nervous system to damage. Annu Rev Neurosci 32:1–32

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • Cuzzocrea S, Chatterjee PK, Mazzon E, Dugo L, Serraino I, Britti D, Mazzullo G, Caputi AP, Thiemermann C (2002) Pyrrolidine dithiocarbamate attenuates the development of acute and chronic inflammation. Br J Pharmacol 135:496–510

    Article  PubMed  CAS  Google Scholar 

  • Dray A (2008) Neuropathic pain: emerging treatments. Br J Anaesth 101:48–58

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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 of acute neuroprotection. Exp Neurol 186:248–251

    Article  PubMed  CAS  Google Scholar 

  • Gabler WL, Creamer HR (1991) Suppression of human neutrophil functions by tetracyclines. J Periodontal Res 26:52–58

    Article  PubMed  CAS  Google Scholar 

  • Golub LM, McNamara TF, D'Angelo G, Greenwald RA, Ramamurthy NS (1987) A non-antibacterial chemically-modified tetracycline inhibits mammalian collagenase activity. J Dent Res 66:1310–1314

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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 glutamatergic neurotransmission and Ca(2+) signalling in hippocampal neurons. Eur J Neurosci 26:2481–2495

    Article  PubMed  Google Scholar 

  • Goulden V, Glass D, Cunliffe WJ (1996) Safety of long-term high-dose minocycline in the treatment of acne. Br J Dermatol 134:693–695

    Article  PubMed  CAS  Google Scholar 

  • Habibi-Asl B, Hassanzadeh K, Charkhpour M (2009) Central administration of minocycline and riluzole prevents morphine-induced tolerance in rats. Anesth Analg 109:936–942

    Article  PubMed  CAS  Google Scholar 

  • Hains BC, Waxman SG (2006) Activated microglia contribute to the maintenance of chronic pain after spinal cord injury. J Neurosci 26:4308–4317

    Article  PubMed  CAS  Google Scholar 

  • Hamann S, Sloan P (2007) Oral naltrexone to enhance analgesia in patients receiving continuous intrathecal morphine for chronic pain: a randomized, double-blind, prospective pilot study. J Opioid Manag 3:137–144

    PubMed  Google Scholar 

  • Hashimoto K, Ishima T (2010) A novel target of action of minocycline in NGF-induced neurite outgrowth in PC12 cells: translation initiation factor eIF4AI. PLoS One 5:e15430

    Article  PubMed  CAS  Google Scholar 

  • Hassanzadeh K, Habibi-asl B, Farajnia S, Roshangar L (2011) Minocycline prevents morphine-induced apoptosis in rat cerebral cortex and lumbar spinal cord: a possible mechanism for attenuating morphine tolerance. Neurotox Res 19:649–659

    Article  PubMed  CAS  Google Scholar 

  • Hu P, McLachlan EM (2002) Macrophage and lymphocyte invasion of dorsal root ganglia after peripheral nerve lesions in the rat. Neuroscience 112:23–38

    Article  PubMed  CAS  Google Scholar 

  • Hu J, Van den Steen PE, Sang QX, Opdenakker G (2007a) Matrix metalloproteinase inhibitors as therapy for inflammatory and vascular diseases. Nat Rev Drug Discov 6:480–498

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  Google Scholar 

  • 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

    Article  PubMed  Google Scholar 

  • Hunskaar S, Hole K (1987) The formalin test in mice: dissociation between inflammatory and non-inflammatory pain. Pain 30:103–114

    Article  PubMed  CAS  Google Scholar 

  • 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 analgesia. Brain Behav Immun 22:1248–1256

    Article  PubMed  CAS  Google Scholar 

  • 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 receptor 4 (TLR4). Eur J Neurosci 28:20–29

    Article  PubMed  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • Hutchinson MR, Zhang Y, Shridhar M, Evans JH, Buchanan MM, Zhao TX, Slivka PF, Coats BD, Rezvani N, Wieseler J, Hughes TS, Landgraf KE, 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

    Article  PubMed  CAS  Google Scholar 

  • Ito N, Obata H, Saito S (2009) Spinal microglial expression and mechanical hypersensitivity in a postoperative pain model: comparison with a neuropathic pain model. Anesthesiology 111:640–648

    Article  PubMed  Google Scholar 

  • 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 23:4017–4022

    PubMed  CAS  Google Scholar 

  • Kim HS, Suh YH (2009) Minocycline and neurodegenerative diseases. Behav Brain Res 196:168–179

    Article  PubMed  CAS  Google Scholar 

  • Kim SS, Kong PJ, Kim BS, Sheen DH, Nam SY, Chun W (2004) Inhibitory action of minocycline on lipopolysaccharide-induced release of nitric oxide and prostaglandin E2 in BV2 microglial cells. Arch Pharm Res 27:314–318

    Article  PubMed  CAS  Google Scholar 

  • Kim TH, Kim HI, Kim J, Park M, Song JH (2011) Effects of minocycline on Na(+) currents in rat dorsal root ganglion neurons. Brain Res 1370:34–42

    Article  PubMed  CAS  Google Scholar 

  • Kwon BK, Sekhon LH, Fehlings MG (2010) Emerging repair, regeneration, and translational research advances for spinal cord injury. Spine 35:S263–S270

    Article  PubMed  Google Scholar 

  • Leblanc BW, Zerah ML, Kadasi LM, Chai N, Saab CY (2011) Minocycline injection in the ventral posterolateral thalamus reverses microglial reactivity and thermal hyperalgesia secondary to sciatic neuropathy. Neurosci Lett 498:138–142

    Article  PubMed  CAS  Google Scholar 

  • 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 115:71–83

    Article  PubMed  CAS  Google Scholar 

  • Lertvorachon J, Kim JP, Soldatov DV, Boyd J, Roman G, Cho SJ, Popek T, Jung YS, Lau PC, Konishi Y (2005) 1,12-Substituted tetracyclines as antioxidant agents. Bioorg Med Chem 13:4627–4637

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • Light RW, Wang NS, Sassoon CS, Gruer SE, Vargas FS (1994) Comparison of the effectiveness of tetracycline and minocycline as pleural sclerosing agents in rabbits. Chest 106:577–582

    Article  PubMed  CAS  Google Scholar 

  • Ma L, Nagai J, Ueda H (2010) Microglial activation mediates de novo lysophosphatidic acid production in a model of neuropathic pain. J Neurochem 115:643–653

    Article  PubMed  CAS  Google Scholar 

  • Mao J, Price DD, Mayer DJ (1994) Thermal hyperalgesia in association with the development of morphine tolerance in rats: roles of excitatory amino acid receptors and protein kinase C. J Neurosci 14:2301–2312

    PubMed  CAS  Google Scholar 

  • Mao J, Sung B, Ji RR, Lim G (2002) Neuronal apoptosis associated with morphine tolerance: evidence for an opioid-induced neurotoxic mechanism. J Neurosci 22:7650–7661

    PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • Mattioli TA, Milne B, Cahill CM (2010) Ultra-low dose naltrexone attenuates chronic morphine-induced gliosis in rats. Mol Pain 6:22

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • Melnikova I (2010) Pain market. Nat Rev Drug Discov 9:589–590

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • Mika J, Rojewska E, Makuch W, Przewlocka B (2010) Minocycline reduces the injury-induced expression of prodynorphin and pronociceptin in the dorsal root ganglion in a rat model of neuropathic pain. Neuroscience 165:1420–1428

    Article  PubMed  CAS  Google Scholar 

  • Milligan ED, Watkins LR (2009) Pathological and protective roles of glia in chronic pain. Nat Rev Neurosci 10:23–36

    Article  PubMed  CAS  Google Scholar 

  • 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 glycoprotein, gp120. Brain Res 861:105–116

    Article  PubMed  CAS  Google Scholar 

  • 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 exogenous and endogenous fractalkine can induce spinal nociceptive facilitation in rats. Eur J Neurosci 20:2294–2302

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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 potassium chloride co-transporter 2 (KCC2) at the spinal cord. Diabetes Obes Metab 13:150–159

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • Mullard A (2011) 2010 FDA drug approvals. Nat Rev Drug Discov 10:82–85

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • Patel RN, Attur MG, Dave MN, Patel IV, Stuchin SA, Abramson SB, Amin AR (1999) A novel mechanism of action of chemically modified tetracyclines: inhibition of COX-2-mediated prostaglandin E2 production. J Immunol 163:3459–3467

    PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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 following trigeminal sensory nerve injury. Pain 121:219–231

    Article  PubMed  CAS  Google Scholar 

  • Poiger H, Schlatter C (1979) Interaction of cations and chelators with the intestinal absorption of tetracycline. Naunyn Schmiedebergs Arch Pharmacol 306:89–92

    Article  PubMed  CAS  Google Scholar 

  • Prado WA (2001) Involvement of calcium in pain and antinociception. Braz J Med Biol Res 34:449–461

    Article  PubMed  CAS  Google Scholar 

  • Pruzanski W, Greenwald RA, Street IP, Laliberte F, Stefanski E, Vadas P (1992) Inhibition of enzymatic activity of phospholipases A2 by minocycline and doxycycline. Biochem Pharmacol 44:1165–1170

    Article  PubMed  CAS  Google Scholar 

  • Pruzanski W, Stefanski E, Vadas P, McNamara TF, Ramamurthy N, Golub LM (1998) Chemically modified non-antimicrobial tetracyclines inhibit activity of phospholipases A2. J Rheumatol 25:1807–1812

    PubMed  CAS  Google Scholar 

  • Raghavendra V, Tanga F, DeLeo JA (2003) Inhibition of microglial activation attenuates the development but not existing hypersensitivity in a rat model of neuropathy. J Pharmacol Exp Ther 306:624–630

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • Roberts J, Ossipov MH, Porreca F (2009) Glial activation in the rostroventromedial medulla promotes descending facilitation to mediate inflammatory hypersensitivity. Eur J Neurosci 30:229–241

    Article  PubMed  Google Scholar 

  • 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 prostaglandin E(2) and TNF. Br J Pharmacol 160:1754–1764

    Article  PubMed  CAS  Google Scholar 

  • Saliba R, Paasch L, El Solh A (2009) Tigecycline attenuates staphylococcal superantigen-induced T-cell proliferation and production of cytokines and chemokines. Immunopharmacol Immunotoxicol 31:583–588

    Article  PubMed  CAS  Google Scholar 

  • 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 pulmonary cytokines and chemokines in a murine model of Mycoplasma pneumoniae pneumonia. Antimicrob Agents Chemother 53:1546–1551

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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 production in mast cells: possible involvement of protein kinase C. Inflamm Res 54:304–312

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  Google Scholar 

  • 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 microglia involved in the anti-allodynic and anti-hyperalgesic effects of electroacupuncture in rat model of monoarthritis? Neurobiol Dis 26:558–568

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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 Neurovirol 10:284–292

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • Smith DL, Woodman B, Mahal A, Sathasivam K, Ghazi-Noori S, Lowden PA, Bates GP, Hockly E (2003) Minocycline and doxycycline are not beneficial in a model of Huntington's disease. Ann Neurol 54:186–196

    Article  PubMed  CAS  Google Scholar 

  • Soleimannejad E, Naghdi N, Semnanian S, Fathollahi Y, Kazemnejad A (2007) Antinociceptive effect of intra-hippocampal CA1 and dentate gyrus injection of MK801 and AP5 in the formalin test in adult male rats. Eur J Pharmacol 562:39–46

    Article  PubMed  CAS  Google Scholar 

  • Sorkin LS, Schäfers M (2007) Immune cells in peripheral nerve. In: DeLeo JA, Sorkin LS, Watkins LR (eds) Immune and glial regulation of pain, 1st edn. IASP Press, Seattle, WA, pp 3–19

    Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • Szeto GL, Pomerantz JL, Graham DR, Clements JE (2011) Minocycline suppresses activation of nuclear factor of activated T cells 1 (NFAT1) in human CD4+ T Cells. J Biol Chem 286:11275–11282

    Article  PubMed  CAS  Google Scholar 

  • 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 Pharmacol 81:393–400

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • Tobinick EL (2009) The value of drug repositioning in the current pharmaceutical market. Drug News Perspect 22:119–125

    Article  PubMed  Google Scholar 

  • Torrance N, Smith BH, Bennett MI, Lee AJ (2006) The epidemiology of chronic pain of predominantly neuropathic origin. Results from a general population survey. J Pain 7:281–289

    Article  PubMed  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • Trujillo KA, Akil H (1991) Inhibition of morphine tolerance and dependence by the NMDA receptor antagonist MK-801. Science 251:85–87

    Article  PubMed  CAS  Google Scholar 

  • Tsuda M, Shigemoto-Mogami Y, Koizumi S, Mizokoshi A, Kohsaka S, Salter MW, Inoue K (2003) P2X4 receptors induced in spinal microglia gate tactile allodynia after nerve injury. Nature 424:778–783

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • Verge GM, Milligan ED, Maier SF, Watkins LR, Naeve GS, Foster AC (2004) Fractalkine (CX3CL1) and fractalkine receptor (CX3CR1) distribution in spinal cord and dorsal root ganglia under basal and neuropathic pain conditions. Eur J Neurosci 20:1150–1160

    Article  PubMed  Google Scholar 

  • Wang LN, Yang JP, Zhan Y, Ji FH, Wang XY, Zuo JL, Xu QN (2011) Minocycline-induced reduction of brain-derived neurotrophic factor expression in relation to cancer-induced bone pain in rats. J Neurosci Res. doi:10.1002/jnr.22788

  • Wardle RA, Poo MM (2003) Brain-derived neurotrophic factor modulation of GABAergic synapses by postsynaptic regulation of chloride transport. J Neurosci 23:8722–8732

    PubMed  CAS  Google Scholar 

  • Watkins LR, Maier SF (2003) Glia: a novel drug discovery target for clinical pain. Nat Rev Drug Discov 2:973–985

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • White JP, Cantor CR (1971) Role of magnesium in the binding of tetracycline to Escherichia coli ribosomes. J Mol Biol 58:397–400

    Article  PubMed  CAS  Google Scholar 

  • WHO (2009) World Health Organization Model List of Essential Medicines. Available on: http://www.who.int/medicines/publications/essentialmedicines/en. Accessed 30 November 2011

  • Willemen HL, Eijkelkamp N, Wang H, Dantzer R, Dorn GW 2nd, Kelley KW, Heijnen CJ, Kavelaars A (2010) Microglial/macrophage GRK2 determines duration of peripheral IL-1beta-induced hyperalgesia: contribution of spinal cord CX3CR1, p38 and IL-1 signaling. Pain 150:550–560

    Article  PubMed  CAS  Google Scholar 

  • Woodcock J (2009) A difficult balance—pain management, drug safety, and the FDA. N Engl J Med 361:2105–2107

    Article  PubMed  CAS  Google Scholar 

  • 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-tetrahydropyridine mouse model of Parkinson disease. J Neurosci 22:1763–1771

    PubMed  CAS  Google Scholar 

  • Younger J, Mackey S (2009) Fibromyalgia symptoms are reduced by low-dose naltrexone: a pilot study. Pain Med 10:663–672

    Article  PubMed  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • Yrjanheikki J, Tikka T, Keinanen R, Goldsteins G, Chan PH, Koistinaho J (1999) A tetracycline derivative, minocycline, reduces inflammation and protects against focal cerebral ischemia with a wide therapeutic window. Proc Natl Acad Sci USA 96:13496–13500

    Article  PubMed  CAS  Google Scholar 

  • Zanjani TM, Sabetkasaei M, Mosaffa N, Manaheji H, Labibi F, Farokhi B (2006) Suppression of interleukin-6 by minocycline in a rat model of neuropathic pain. Eur J Pharmacol 538:66–72

    Article  PubMed  CAS  Google Scholar 

  • Zhao P, Waxman SG, Hains BC (2007a) Extracellular signal-regulated kinase-regulated microglia-neuron signaling by prostaglandin E2 contributes to pain after spinal cord injury. J Neurosci 27:2357–2368

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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 of spinal microglia in rat. Brain Behav Immun 25:322–334

    Article  PubMed  CAS  Google Scholar 

  • 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 cytochrome c release and delays progression of amyotrophic lateral sclerosis in mice. Nature 417:74–78

    Article  PubMed  CAS  Google Scholar 

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Acknowledgements

We acknowledge Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES, Ministry of Education, Brazil), Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq, Ministry of Science and Technology, Brazil), Fundação de Apoio à Pesquisa do Estado de Minas Gerais (FAPEMIG, Minas Gerais, Brazil) and Pró-Reitoria de Pesquisa (PRPq) da UFMG for constant support.

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  1. Departamento de Fisiologia e Biofísica, Instituto de Ciências Biológicas (ICB), Bloco A4, Sala 168, Universidade Federal de Minas Gerais (UFMG), Avenida Antônio Carlos 6627, 31270-901, Belo Horizonte, Brazil

    Leandro F. S. Bastos & Márcio F. D. Moraes

  2. Departamento de Farmacologia, Instituto de Ciências Biológicas (ICB), Universidade Federal de Minas Gerais (UFMG), Avenida Antônio Carlos 6627, 31270-901, Belo Horizonte, Brazil

    Antônio C. P. de Oliveira

  3. Department of Psychology and Neuroscience, University of Colorado Boulder, Boulder, CO, USA

    Linda R. Watkins

  4. Departamento de Produtos Farmacêuticos, Faculdade de Farmácia, Universidade Federal de Minas Gerais (UFMG), Avenida Antônio Carlos 6627, 31270-901, Belo Horizonte, Brazil

    Márcio M. Coelho

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  1. Leandro F. S. Bastos
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  2. Antônio C. P. de Oliveira
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Correspondence to Leandro F. S. Bastos.

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Bastos, L.F.S., de Oliveira, A.C.P., Watkins, L.R. et al. Tetracyclines and pain. Naunyn-Schmiedeberg's Arch Pharmacol 385, 225–241 (2012). https://doi.org/10.1007/s00210-012-0727-1

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