Streptozotocin-Induced Early Thermal Hyperalgesia is independent of Glycemic State of Rats: Role of Transient Receptor Potential Vanilloid 1(TRPV1) and Inflammatory mediators

Molecular Pain

Louis S Premkumar¹  Linlin Zhong¹  Mruvil Abooj¹  Christine A Bosgraaf¹  Mahendra Bishnoi¹ 

[1] Department of Pharmacology, Southern Illinois University School of Medicine, Springfield, IL-62702, USA

关键词: TRPV1;    streptozotocin;    resiniferatoxin;    microglia;    Inflammation;   

Others  :  865855
DOI  :  10.1186/1744-8069-7-52

 received in 2011-04-07, accepted in 2011-07-27,  发布年份 2011

【 摘 要 】

Background

Streptozotocin (STZ) is used as a common tool to induce diabetes and to study diabetes-induced complications including diabetic peripheral neuropathy (DPN). Previously, we have reported that STZ induces a direct effect on neurons through expression and function of the Transient receptor potential vanilloid 1 (TRPV1) channel in sensory neurons resulting in thermal hyperalgesia, even in non-diabetic STZ-treated mice. In the present study, we investigated the role of expression and function of TRPV1 in the central sensory nerve terminals in the spinal cord in STZ-induced hyperalgesia in rats.

Results

We found that a proportion of STZ-treated rats were normoglycemic but still exhibited thermal hyperalgesia and mechanical allodynia. Immunohistochemical data show that STZ treatment, irrespective of glycemic state of the animal, caused microglial activation and increased expression of TRPV1 in spinal dorsal horn. Further, there was a significant increase in the levels of pro-inflammatory mediators (IL-1β, IL-6 and TNF-α) in spinal cord tissue, irrespective of the glycemic state. Capsaicin-stimulated release of calcitonin gene related peptide (CGRP) was significantly higher in the spinal cord of STZ-treated animals. Intrathecal administration of resiniferatoxin (RTX), a potent TRPV1 agonist, significantly attenuated STZ-induced thermal hyperalgesia, but not mechanical allodynia. RTX treatment also prevented the increase in TRPV1-mediated neuropeptide release in the spinal cord tissue.

Conclusions

From these results, it is concluded that TRPV1 is an integral component of initiating and maintaining inflammatory thermal hyperalgesia, which can be alleviated by intrathecal administration of RTX. Further, the results suggest that enhanced expression and inflammation-induced sensitization of TRPV1 at the spinal cord may play a role in central sensitization in STZ-induced neuropathy.

【 授权许可】

   
2011 Bishnoi et al; licensee BioMed Central Ltd.

【 图 表 】

【 参考文献 】

• [1]Standell E, Decio EL, Korsgren O, Sandler S: Functional characteristics of cultured mouse pancreatic islets following exposure to different streptozotocin concentrations. Mol Cell Endocrinol 1988, 59:83-91.
• [2]Turk J, Corbett JA, Ramanadham S, Bohrer A, McDaniel ML: Biochemical evidence for nitric oxide formation from streptozotocin in isolated pancreatic islets. Biochem Biophys Res Commun 1993, 197:1458-1464.
• [3]Kroncke KD, Fehsel K, Sommer A, Rodriguez ML, Kolb-Bachofen V: Nitric oxide generation during cellular metabolization of the diabetogenic N-methyl-N-nitroso-urea streptozotozin contributes to islet cell DNA damage. Biol Chem 1995, 376:179-185.
• [4]Roos MD, Wen X, Kaihong S, Clark JA, Xiaoyong Y, Chin E, Paterson AJ, Kudlow JE: Streptozotocin, an analog of N-acetylglucosamine, blocksthe removal of O-GlcNAc from intracellular proteins. Proc Assoc Am Physicians 1998, 110:1-11.
• [5]Hanover JA, Lai Z, Le G, Lubas WA, Sato SM: Elevated O-linkedN-acetylglucosamine metabolism in pancreatic beta-cells. Arch Biochem Biophys 1999, 367:51-60.
• [6]Liu K, Paterson AJ, Chin E, Kudlow JE: Glucose stimulates proteinmodification by O-linked GlcNAc in pancreatic β-cells: linkage of O-linked GlcNAc tob-cell death. Proc Natl Acad Sci USA 2000, 97:2820-2825.
• [7]Courteix C, Bardin M, Massol J, Fialip J, Lavarenne J, Eschalier A: Daily insulin treatment relieves long-term hyperalgesia in streptozotocin diabetic rats. Neuroreport 1996, 7:1922-1924.
• [8]Sugimoto K, Murakawa Y, Sima AA: Diabetic neuropathy a continuing enigma. Diabetes Metab Res Rev 2000, 16:408-433.
• [9]Chen SR, Pan HL: Hypersensitivity of spinothalamic tract neurons associated with diabetic neuropathic pain in rats. J Neurophysiol 2002, 87:2726-2733.
• [10]Zhuang HX, Wuarin L, Fei ZJ, Ishii DN: Insulin-like growth factor (IGF) gene expression is reduced in neural tissues and liver from rats with non-insulin-dependent diabetes mellitus, and IGF treatment ameliorates diabetic neuropathy. J Pharmacol Exp Ther 1997, 283:366-374.
• [11]Brussee V, Cunningham FA, Zochodne DW: Direct insulin signaling of neurons reverses diabetic neuropathy. Diabetes 2004, 53:1824-1830.
• [12]Pabbidi RM, Cao DS, Parihar A, Pauza ME, Premkumar LS: Direct role of streptozotocin in inducing thermal hyperalgesia by enhanced expression of transient receptor potential vanilloid 1 in sensory neurons. Mol Pharmacol 2008, 73:995-1004.
• [13]Romanovsky D, Wang J, Al-Chaer ED, Stimers JR, Dobretsov M: Comparison of metabolic and neuropathy profiles of rats with streptozotocin-induced overt and moderate insulinopenia. Neuroscience 2010, 170:337-347.
• [14]Hoyer S, Lannert H: Long-term abnormalities in brain glucose/energy metabolism after inhibition of the neuronal insulin receptor: implication of tau-protein. J Neural Transm 2007, 72:195-202.
• [15]Scholz J, Woolf CJ: The neuropathic pain triad: neurons, immune cells and glia. Nat Neurosci 2007, 10:1361-1368.
• [16]Wodarski R, Clark AK, Grist J, Marchand F, Malcangio M: Gabapentin reverses microglial activation in the spinal cord of streptozotocin-induced diabetic rats. Eur J Pain 2009, 13:807-811.
• [17]Watkins LR, Milligan ED, Maier SF: Glial proinflammatory cytokines mediate exaggerated pain states: implications for clinical pain. Glia 2008, 56:378-386.
• [18]Tsuda M, Ueno H, Kataoka A, Tozaki-Saitoh H, Inoue K: Activation of dorsal horn microglia contributes to diabetes-induced tactile allodynia via extracellular signal-regulated protein kinase signaling. Adv Exp Med Biol 2003, 521:1-21.
• [19]Sweitzer SM, Peters MC, Ma JY, Kerr I, Mangadu R, Chakravarty S, Dugar S, Medicherla S, Protter AA, Yeomans DC: Peripheral and central p38 MAPK mediates capsaicin-induced hyperalgesia. Pain 2004, 111:278-285.
• [20]Daulhac L, Mallet C, Courteix C, Etienne M, Duroux E, Privat AM, Eschalier A, Fialip J: Diabetes-induced mechanical hyperalgesia involves spinal mitogen-activated protein kinase activation in neurons and microglia via N-methyl-D-aspartate-dependent mechanisms. Mol Pharmacol 2006, 70:1246-1254.
• [21]Kohno T: Neuropathic pain and neuron-glia interactions in the spinal cord. J Anesth 2010, 24:325-327.
• [22]Gao YJ, Ji RR: Targeting astrocyte signaling for chronic pain. Neurotherapeutics 2010, 7:482-493.
• [23]Spicarova D, Palecek JJ: Tumor necrosis factor alpha sensitizes spinal cord TRPV1 receptors to the endogenous agonist N-oleoyldopamine. Neuroinflammation 2010, 7:49. BioMed Central Full Text
• [24]Westlund KN, Kochukov MY, Lu Y, McNearney TA: Impact of central and peripheral TRPV1 and ROS levels on proinflammatory mediators and nociceptive behavior. Mol Pain 2010, 6:46. BioMed Central Full Text
• [25]Woolf CJ: Central sensitization: implications for the diagnosis and treatment of pain. Pain 2011, 152:S2-15.
• [26]Raisinghani M, Pabbidi RM, Premkumar LS: Activation of transient receptor potential vanilloid 1 (TRPV1) by resiniferatoxin. J Physiol 2005, 567:771-786.
• [27]Jeffry JA, Yu SQ, Sikand P, Parihar A, Evans MS, Premkumar LS: Selective targeting of TRPV1 expressing sensory nerve terminals in the spinal cord for long lasting analgesia. PLoS One 2009, 4(9):e7021.
• [28]Premkumar LS: Targeting TRPV1 as an alternative approach to narcotic analgesics to treat chronic pain conditions. AAPS J 2010, 12:361-370.
• [29]Bishnoi M, Bosgraaf C, Premkumar LS: Preservation of acute pain and efferent functions following intrathecal resiniferatoxin induced analgesia in rats. J Pain 2011, in press.
• [30]Neubert JK, Karai L, Jun JH, Kim HS, Olah Z, Iadarola MJ: Peripherally induced resiniferatoxin analgesia. Pain 2003, 104:219-228.
• [31]Brown DC, Iadarola MJ, Perkowski SZ, Erin H, Shofer F, Laszlo KJ, Olah Z, Mannes AJ: Physiologic and antinociceptive effects of intrathecal resiniferatoxin in a canine bone cancer model. Anesthesiology 2005, 103:1052-1059.
• [32]Sikand P, Premkumar LS: Potentiation of glutamatergic synaptic transmission by protein kinase C-mediated sensitization of TRPV1 at the first sensory synapse. J Physiol 2007, 581:631-647.
• [33]Pabbidi RM, Yu SQ, Peng S, Khardori R, Pauza ME, Premkumar LS: Influence of TRPV1 on diabetes-induced alterations in thermal pain sensitivity. Mol Pain 2008, 4:9. BioMed Central Full Text
• [34]Obrosova IG: Diabetic painful and insensate neuropathy: pathogenesis and potential treatments. Neurotherapeutics 2009, 6:638-647.
• [35]Mishra SK, Hoon MA: Ablation of TrpV1 neurons reveal their selective role in thermal pain sensation. Mol Cell Neurosci 2010, 43:157-163.
• [36]Cardinal JW, Allan DJ, Cameron DP: Differential metabolite accumulation may be the cause of strain differences in sensitivity to streptozotocin-induced beta cell death in inbred mice. Endocrinology 1998, 139:2885-2891.
• [37]Cardinal JW, Allan DJ, Cameron DP: Poly(ADP-ribose)polymerase activation determines strain sensitivity to streptozotocin-induced beta cell death in inbred mice. J Mol Endocrinol 1999, 22:65-70.
• [38]Yang H, Wright JR Jr: Human beta cells are exceedingly resistant to streptozotocin in vivo. Endocrinology 2002, 143:2491-2495.
• [39]Dobretsov M, Romanovsky D, Stimers JR: Early diabetic neuropathy: triggers and mechanisms. World J Gastroenterol 2007, 13:175-191.
• [40]Romanovsky D, Hastings SL, Stimers JR, Dobretsov M: Relevance of hyperglycemia to early mechanical hyperalgesia in streptozotocin-induced diabetes. J Peripher Nerv Syst 2004, 9:62-69.
• [41]Romanovsky D, Cruz NF, Dienel GA, Dobretsov M: Mechanical hyperalgesia correlates with insulin deficiency in normoglycemic streptozotocin-treated rats. Neurobiol Dis 2006, 24:384-394.
• [42]Thye-Ronn P, Sindrup SH, Arendt-Nielsen L, Brennum J, Hother-Nielsen O, Beck-Nielsen H: Effect of short-term hyperglycemia per se on nociceptive and non-nociceptive thresholds. Pain 1994, 56:43-49.
• [43]Zhuang HX, Wuarin L, Fei ZJ, Ishii DN: Insulin-like growth factor (IGF) gene expression is reduced in neural tissues and liver from rats with non-insulin-dependent diabetes mellitus, and IGF treatment ameliorates diabetic neuropathy. J Pharmacol Exp Ther 1997, 283:366-374.
• [44]Dobretsov M, Hastings SL, Romanovsky D, Stimers JR, Zhang JM: Mechanical hyperalgesia in rat models of systemic and local hyperglycemia. Brain Res 2003, 960:174-183.
• [45]Maneuf YP, Blake R, Andrews NA, McKnight AT: Reduction by gabapentin of K+-evoked release of [3H]-glutamate from the caudal trigeminal nucleus of the streptozotocin-treated rat. Br J Pharmacol 2004, 141:574-579.
• [46]Seki N, Shirasaki H, Kikuchi M, Himi T: Capsaicin induces the production of IL-6 in human upper respiratory epithelial cells. Life Sci 2007, 80:1592-1597.
• [47]Zhang F, Yang H, Wang Z, Mergler S, Liu H, Kawakita T, Tachado SD, Pan Z, Capó-Aponte JE, Pleyer U, Koziel H, Kao WW, Reinach PS: Transient receptor potential vanilloid 1 activation induces inflammatory cytokine release in corneal epithelium through MAPK signaling. J Cell Physiol 2007, 213:730-739.
• [48]Sappington RM, Calkins DJ: Contribution of TRPV1 to microglia-derived IL-6 and NFkappaB translocation with elevated hydrostatic pressure. Invest Ophthalmol Vis Sci 2008, 49:3004-3017.
• [49]Binshtok AM, Wang H, Zimmermann K, Amaya F, Vardeh D, Shi L, Brenner GJ, Ji RR, Bean BP, Woolf CJ, Samad TA: Nociceptors are interleukin-1beta sensors. J Neurosci 2008, 28:14062-14073.
• [50]Hensellek S, Brell P, Schaible HG, Bräuer R, Segond von Banchet G: The cytokine TNFalpha increases the proportion of DRG neurones expressing the TRPV1 receptor via the TNFR1 receptor and ERK activation. Mol Cell Neurosci 2007, 36:381-391.
• [51]Ma F, Zhang L, Westlund KN: Reactive oxygen species mediate TNFR1 increase after TRPV1 activation in mouse DRG neurons. Mol Pain 2009, 5:31. BioMed Central Full Text
• [52]Schaible HG, von Banchet GS, Boettger MK, Bräuer R, Gajda M, Richter F, Hensellek S, Brenn D, Natura G: The role of proinflammatory cytokines in the generation and maintenance of joint pain. Ann N Y Acad Sci 2010, 1193:60-69.
• [53]Gosselin RD, Dansereau MA, Pohl M, Kitabgi P, Beaudet N, Sarret P, Mélik Parsadaniantz S: Chemokine network in the nervous system: a new target for pain relief. Curr Med Chem 2008, 15:2866-2875.
• [54]Dansereau MA, Gosselin RD, Pohl M, Pommier B, Mechighel P, Mauborgne A, Rostene W, Kitabgi P, Beaudet N, Sarret P, Melik-Parsadaniantz S: Spinal CCL2 pronociceptive action is no longer effective in CCR2 receptor antagonist-treated rats. J Neurochem 2008, 106:757-769.
• [55]Thacker MA, Clark AK, Bishop T, Grist J, Yip PK, Moon LD, Thompson SW, Marchand F, McMahon SB: CCL2 is a key mediator of microglia activation in neuropathic pain states. Eur J Pain 2009, 13:263-272.
• [56]Jung H, Toth PT, White FA, Miller RJ: Monocyte chemoattractant protein-1 functions as a neuromodulator in dorsal root ganglia neurons. Neurochem 2008, 104:254-263.
• [57]Kim SR, Kim SU, Oh U, Jin BK: Transient receptor potential vanilloid subtype 1 mediates microglial cell death in vivo and in vitro via Ca2+-mediated mitochondrial damage and cytochrome c release. J Immunol 2006, 177:4322-4329.
• [58]Lappin SC, Randall AD, Gunthorpe MJ, Morisset V: TRPV1 antagonist, SB-366791, inhibits glutamatergic synaptic transmission in rat spinal dorsal horn following peripheral inflammation. Eur J Pharmacol 2006, 540:73-81.
• [59]Chen Y, Willcockson HH, Valtschanoff JG: Influence of the vanilloid receptor TRPV1 on the activation of spinal cord glia in mouse models of pain. Exp Neurol 2009, 220:383-390.
• [60]Caterina MJ, Leffler A, Malmberg AB, Martin WJ, Trafton J, Petersen-Zeitz KR, Koltzenburg M, Basbaum AI, Julius D: Impaired nociception and pain sensation in mice lacking the capsaicin receptor. Science 2000, 288:306-313.
• [61]Wong GY, Gavva NR: Therapeutic potential of vanilloid receptor TRPV1 agonists and antagonists as analgesics: Recent advances and setbacks. Brain Res Rev 2009, 60:267-277.
• [62]Kamei J, Zushida K, Morita K, Sasaki M, Tanaka S: Role of vanilloid VR1 receptor in thermal allodynia and hyperalgesia in diabetic mice. Eur J Pharmacol 2001, 422:83-86.
• [63]Mestre C, Pélissier T, Fialip J, Wilcox G, Eschalier A: A method to perform direct transcutaneous intrathecal injection in rats. J Pharmacol Toxicol Methods 1994, 32:197-200.