Rapamycin ameliorates neuropathic pain by activating autophagy and inhibiting interleukin-1β in the rat spinal cord

Abstract

Autophagy acts as an important homoeostatic mechanism by degradation of cytosolic constituents and plays roles in many physiological processes. Recent studies demonstrated that autophagy can also regulate the production and secretion of the proinflammatory cytokine interleukin-1β (IL-1β), which plays a critical role in the development and maintenance of neuropathic pain. In the present study, the paw withdrawal threshold (PWT) and paw withdrawal latency (PWL) were significantly decreased after spinal nerve ligation (SNL), and the changes were accompanied by inhibited autophagy in the spinal microglia and increased mRNA and protein levels of IL-1β in the ipsilateral spinal cord. We then investigated the antinociceptive effect of rapamycin, a widely used autopahgy inducer, on SNL-induced neuropathic pain in rats and found that treatment with intrathecal rapamycin significantly attenuated the mechanical allodynia and thermal hyperalgesia. Moreover, rapamycin significantly enhanced autophagy in the spinal microglia, whereas it reduced the mRNA and protein levels of IL-1β in the ipsilateral spinal cord. Our results showed that rapamycin could ameliorate neuropathic pain by activating autophagy and inhibiting IL-1β in the spinal cord.

Keywords

rapamycin / autophagy / interleukin-1β / neuropathic pain

References

[1] BaronR, BinderA, WasnerG. Neuropathic pain: diagnosis, pathophysiological mechanisms, and treatment. Lancet Neurol, 2010, 9(8): 807-819 PMID: 20650402

[2] MizushimaN, KomatsuM. Autophagy: renovation of cells and tissues. Cell, 2011, 147(4): 728-741 PMID: 22078875

[3] LiuCL, ChenS, DietrichD, et al. . Changes in autophagy after traumatic brain injury. J Cereb Blood Flow Metab, 2008, 28(4): 674-683 PMCID: 2672103 PMID: 18059433

[4] SadasivanS, DunnWJ, HayesRL, et al. . Changes in autophagy proteins in a rat model of controlled cortical impact induced brain injury. Biochem Biophys Res Commun, 2008, 373(4): 478-481 PMID: 18486600

[5] ZhangYB, LiSX, ChenXP, et al. . Autophagy is activated and might protect neurons from degeneration after traumatic brain injury. Neurosci Bull, 2008, 24(3): 143-149 PMID: 18500386

[6] SmithCM, ChenY, SullivanML, et al. . Autophagy in acute brain injury: feast, famine, or folly?. Neurobiol Dis, 2011, 43(1): 52-59 PMCID: 3046326 PMID: 20883784

[7] KannoH, OzawaH, SekiguchiA, et al. . The role of autophagy in spinal cord injury. Autophagy, 2009, 5(3): 390-392 PMID: 19158496

[8] ChenHC, FongTH, LeeAW, et al. . Autophagy is activated in injured neurons and inhibited by methylprednisolone after experimental spinal cord injury. Spine, 2012, 37(6): 470-475 PMID: 21587101

[9] BerliocchiL, RussoR, MaiaruM, et al. . Autophagy impairment in a mouse model of neuropathic pain. Mol Pain, 2011, 7: 83 PMCID: 3234188 PMID: 22023914

[10] LevineB, MizushimaN, VirginHW. Autophagy in immunity and inflammation. Nature, 2011, 469(7330): 323-335 PMCID: 3131688 PMID: 21248839

[11] SaitohT, FujitaN, JangMH, et al. . Loss of the autophagy protein Atg16L1 enhances endotoxin-induced IL-1beta production. Nature, 2008, 456(7219): 264-268 PMID: 18849965

[12] HarrisJ, HartmanM, RocheC, et al. . Autophagy controls IL-1beta secretion by targeting pro-IL-1beta for degradation. J Biol Chem, 2011, 286(11): 9587-9597 PMCID: 3058966 PMID: 21228274

[13] NakahiraK, HaspelJA, RathinamVA, et al. . Autophagy proteins regulate innate immune responses by inhibiting the release of mitochondrial DNA mediated by the NALP3 inflammasome. Nat Immunol, 2011, 12(3): 222-230 PMCID: 3079381 PMID: 21151103

[14] ShiCS, ShenderovK, HuangNN, et al. . Activation of autophagy by inflammatory signals limits IL-1beta production by targeting ubiquitinated inflammasomes for destruction. Nat Immunol, 2012, 13(3): 255-263 PMCID: 4116819 PMID: 22286270

[15] RenK, TorresR. Role of interleukin-1beta during pain and inflammation. Brain Res Rev, 2009, 60(1): 57-64 PMCID: 3076185 PMID: 19166877

[16] KiguchiN, KobayashiY, KishiokaS. Chemokines and cytokines in neuroinflammation leading to neuropathic pain. Curr Opin Pharmacol, 2012, 12(1): 55-61 PMID: 22019566

[17] WolfG, GabayE, TalM, et al. . Genetic impairment of interleukin-1 signaling attenuates neuropathic pain, autotomy, and spontaneous ectopic neuronal activity, following nerve injury in mice. Pain, 2006, 120(3): 315-324 PMID: 16426759

[18] RaughtB, GingrasA C, SonenbergN. The target of rapamycin (TOR) proteins. Proc Natl Acad Sci USA, 2001, 98(13): 7037-7044 PMCID: 34619 PMID: 11416184

[19] WenYD, ShengR, ZhangLS, et al. . Neuronal injury in rat model of permanent focal cerebral ischemia is associated with activation of autophagic and lysosomal pathways. Autophagy, 2008, 4(6): 762-769 PMID: 18567942

[20] HeY, WanS, HuaY, et al. . Autophagy after experimental intracerebral hemorrhage. J Cereb Blood Flow Metab, 2008, 28(5): 897-905 PMID: 17987045

[21] AlirezaeiM, KemballCC, WhittonJL. Autophagy, inflammation and neurodegenerative disease. Eur J Neurosci, 2011, 33(2): 197-204 PMCID: 3059259 PMID: 21138487

[22] ShihMH, KaoSC, WangW, et al. . Spinal cord NMDA receptor-mediated activation of mammalian target of rapamycin is required for the development and maintenance of bone cancer-induced pain hypersensitivities in rats. J Pain, 2012, 13(4): 338-349 PMCID: 3321092 PMID: 22341316

[23] SakuraS, KiriharaY, MugurumaT, et al. . The comparative neurotoxicity of intrathecal lidocaine and bupivacaine in rats. Anesth Analg, 2005, 101(2): 541-547 PMID: 16037173

[24] KimSH, ChungJM. An experimental model for peripheral neuropathy produced by segmental spinal nerve ligation in the rat. Pain, 1992, 50(3): 355-363 PMID: 1333581

[25] NorstedGE, CodeluppiS, GregoryJA, et al. . Mammalian target of rapamycin in spinal cord neurons mediates hypersensitivity induced by peripheral inflammation. Neuroscience, 2010, 169(3): 1392-1402

[26] YanW, ZhangH, BaiX, et al. . Autophagy activation is involved in neuroprotection induced by hyperbaric oxygen preconditioning against focal cerebral ischemia in rats. Brain Res, 2011, 1402: 109-121 PMID: 21684529

[27] MyersB, Greenwood-VanMB. Elevated corticosterone in the amygdala leads to persistent increases in anxiety-like behavior and pain sensitivity. Behav Brain Res, 2010, 214(2): 465-469 PMID: 20573588

[28] HargreavesK, DubnerR, BrownF, et al. . A new and sensitive method for measuring thermal nociception in cutaneous hyperalgesia. Pain, 1988, 32(1): 77-88 PMID: 3340425

[29] HiraiK, AlievG, NunomuraA, et al. . Mitochondrial abnormalities in Alzheimer’s disease. J Neurosci, 2001, 21(9): 3017-3023 PMID: 11312286

[30] KawasakiY, XuZZ, WangX, et al. . Distinct roles of matrix metalloproteases in the early- and late-phase development of neuropathic pain. Nat Med, 2008, 14(3): 331-336 PMCID: 2279180 PMID: 18264108

[31] RavikumarB, SarkarS, DaviesJE, et al. . Regulation of mammalian autophagy in physiology and pathophysiology. Physiol Rev, 2010, 90(4): 1383-1435 PMID: 20959619

[32] GuoY, WangJ, WangZ, et al. . Melatonin protects N2a against ischemia/reperfusion injury through autophagy enhancement. J Huazhong Univ Sci Technolog [Med Sci], 2010, 30(1): 1-7

[33] ZhangE, YiMH, KoY, et al. . Expression of LC3 and Beclin 1 in the spinal dorsal horn following spinal nerve ligation-induced neuropathic pain. Brain Res, 2013, 1519: 31-39 PMID: 23665054

[34] ZhouX, ZhouJ, LiX, et al. . GSK-3beta inhibitors suppressed neuroinflammation in rat cortex by activating autophagy in ischemic brain injury. Biochem Biophys Res Commun, 2011, 411(2): 271-275 PMID: 21723251

[35] SchafersM, SorkinL. Effect of cytokines on neuronal excitability. Neurosci Lett, 2008, 437(3): 188-193 PMID: 18420346

[36] McmahonSB, CaffertyWB, MarchandF. Immune and glial cell factors as pain mediators and modulators. Exp Neurol, 2005, 192(2): 444-462 PMID: 15755561

[37] HarrisJ. Autophagy and IL-1 family cytokines. Front Immunol, 2013, 4: 83 PMCID: 3617358 PMID: 23577011

[38] ShiG, ShiJ, LiuK, et al. . Increased miR-195 aggravates neuropathic pain by inhibiting autophagy following peripheral nerve injury. Glia, 2013, 61(4): 504-512 PMID: 23361941