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Alendronate Attenuates Spinal Microglial Activation and Neuropathic Pain

      Highlights

      • Alendronate significantly prevented development of chronic constriction injury–induced mechanical/thermal hypersensitivity, after intrathecal and intra-peritoneal administration.
      • Chronic constriction injury–induced microglial activation and phosphorylation of p38 in the spinal cord were attenuated by alendronate administration.
      • Alendronate downregulated phosphorylated p38 expression and decreased the expression of inflammatory cytokines (tumor necrosis factor α, and interleukins 1β and 6) in lipopolysaccharide-stimulated primary microglia culture.

      Abstract

      Many derivatives of bisphosphonates, which are inhibitors of bone resorption, have been developed as promising agents for painful pathologies in patients with bone resorption-related diseases. The mechanism for pain relief by bisphosphonates remains uncertain. Studies have reported that bisphosphonates could reduce central neurochemical changes involved in the generation and maintenance of bone cancer pain. In this study, we hypothesized that bisphosphonates would inhibit spinal microglial activation and prevent the development of hyperalgesia caused by peripheral tissue injury. We investigated the effects of alendronate (a nitrogen-containing bisphosphonate) on the development of neuropathic pain and its role in modulating microglial activation in vivo and in vitro. Intrathecal and intraperitoneal administration of alendronate relieved neuropathic pain behaviors induced by chronic constriction sciatic nerve injury. Alendronate also significantly attenuated spinal microglial activation and p38 mitogen-activated protein kinase (MAPK) phosphorylation without affecting astrocytes. In vitro, alendronate downregulated phosphorylated p38 and phosphorylated extracellular signal regulated kinase expression in lipopolysaccharide-stimulated primary microglia within 1 hour, and pretreatment with alendronate for 12 and 24 hours decreased the expression of inflammatory cytokines (tumor necrosis factor α, and interleukins 1β and 6). These findings indicate that alendronate could effectively relieve chronic constriction sciatic nerve injury–induced neuropathic pain by at least partially inhibiting the activation of spinal microglia and the p38 MAPK signaling pathway.

      Perspective

      Alendronate could relieve neuropathic pain behaviors in animals by inhibiting the activation of spinal cord microglia and the p38 MAPK cell signaling pathway. Therapeutic applications of alendronate may be extended beyond bone metabolism–related disease.

      Key words

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      References

        • Ash P.
        • Loutit J.F.
        • Townsend K.M.
        Osteoclasts derived from haematopoietic stem cells.
        Nature. 1980; 283: 669-670
        • Bagriyanik H.A.
        • Ersoy N.
        • Cetinkaya C.
        • Ikizoglu E.
        • Kutri D.
        • Ozcana T.
        • Kamanga L.G.
        • Kiray M.
        The effects of resveratrol on chronic constriction injury of sciatic nerve in rats.
        Neurosci Lett. 2014; 561: 123-127
        • Bennett G.J.
        • Xie Y.K.
        A peripheral mononeuropathy in rat that produces disorders of pain sensation like those seen in man.
        Pain. 1988; 33: 87-107
        • Bianchi M.
        • Franchi S.
        • Ferrario P.
        • Sotgiu M.L.
        • Sacerdote P.
        Effects of the bisphosphonate ibandronate on hyperalgesia, substance P, and cytokine levels in a rat model of persistent inflammatory pain.
        Eur J Pain. 2008; 12: 284-292
        • Black D.M.
        • Bauer D.C.
        • Schwartz A.V.
        • Cummings S.R.
        • Rosen C.J.
        Continuing bisphosphonate treatment for osteoporosis–for whom and for how long?.
        N Engl J Med. 2012; 366: 2051-2053
        • Boddeke E.W.
        Involvement of chemokines in pain.
        Eur J Pharmacol. 2001; 429: 115-119
        • Bonabello A.
        • Galmozzi M.R.
        • Bruzzese T.
        • Zara G.P.
        Analgesic effect of bisphosphonates in mice.
        Pain. 2001; 91: 269-275
        • Bonjour J.P.
        • Theintz G.
        • Law F.
        • Slosman D.
        • Rizzoli R.
        Peak bone mass.
        Osteoporosis Int. 1994; 4: 7-13
        • Chen X.Y.
        • Li K.
        • Light A.R.
        • Fu K.Y.
        Simvastatin attenuates formalin-induced nociceptive behaviors by inhibiting microglial RhoA and p38 MAPK activation.
        J Pain. 2013; 14: 1310-1319
        • Colburn R.W.
        • DeLeo J.A.
        The effect of perineural colchicine on nerve injury-induced spinal glial activation and neuropathic pain behavior.
        Brain Res Bull. 1999; 49: 419-427
        • Colburn R.W.
        • Rickman A.J.
        • DeLeo J.A.
        The effect of site and type of nerve injury on spinal glial activation and neuropathic pain behavior.
        Exp Neurol. 1999; 157: 289-304
        • DeLeo J.A.
        • Yezierski R.P.
        The role of neuroinflammation and neuroimmune activation in persistent pain.
        Pain. 2001; 90: 1-6
        • Echeverry S.
        • Shi X.Q.
        • Zhang J.
        Characterization of cell proliferation in rat spinal cord following peripheral nerve injury and the relationship with neuropathic pain.
        Pain. 2008; 135: 37-47
        • Filipponi P.
        • Pedetti M.
        • Beghe F.
        • Giovagnini B.
        • Miam M.
        • Cristallini S.
        Effects of two different bisphosphonates on Paget’s disease of bone: ICTP assessed.
        Bone. 1994; 15: 261-267
        • Fu K.Y.
        • Tan Y.H.
        • Sung B.
        • Mao J.
        Peripheral formalin injection induces unique spinal cord microglial phenotypic changes.
        Neurosci Lett. 2009; 449: 234-239
        • Giulian D.
        • Baker T.J.
        Characterization of ameboid microglia isolated from developing mammalian brain.
        J Neurosci. 1986; 6: 2163-2178
        • Goicoechea C.
        • Porras E.
        • Alfaro M.J.
        • Martin M.I.
        Alendronate induces antinociception in mice, not related with its effects in bone.
        Jpn J Pharmacol. 1999; 79: 433-437
        • Green J.R.
        • Muller K.
        • Jaeggi K.A.
        Preclinical pharmacology of CGP 42'446, a new, potent, heterocyclic bisphosphonate compound.
        J Bone Miner Res. 1994; 9: 745-751
        • Gruol D.L.
        • Nelson T.E.
        Physiological and pathological roles of interleukin-6 in the central nervous system.
        Mol Neurobiol. 1997; 15: 307-339
        • Han S.R.
        • Yang G.Y.
        • Ahn M.H.
        • Kim M.J.
        • Ju J.S.
        • Bae Y.C.
        • Ahn D.K.
        Blockade of microglial activation reduces mechanical allodynia in rats with compression of the trigeminal ganglion.
        Prog Neuropsychopharmacol Biol Psychiatry. 2012; 36: 52-59
        • Hargreaves K.
        • Dubner R.
        • Brown F.
        • Flores C.
        • Joris J.
        A new and sensitive method for measuring thermal nociception in cutaneous hyperalgesia.
        Pain. 1988; 32: 77-88
        • Hermiston M.L.
        • Xu Z.
        • Weiss A.
        CD45: A critical regulator of signaling thresholds in immune cells.
        Annual review of immunology. 2003; 21: 107-137
        • Hopkins S.J.
        • Rothwell N.J.
        Cytokines and the nervous system. I: Expression and recognition.
        Trends Neurosci. 1995; 18: 83-88
        • Hosfield D.J.
        • Zhang Y.
        • Dougan D.R.
        • Broun A.
        • Tari L.W.
        • Swanson R.V.
        • Finn J.
        Structural basis for bisphosphonate-mediated inhibition of isoprenoid biosynthesis.
        J Biol Chem. 2004; 279: 8526-8529
        • Hu B.
        • Doods H.
        • Treede R.D.
        • Ceci A.
        Depression-like behaviour in rats with mononeuropathy is reduced by the CB2-selective agonist GW405833.
        Pain. 2009; 143: 206-212
        • Inoue M.
        • Rashid M.H.
        • Fujita R.
        • Contos J.J.
        • Chun J.
        • Ueda H.
        Initiation of neuropathic pain requires lysophosphatidic acid receptor signaling.
        Nat Med. 2004; 10: 712-718
        • Iwamoto J.
        • Makita K.
        • Sato Y.
        • Takeda T.
        • Matsumoto H.
        Alendronate is more effective than elcatonin in improving pain and quality of life in postmenopausal women with osteoporosis.
        Osteoporosis Int. 2011; 22: 2735-2742
        • Jin S.X.
        • Zhuang Z.Y.
        • Woolf C.J.
        • Ji R.R.
        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. 2003; 23: 4017-4022
        • Kamaraju A.K.
        • Roberts A.B.
        Role of Rho/ROCK and p38 MAP kinase pathways in transforming growth factor-beta-mediated Smad-dependent growth inhibition of human breast carcinoma cells in vivo.
        J Biol Chem. 2005; 280: 1024-1036
        • Katsura H.
        • Obata K.
        • Mizushima T.
        • Sakurai J.
        • Kobayashi K.
        • Yamanaka H.
        • Dai Y.
        • Fukuoka T.
        • Sakagami M.
        • Noguchi K.
        Activation of Src-family kinases in spinal microglia contributes to mechanical hypersensitivity after nerve injury.
        J Neurosci. 2006; 26: 8680-8690
        • Keen R.W.
        • Spector T.D.
        Alendronate: A new bisphosphonate for the treatment of osteoporosis.
        Br J Clin Pract. 1996; 50: 211-217
        • Kontinen V.K.
        • Ahnaou A.
        • Drinkenburg W.H.
        • Meert T.F.
        Sleep and EEG patterns in the chronic constriction injury model of neuropathic pain.
        Physiol Behav. 2003; 78: 241-246
        • Koyama Y.
        • Kimura Y.
        • Yoshioka Y.
        • Wakamatsu D.
        • Kozaki R.
        • Hashimoto H.
        • Matsuda T.
        • Baba A.
        Serum-deprivation induces cell death of rat cultured microglia accompanied with expression of Bax protein.
        Jpn J Pharmacol. 2000; 83: 351-354
        • Latremoliere A.
        • Woolf C.J.
        Central sensitization: A generator of pain hypersensitivity by central neural plasticity.
        J Pain. 2009; 10: 895-926
        • Lee M.K.
        • Han S.R.
        • Park M.K.
        • Kim M.J.
        • Bae Y.C.
        • Kim S.K.
        • Park J.S.
        • Ahn D.K.
        Behavioral evidence for the differential regulation of p-p38 MAPK and p-NF-kappaB in rats with trigeminal neuropathic pain.
        Mol Pain. 2011; 7: 57
        • Li K.
        • Tan Y.H.
        • Light A.R.
        • Fu K.Y.
        Different peripheral tissue injury induces differential phenotypic changes of spinal activated microglia.
        Clin Dev Immunol. 2013; 901420: 2013
        • Liu B.
        • Wang K.
        • Gao H.M.
        • Mandavilli B.
        • Wang J.Y.
        • Hong J.S.
        Molecular consequences of activated microglia in the brain: overactivation induces apoptosis.
        J Neurochem. 2001; 77: 182-189
        • Mackey S.
        • Feinberg S.
        Pharmacologic therapies for complex regional pain syndrome.
        Curr Pain Headache Rep. 2007; 11: 38-43
        • Malan T.P.
        • Ossipov M.H.
        • Gardell L.R.
        • Ibrahim M.
        • Bian D.
        • Lai J.
        • Porreca F.
        Extraterritorial neuropathic pain correlates with multisegmental elevation of spinal dynorphin in nerve-injured rats.
        Pain. 2000; 86: 185-194
        • Mika J.
        Modulation of microglia can attenuate neuropathic pain symptoms and enhance morphine effectiveness.
        Pharmacol Rep. 2008; 60: 297-307
        • Milligan E.D.
        • Watkins L.R.
        Pathological and protective roles of glia in chronic pain.
        Nat Rev Neurosci. 2009; 10: 23-36
        • Moon H.J.
        • Yun Y.P.
        • Han C.W.
        • Kim M.S.
        • Kim S.E.
        • Bae M.S.
        • Kim G.T.
        • Choi Y.S.
        • Hwang E.H.
        • Lee J.W.
        • Lee J.M.
        • Lee C.H.
        • Kim D.S.
        • Kwon I.K.
        Effect of heparin and alendronate coating on titanium surfaces on inhibition of osteoclast and enhancement of osteoblast function.
        Biochem Biophys Res Comm. 2011; 413: 194-200
        • Ohsawa M.
        • Mutoh J.
        • Hisa H.
        Mevalonate sensitizes the nociceptive transmission in the mouse spinal cord.
        Pain. 2008; 134: 285-292
        • Ono K.
        • Han J.
        The p38 signal transduction pathway: Activation and function.
        Cell Signal. 2000; 12: 1-13
        • Oura S.
        • Sakurai T.
        • Yoshimura G.
        • Tamaki T.
        • Umemura T.
        • Kokawa Y.
        • Naito Y.
        Gan To Kagaku Ryoho. 2000; 27 ([in Japanese]): 633-637
        • Owens J.M.
        • Fuller K.
        • Chambers T.J.
        Osteoclast activation: Potent inhibition by the bisphosphonate alendronate through a nonresorptive mechanism.
        J Cell Physiol. 1997; 172: 79-86
        • Padi S.S.
        • Kulkarni S.K.
        Minocycline prevents the development of neuropathic pain, but not acute pain: Possible anti-inflammatory and antioxidant mechanisms.
        Eur J Pharmacol. 2008; 601: 79-87
        • Penninger J.M.
        • Irie-Sasaki J.
        • Sasaki T.
        • Oliveira-dos-Santos A.J.
        CD45: New jobs for an old acquaintance.
        Nat Immunol. 2001; 2: 389-396
        • Pullikuth A.K.
        • Catling A.D.
        Scaffold mediated regulation of MAPK signaling and cytoskeletal dynamics: A perspective.
        Cell Signal. 2007; 19: 1621-1632
        • Rogers M.J.
        • Crockett J.C.
        • Coxon F.P.
        • Monkkonen J.
        Biochemical and molecular mechanisms of action of bisphosphonates.
        Bone. 2011; 49: 34-41
        • Rogers M.J.
        • Gordon S.
        • Benford H.L.
        • Coxon F.P.
        • Luckman S.P.
        • Monkkonen J.
        • Frith J.C.
        Cellular and molecular mechanisms of action of bisphosphonates.
        Cancer. 2000; 88: 2961-2978
        • Rozas G.
        • Lopez-Martin E.
        • Guerra M.J.
        • Labandeira-Garcia J.L.
        The overall rod performance test in the MPTP-treated-mouse model of Parkinsonism.
        J Neurosci Methods. 1998; 83: 165-175
        • Ruperez M.
        • Rodrigues-Diez R.
        • Blanco-Colio L.M.
        • Sanchez-Lopez E.
        • Rodriguez-Vita J.
        • Esteban V.
        • Carvajal G.
        • Plaza J.J.
        • Egido J.
        • Ruiz-Ortega M.
        HMG-CoA reductase inhibitors decrease angiotensin II-induced vascular fibrosis: Role of RhoA/ROCK and MAPK pathways.
        Hypertension. 2007; 50: 377-383
        • Schmidt A.
        • Rutledge S.J.
        • Endo N.
        • Opas E.E.
        • Tanaka H.
        • Wesolowski G.
        • Leu C.T.
        • Huang Z.
        • Ramachandaran C.
        • Rodan S.B.
        • Rodan G.A.
        Protein-tyrosine phosphatase activity regulates osteoclast formation and function: Inhibition by alendronate.
        Proc Natl Acad Sci U S A. 1996; 93: 3068-3073
        • Schwei M.J.
        • Honore P.
        • Rogers S.D.
        • Salak-Johnson J.L.
        • Finke M.P.
        • Ramnaraine M.L.
        • Clohisy D.R.
        • Mantyh P.W.
        Neurochemical and cellular reorganization of the spinal cord in a murine model of bone cancer pain.
        J Neurosci. 1999; 19: 10886-10897
        • Senokuchi T.
        • Matsumura T.
        • Sakai M.
        • Yano M.
        • Taguchi T.
        • Matsuo T.
        • Sonoda K.
        • Kukidome D.
        • Imoto K.
        • Nishikawa T.
        • Kim-Mitsuyama S.
        • Takuwa Y.
        • Araki E.
        Statins suppress oxidized low density lipoprotein-induced macrophage proliferation by inactivation of the small G protein-p38 MAPK pathway.
        J Biol Chem. 2005; 280: 6627-6633
        • Sevcik M.A.
        • Luger N.M.
        • Mach D.B.
        • Sabino M.A.
        • Peters C.M.
        • Ghilardi J.R.
        • Schwei M.J.
        • Rohrich H.
        • De Felipe C.
        • Kuskowski M.A.
        • Mantyh P.W.
        Bone cancer pain: The effects of the bisphosphonate alendronate on pain, skeletal remodeling, tumor growth and tumor necrosis.
        Pain. 2004; 111: 169-180
        • Shi X.Q.
        • Lim T.K.
        • Lee S.
        • Zhao Y.Q.
        • Zhang J.
        Statins alleviate experimental nerve injury-induced neuropathic pain.
        Pain. 2011; 152: 1033-1043
        • Song J.X.
        • Ren J.Y.
        • Chen H.
        Simvastatin reduces lipoprotein-associated phospholipase A2 in lipopolysaccharide-stimulated human monocyte-derived macrophages through inhibition of the mevalonate-geranylgeranyl pyrophosphate-RhoA-p38 mitogen-activated protein kinase pathway.
        J Cardiovasc Pharmacol. 2011; 57: 213-222
        • Tal M.
        • Bennett G.J.
        Extra-territorial pain in rats with a peripheral mononeuropathy: Mechano-hyperalgesia and mechano-allodynia in the territory of an uninjured nerve.
        Pain. 1994; 57: 375-382
        • Tanga F.Y.
        • Raghavendra V.
        • DeLeo J.A.
        Quantitative real-time RT-PCR assessment of spinal microglial and astrocytic activation markers in a rat model of neuropathic pain.
        Neurochem Int. 2004; 45: 397-407
        • Tatsumi S.
        • Mabuchi T.
        • Katano T.
        • Matsumura S.
        • Abe T.
        • Hidaka H.
        • Suzuki M.
        • Sasaki Y.
        • Minami T.
        • Ito S.
        Involvement of Rho-kinase in inflammatory and neuropathic pain through phosphorylation of myristoylated alanine-rich C-kinase substrate (MARCKS).
        Neuroscience. 2005; 131: 491-498
        • Terayama R.
        • Omura S.
        • Fujisawa N.
        • Yamaai T.
        • Ichikawa H.
        • Sugimoto T.
        Activation of microglia and p38 mitogen-activated protein kinase in the dorsal column nucleus contributes to tactile allodynia following peripheral nerve injury.
        Neuroscience. 2008; 153: 1245-1255
        • Tsuda M.
        • Inoue K.
        • Salter M.W.
        Neuropathic pain and spinal microglia: A big problem from molecules in “small” glia.
        Trends Neurosci. 2005; 28: 101-107
        • Tsuda M.
        • Mizokoshi A.
        • Shigemoto-Mogami Y.
        • Koizumi S.
        • Inoue K.
        Activation of p38 mitogen-activated protein kinase in spinal hyperactive microglia contributes to pain hypersensitivity following peripheral nerve injury.
        Glia. 2004; 45: 89-95
        • Vanderah T.W.
        • Laughlin T.
        • Lashbrook J.M.
        • Nichols M.L.
        • Wilcox G.L.
        • Ossipov M.H.
        • Malan Jr., T.P.
        • Porreca F.
        Single intrathecal injections of dynorphin A or des-Tyr-dynorphins produce long-lasting allodynia in rats: Blockade by MK-801 but not naloxone.
        Pain. 1996; 68: 275-281
        • Wang Z.
        • Gardell L.R.
        • Ossipov M.H.
        • Vanderah T.W.
        • Brennan M.B.
        • Hochgeschwender U.
        • Hruby V.J.
        • Malan Jr., T.P.
        • Lai J.
        • Porreca F.
        Pronociceptive actions of dynorphin maintain chronic neuropathic pain.
        J Neurosci. 2001; 21: 1779-1786
        • Watkins L.R.
        • Maier S.F.
        Glia: A novel drug discovery target for clinical pain.
        Nat Rev Drug Discov. 2003; 2: 973-985
        • Watkins L.R.
        • Milligan E.D.
        • Maier S.F.
        Glial proinflammatory cytokines mediate exaggerated pain states: Implications for clinical pain.
        Adv Exp Med Biol. 2003; 521: 1-21
        • Whitaker M.
        • Guo J.
        • Kehoe T.
        • Benson G.
        Bisphosphonates for osteoporosis–where do we go from here?.
        N Engl J Med. 2012; 366: 2048-2051
        • Woolf C.J.
        • Mannion R.J.
        Neuropathic pain: Aetiology, symptoms, mechanisms, and management.
        Lancet. 1999; 353: 1959-1964
        • Yaksh T.L.
        • Rudy T.A.
        Chronic catheterization of the spinal subarachnoid space.
        Physiol Behav. 1976; 17: 1031-1036
        • Zeidan A.
        • Javadov S.
        • Karmazyn M.
        Essential role of Rho/ROCK-dependent processes and actin dynamics in mediating leptin-induced hypertrophy in rat neonatal ventricular myocytes.
        Cardiovasc Res. 2006; 72: 101-111
        • Zhu J.W.
        • Brdicka T.
        • Katsumoto T.R.
        • Lin J.
        • Weiss A.
        Structurally distinct phosphatases CD45 and CD148 both regulate B cell and macrophage immunoreceptor signaling.
        Immunity. 2008; 28: 183-196