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Molecular Pain

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Open Access 01-12-2010 | Research

p38 mediates mechanical allodynia in a mouse model of type 2 diabetes

Authors: Hsinlin T Cheng, Jacqueline R Dauch, Sang Su Oh, John M Hayes, Yu Hong, Eva L Feldman

Published in: Molecular Pain | Issue 1/2010

Abstract

Background

Painful Diabetic Neuropathy (PDN) affects more than 25% of patients with type 2 diabetes; however, the pathogenesis remains unclear due to lack of knowledge of the molecular mechanisms leading to PDN. In our current study, we use an animal model of type 2 diabetes in order to understand the roles of p38 in PDN. Previously, we have demonstrated that the C57BLK db/db (db/db) mouse, a model of type 2 diabetes that carries the loss-of-function leptin receptor mutant, develops mechanical allodynia in the hind paws during the early stage (6-12 wk of age) of diabetes. Using this timeline of PDN, we can investigate the signaling mechanisms underlying mechanical allodynia in the db/db mouse.

Results

We studied the role of p38 in lumbar dorsal root ganglia (LDRG) during the development of mechanical allodynia in db/db mice. p38 phosphorylation was detected by immunoblots at the early stage of mechanical allodynia in LDRG of diabetic mice. Phosphorylated p38 (pp38) immunoreactivity was detected mostly in the small- to medium-sized LDRG neurons during the time period of mechanical allodynia. Treatment with an antibody against nerve growth factor (NGF) significantly inhibited p38 phosphorylation in LDRG of diabetic mice. In addition, we detected higher levels of inflammatory mediators, including cyclooxygenase (COX) 2, inducible nitric oxide synthases (iNOS), and tumor necrosis factor (TNF)-α in LDRG neurons of db/db mice compared to non-diabetic db+ mice. Intrathecal delivery of SB203580, a p38 inhibitor, significantly inhibited the development of mechanical allodynia and the upregulation of COX2, iNOS and TNF-α.

Conclusions

Our findings suggest that NGF activated-p38 phosphorylation mediates mechanical allodynia in the db/db mouse by upregulation of multiple inflammatory mediators in LDRG.

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Boulton AJ, Vinik AI, Arezzo JC, Bril V, Feldman EL, Freeman R, Malik RA, Maser RE, Sosenko JM, Ziegler D: Diabetic neuropathies: a statement by the American Diabetes Association. Diabetes care 2005, 28: 956–962. 10.2337/diacare.28.4.956PubMedCrossRef

Feldman EL, Stevens MJ, Russell JW, Peltier A, Inzucchi S, Porte JD, Sherwin RS, Baron A: Somatosensory neuropathy. In The Diabetes Mellitus Manual. Volume 6. McGraw-Hill; 2005:366–384.

Edwards JL, Vincent AM, Cheng HT, Feldman EL: Diabetic neuropathy: mechanisms to management. Pharmacology & therapeutics 2008, 120: 1–34.CrossRef

Singleton JR, Smith AG, Russell J, Feldman EL: Polyneuropathy with Impaired Glucose Tolerance: Implications for Diagnosis and Therapy. CurrTreatOptionsNeurol 2005, 7: 33–42.

Singleton JR, Smith AG, Bromberg MB: Painful sensory polyneuropathy associated with impaired glucose tolerance. Muscle & nerve 2005, 24: 1225–1228.CrossRef

Barrett AM, Lucero MA, Le T, Robinson RL, Dworkin RH, Chappell AS: Epidemiology, public health burden, and treatment of diabetic peripheral neuropathic pain: a review. Pain medicine (Malden, Mass) 2007,8(Suppl 2):S50-S62. 10.1111/j.1526-4637.2006.00179.xCrossRef

Ji RR, Gereau RWt, Malcangio M, Strichartz GR: MAP kinase and pain. Brain research reviews 2009, 60: 135–148. 10.1016/j.brainresrev.2008.12.011PubMedCentralPubMedCrossRef

Obata K, Noguchi K: MAPK activation in nociceptive neurons and pain hypersensitivity. Life Sci 2004, 74: 2643–2653. 10.1016/j.lfs.2004.01.007PubMedCrossRef

Cuenda A, Rousseau S: p38 MAP-kinases pathway regulation, function and role in human diseases. Biochim Biophys Acta 2007, 1773: 1358–1375. 10.1016/j.bbamcr.2007.03.010PubMedCrossRef

10.

Ji RR, Samad TA, Jin SX, Schmoll R, Woolf CJ: p38 MAPK activation by NGF in primary sensory neurons after inflammation increases TRPV1 levels and maintains heat hyperalgesia. Neuron 2002, 36: 57–68. 10.1016/S0896-6273(02)00908-XPubMedCrossRef

11.

Sung CS, Wen ZH, Chang WK, Chan KH, Ho ST, Tsai SK, Chang YC, Wong CS: Inhibition of p38 mitogen-activated protein kinase attenuates interleukin-1beta-induced thermal hyperalgesia and inducible nitric oxide synthase expression in the spinal cord. Journal of neurochemistry 2005, 94: 742–752. 10.1111/j.1471-4159.2005.03226.xPubMedCrossRef

12.

Svensson CI, Hua XY, Protter AA, Powell HC, Yaksh TL: Spinal p38 MAP kinase is necessary for NMDA-induced spinal PGE(2) release and thermal hyperalgesia. Neuroreport 2003, 14: 1153–1157. 10.1097/00001756-200306110-00010PubMedCrossRef

13.

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. 10.1002/glia.10308PubMedCrossRef

14.

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. Molecular pharmacology 2006, 70: 1246–1254. 10.1124/mol.106.025478PubMedCrossRef

15.

Cheng HT, Dauch JR, Hayes JM, Hong Y, Feldman EL: Nerve growth factor mediates mechanical allodynia in a mouse model of type 2 diabetes. J Neuropathol Exp Neurol 2009, 68: 1229–1243. 10.1097/NEN.0b013e3181bef710PubMedCentralPubMedCrossRef

16.

Hummel KP, Dickie MM, Coleman DL: Diabetes, a new mutation in the mouse. Science (New York, NY) 1966, 153: 1127–1128.CrossRef

17.

Sullivan KA, Hayes JM, Wiggin TD, Backus C, Su Oh S, Lentz SI, Brosius F: Mouse models of diabetic neuropathy. Neurobiology of disease 2007, 28: 276–285. 10.1016/j.nbd.2007.07.022PubMedCentralPubMedCrossRef

18.

Cheng HL, Feldman EL: Bidirectional regulation of p38 kinase and c-Jun N-terminal protein kinase by insulin-like growth factor-I. J Biol Chem 1998, 273: 14560–14565. 10.1074/jbc.273.23.14560PubMedCrossRef

19.

Adhikary L, Chow F, Nikolic-Paterson DJ, Stambe C, Dowling J, Atkins RC, Tesch GH: Abnormal p38 mitogen-activated protein kinase signalling in human and experimental diabetic nephropathy. Diabetologia 2004, 47: 1210–1222. 10.1007/s00125-004-1437-0PubMedCrossRef

20.

Brown KK, Heitmeyer SA, Hookfin EB, Hsieh L, Buchalova M, Taiwo YO, Janusz MJ: P38 MAP kinase inhibitors as potential therapeutics for the treatment of joint degeneration and pain associated with osteoarthritis. J Inflamm (Lond) 2008, 5: 22. 10.1186/1476-9255-5-22CrossRef

21.

Cottrell JA, Meyenhofer M, Medicherla S, Higgins L, O'Connor JP: Analgesic effects of p38 kinase inhibitor treatment on bone fracture healing. Pain 2009, 142: 116–126. 10.1016/j.pain.2008.12.019PubMedCrossRef

22.

Cheng HT, Suzuki M, Hegarty DM, Xu Q, Weyerbacher AR, South SM, Ohata M, Inturrisi CE: Inflammatory pain-induced signaling events following a conditional deletion of the N-methyl-D-aspartate receptor in spinal cord dorsal horn. Neuroscience 2008, 155: 948–958. 10.1016/j.neuroscience.2008.06.024PubMedCentralPubMedCrossRef

23.

Hasegawa S, Kohro Y, Tsuda M, Inoue K: Activation of cytosolic phospholipase A2 in dorsal root ganglion neurons by Ca2+/calmodulin-dependent protein kinase II after peripheral nerve injury. Mol Pain 2009, 5: 22. 10.1186/1744-8069-5-22PubMedCentralPubMedCrossRef

24.

Sweitzer SM, Medicherla S, Almirez R, Dugar S, Chakravarty S, Shumilla JA, Yeomans DC, Protter AA: Antinociceptive action of a p38alpha MAPK inhibitor, SD-282, in a diabetic neuropathy model. Pain 2004, 109: 409–419. 10.1016/j.pain.2004.02.016PubMedCrossRef

25.

Crown ED, Gwak YS, Ye Z, Johnson KM, Hulsebosch CE: Activation of p38 MAP kinase is involved in central neuropathic pain following spinal cord injury. Exp Neurol 2008, 213: 257–267. 10.1016/j.expneurol.2008.05.025PubMedCentralPubMedCrossRef

26.

Mizushima T, Obata K, Yamanaka H, Dai Y, Fukuoka T, Tokunaga A, Mashimo T, Noguchi K: Activation of p38 MAPK in primary afferent neurons by noxious stimulation and its involvement in the development of thermal hyperalgesia. Pain 2005, 113: 51–60. 10.1016/j.pain.2004.09.038PubMedCrossRef

27.

Amaya F, Samad TA, Barrett L, Broom DC, Woolf CJ: Periganglionic inflammation elicits a distally radiating pain hypersensitivity by promoting COX-2 induction in the dorsal root ganglion. Pain 2009, 142: 59–67. 10.1016/j.pain.2008.11.013PubMedCentralPubMedCrossRef

28.

Lee KM, Jeon SM, Cho HJ: Tumor necrosis factor receptor 1 induces interleukin-6 upregulation through NF-kappaB in a rat neuropathic pain model. Eur J Pain 2009, 13: 794–806. 10.1016/j.ejpain.2008.09.009PubMedCrossRef

29.

Obata K, Yamanaka H, Kobayashi K, Dai Y, Mizushima T, Katsura H, Fukuoka T, Tokunaga A, Noguchi K: Role of mitogen-activated protein kinase activation in injured and intact primary afferent neurons for mechanical and heat hypersensitivity after spinal nerve ligation. J Neurosci 2004, 24: 10211–10222. 10.1523/JNEUROSCI.3388-04.2004PubMedCrossRef

30.

Obata K, Katsura H, Mizushima T, Yamanaka H, Kobayashi K, Dai Y, Fukuoka T, Tokunaga A, Tominaga M, Noguchi K: TRPA1 induced in sensory neurons contributes to cold hyperalgesia after inflammation and nerve injury. The Journal of clinical investigation 2005, 115: 2393–2401. 10.1172/JCI25437PubMedCentralPubMedCrossRef

31.

Puntambekar P, Mukherjea D, Jajoo S, Ramkumar V: Essential role of Rac1/NADPH oxidase in nerve growth factor induction of TRPV1 expression. Journal of neurochemistry 2005, 95: 1689–1703. 10.1111/j.1471-4159.2005.03518.xPubMedCrossRef

32.

Cui XY, Dai Y, Wang SL, Yamanaka H, Kobayashi K, Obata K, Chen J, Noguchi K: Differential activation of p38 and extracellular signal-regulated kinase in spinal cord in a model of bee venom-induced inflammation and hyperalgesia. Mol Pain 2008, 4: 17. 10.1186/1744-8069-4-17PubMedCentralPubMedCrossRef

33.

Inoue K, Tsuda M, Koizumi S: Chronic pain and microglia: the role of ATP. Novartis Found Symp 2004, 261: 55–64. discussion 64–57, 149–154 full_textPubMedCrossRef

34.

Aoki Y, An HS, Takahashi K, Miyamoto K, Lenz ME, Moriya H, Masuda K: Axonal growth potential of lumbar dorsal root ganglion neurons in an organ culture system: response of nerve growth factor-sensitive neurons to neuronal injury and an inflammatory cytokine. Spine (Phila Pa 1976) 2007, 32: 857–863.CrossRef

35.

Ramer MS, Bradbury EJ, McMahon SB: Nerve growth factor induces P2X(3) expression in sensory neurons. Journal of neurochemistry 2001, 77: 864–875. 10.1046/j.1471-4159.2001.00288.xPubMedCrossRef

36.

Igwe OJ: c-Src kinase activation regulates preprotachykinin gene expression and substance P secretion in rat sensory ganglia. Eur J Neurosci 2003, 18: 1719–1730. 10.1046/j.1460-9568.2003.02878.xPubMedCrossRef

37.

Joachim RA, Kuhlmei A, Dinh QT, Handjiski B, Fischer T, Peters EM, Klapp BF, Paus R, Arck PC: Neuronal plasticity of the "brain-skin connection": stress-triggered up-regulation of neuropeptides in dorsal root ganglia and skin via nerve growth factor-dependent pathways. J Mol Med 2007, 85: 1369–1378. 10.1007/s00109-007-0236-8PubMedCrossRef

38.

Kellogg AP, Cheng HT, Pop-Busui R: Cyclooxygenase-2 pathway as a potential therapeutic target in diabetic peripheral neuropathy. Curr Drug Targets 2008, 9: 68–76. 10.2174/138945008783431691PubMedCrossRef

39.

Yabuki A, Tahara T, Taniguchi K, Matsumoto M, Suzuki S: Neuronal nitric oxide synthase and cyclooxygenase-2 in diabetic nephropathy of type 2 diabetic OLETF rats. Exp Anim 2006, 55: 17–25. 10.1538/expanim.55.17PubMedCrossRef

40.

Bujalska M, Tatarkiewicz J, Corde A, Gumulka SW: Effect of cyclooxygenase and nitric oxide synthase inhibitors on streptozotocin-induced hyperalgesia in rats. Pharmacology 2008, 81: 151–157. 10.1159/000110787PubMedCrossRef

41.

Kitazawa M, Shibata Y, Hashimoto S, Ohizumi Y, Yamakuni T: Proinsulin C-peptide stimulates a PKC/IkappaB/NF-kappaB signaling pathway to activate COX-2 gene transcription in Swiss 3T3 fibroblasts. J Biochem 2006, 139: 1083–1088. 10.1093/jb/mvj122PubMedCrossRef

42.

Vareniuk I, Pavlov IA, Obrosova IG: Inducible nitric oxide synthase gene deficiency counteracts multiple manifestations of peripheral neuropathy in a streptozotocin-induced mouse model of diabetes. Diabetologia 2008, 51: 2126–2133. 10.1007/s00125-008-1136-3PubMedCentralPubMedCrossRef

43.

Cameron NE, Gibson TM, Nangle MR, Cotter MA: Inhibitors of advanced glycation end product formation and neurovascular dysfunction in experimental diabetes. Annals of the New York Academy of Sciences 2005, 1043: 784–792. 10.1196/annals.1333.091PubMedCrossRef

44.

Khan N, Bakshi KS, Jaggi AS, Singh N: Ameliorative potential of spironolactone in diabetes induced hyperalgesia in mice. Yakugaku Zasshi 2009, 129: 593–599. 10.1248/yakushi.129.593PubMedCrossRef

45.

Sherry CL, O'Connor JC, Kramer JM, Freund GG: Augmented lipopolysaccharide-induced TNF-alpha production by peritoneal macrophages in type 2 diabetic mice is dependent on elevated glucose and requires p38 MAPK. J Immunol 2007, 178: 663–670.PubMedCrossRef

46.

Thieringer R, Fenyk-Melody JE, Grand CB, Shelton BA, Detmers PA, Somers EP, Carbin L, Moller DE, Wright SD, Berger J: Activation of peroxisome proliferator-activated receptor gamma does not inhibit IL-6 or TNF-alpha responses of macrophages to lipopolysaccharide in vitro or in vivo. J Immunol 2000, 164: 1046–1054.PubMedCrossRef

47.

Wen Y, Gu J, Li SL, Reddy MA, Natarajan R, Nadler JL: Elevated glucose and diabetes promote interleukin-12 cytokine gene expression in mouse macrophages. Endocrinology 2006, 147: 2518–2525. 10.1210/en.2005-0519PubMedCrossRef

48.

Xu JT, Xin WJ, Zang Y, Wu CY, Liu XG: The role of tumor necrosis factor-alpha in the neuropathic pain induced by Lumbar 5 ventral root transection in rat. Pain 2006, 123: 306–321. 10.1016/j.pain.2006.03.011PubMedCrossRef

49.

Schafers M, Geis C, Brors D, Yaksh TL, Sommer C: Anterograde transport of tumor necrosis factor-alpha in the intact and injured rat sciatic nerve. J Neurosci 2002, 22: 536–545.PubMed

50.

Jin X, Gereau RWt: Acute p38-mediated modulation of tetrodotoxin-resistant sodium channels in mouse sensory neurons by tumor necrosis factor-alpha. J Neurosci 2006, 26: 246–255. 10.1523/JNEUROSCI.3858-05.2006PubMedCrossRef

51.

Kleibeuker W, Gabay E, Kavelaars A, Zijlstra J, Wolf G, Ziv N, Yirmiya R, Shavit Y, Tal M, Heijnen CJ: IL-1 beta signaling is required for mechanical allodynia induced by nerve injury and for the ensuing reduction in spinal cord neuronal GRK2. Brain Behav Immun 2008, 22: 200–208. 10.1016/j.bbi.2007.07.009PubMedCrossRef

52.

O'Connor AB, Dworkin RH: Treatment of neuropathic pain: an overview of recent guidelines. Am J Med 2009, 122: S22-S32. 10.1016/j.amjmed.2009.04.007PubMedCrossRef

53.

Coulthard LR, White DE, Jones DL, McDermott MF, Burchill SA: p38(MAPK): stress responses from molecular mechanisms to therapeutics. Trends Mol Med 2009, 15: 369–379. 10.1016/j.molmed.2009.06.005PubMedCentralPubMedCrossRef

54.

Dixon WJ: Efficient analysis of experimental observations. Annu Rev Pharmacol Toxicol 1980, 20: 441–462. 10.1146/annurev.pa.20.040180.002301PubMedCrossRef

55.

Chaplan SR, Bach FW, Pogrel JW, Chung JM, Yaksh TL: Quantitative assessment of tactile allodynia in the rat paw. J Neurosci Methods 1994, 53: 55–63. 10.1016/0165-0270(94)90144-9PubMedCrossRef

56.

Kabashi E, Agar JN, Hong Y, Taylor DM, Minotti S, Figlewicz DA, Durham HD: Proteasomes remain intact, but show early focal alteration in their composition in a mouse model of amyotrophic lateral sclerosis. Journal of neurochemistry 2008.

57.

Feugeas JP, Dosquet C, Wautier JL, Montchamp-Moreau C, Krishnamoorthy R, Caillens H: [Dysregulation of in vitro TNF-beta production in insulin-dependent diabetes mellitus]. C R Acad Sci III 1993, 316: 1255–1259.PubMed

58.

Wild KD, Bian D, Zhu D, Davis J, Bannon AW, Zhang TJ, Louis JC: Antibodies to nerve growth factor reverse established tactile allodynia in rodent models of neuropathic pain without tolerance. J Pharmacol Exp Ther 2007, 322: 282–287. 10.1124/jpet.106.116236PubMedCrossRef

Title: p38 mediates mechanical allodynia in a mouse model of type 2 diabetes
Authors: Hsinlin T Cheng
Jacqueline R Dauch
Sang Su Oh
John M Hayes
Yu Hong
Eva L Feldman
Publication date: 01-12-2010
Publisher: BioMed Central
Published in: Molecular Pain / Issue 1/2010
Electronic ISSN: 1744-8069
DOI: https://doi.org/10.1186/1744-8069-6-28

Keynote webinar | Spotlight on medication adherence

Springer Medicine

p38 mediates mechanical allodynia in a mouse model of type 2 diabetes

Abstract

Background

Results

Conclusions

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Background

Results

Conclusions

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