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Open Access 01-12-2011 | Research

PKMζ is essential for spinal plasticity underlying the maintenance of persistent pain

Authors: Andre Laferrière, Mark H Pitcher, Anne Haldane, Yue Huang, Virginia Cornea, Naresh Kumar, Todd C Sacktor, Fernando Cervero, Terence J Coderre

Published in: Molecular Pain | Issue 1/2011

Abstract

Background

Chronic pain occurs when normally protective acute pain becomes pathologically persistent. We examined here whether an isoform of protein kinase C (PKC), PKMζ, that underlies long-term memory storage in various brain regions, also sustains nociceptive plasticity in spinal cord dorsal horn (SCDH) mediating persistent pain.

Results

Cutaneous injury or spinal stimulation produced persistent increases of PKMζ, but not other atypical PKCs in SCDH. Inhibiting spinal PKMζ, but not full-length PKCs, reversed plasticity-dependent persistent painful responses to hind paw formalin and secondary mechanical hypersensitivity and SCDH neuron sensitization after hind paw capsaicin, without affecting peripheral sensitization-dependent primary heat hypersensitivity after hind paw capsaicin. Inhibiting spinal PKMζ, but not full-length PKCs, also reversed mechanical hypersensitivity in the rat hind paw induced by spinal stimulation with intrathecal dihydroxyphenylglycine. Spinal PKMζ inhibition also alleviated allodynia 3 weeks after ischemic injury in rats with chronic post-ischemia pain (CPIP), at a point when allodynia depends on spinal changes. In contrast, spinal PKMζ inhibition did not affect allodynia in rats with chronic contriction injury (CCI) of the sciatic nerve, or CPIP rats early after ischemic injury, when allodynia depends on ongoing peripheral inputs.

Conclusions

These results suggest spinal PKMζ is essential for the maintenance of persistent pain by sustaining spinal nociceptive plasticity.

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Woolf CJ, Salter MW: Neuronal plasticity: increasing the gain in pain. Science 2000, 288: 1765–1769. 10.1126/science.288.5472.1765CrossRef

Kuner R: Central mechanisms of pathological pain. Nat Med 2010, 16: 1258–1266. 10.1038/nm.2231CrossRef

Ji RR, Kawasaki Y, Zhuang ZY, Wen YR, Zhang YQ: Protein kinases as potential targets for the treatment of pathological pain. Handb Exp Pharmacol 2007, 177: 359–389.CrossRef

Mao J, Price DD, Phillips LL, Lu J, Mayer DJ: Increases in protein kinase C gamma immunoreactivity in the spinal cord dorsal horn of rats with painful mononeuropathy. Neurosci Lett 1995, 198: 75–78. 10.1016/0304-3940(95)11975-3CrossRef

Miletic V, Bowen KK, Miletic G: Loose ligation of the rat sciatic nerve is accompanied by changes in the subcellular content of protein kinase C beta II and gamma in the spinal dorsal horn. Neurosci Lett 2000, 288: 199–202. 10.1016/S0304-3940(00)01237-4CrossRef

Narita M, Oe K, Kato H, Shibasaki M, Narita M, Yajima Y, Yamazaki M, Suzuki T: Implication of spinal protein kinase C in the suppression of morphine-induced rewarding effect under a neuropathic pain-like state in mice. Neuroscience 2004, 125: 545–551. 10.1016/j.neuroscience.2004.02.022CrossRef

Sweitzer SM, Wong SM, Peters MC, Mochly-Rosen D, Yeomans DC, Kendig JJ: Protein kinase C epsilon and gamma, involvement in formalin-induced nociception in neonatal rats. J Pharmacol Exp Ther 2004, 309: 616–625. 10.1124/jpet.103.060350CrossRef

Zhou Y, Li GD, Zhao ZQ: State-dependent phosphorylation of epsilon-isozyme of protein kinase C in adult rat dorsal root ganglia after inflammation and nerve injury. J Neurochem 2003, 85: 571–580. 10.1046/j.1471-4159.2003.01675.xCrossRef

Aley KO, Messing RO, Mochly-Rosen D, Levine JD: Chronic hypersensitivity for inflammatory nociceptor sensitization mediated by the epsilon isozyme of protein kinase C. J Neurosci 2000, 20: 4680–4685.

10.

Khasar SG, Lin YH, Martin A, Dadgar J, McMahon T, Wang D, Hundle B, Aley KO, Isenberg W, McCarter G, Green PG, Hodge CW, Levine JD, Messing RO: A novel nociceptor signaling pathway revealed in protein kinase C epsilon mutant mice. Neuron 1999, 24: 253–260. 10.1016/S0896-6273(00)80837-5CrossRef

11.

Malmberg AB, Chen C, Tonegawa S, Basbaum AI: Preserved acute pain and reduced neuropathic pain in mice lacking PKCgamma. Science 1997, 278: 279–283. 10.1126/science.278.5336.279CrossRef

12.

Hernandez AI, Blace N, Crary JF, Serrano PA, Leitges M, Libien JM, Weinstein G, Tcherapanov A, Sacktor TC, Implications for the molecular mechanism of memory: Protein kinase M zeta synthesis from a brain mRNA encoding an independent protein kinase C zeta catalytic domain. J Biol Chem 2003, 278: 40305–40316. 10.1074/jbc.M307065200CrossRef

13.

Sacktor TC, Osten P, Valsamis H, Jiang X, Naik MU, Sublette E: Persistent activation of the zeta isoform of protein kinase C in the maintenance of long-term potentiation. Proc Natl Acad Sci USA 1993, 90: 8342–8346. 10.1073/pnas.90.18.8342PubMedCentralCrossRef

14.

Ling DS, Benardo LS, Serrano PA, Blace N, Kelly MT, Crary JF, Sacktor TC: Protein kinase Mzeta is necessary and sufficient for LTP maintenance. Nat Neurosci 2002, 5: 295–296. 10.1038/nn829CrossRef

15.

Pastalkova E, Serrano P, Pinkhasova D, Wallace E, Fenton AA, Sacktor TC: Storage of spatial information by the maintenance mechanism of LTP. Science 2006, 313: 1141–1144. 10.1126/science.1128657CrossRef

16.

Serrano P, Friedman EL, Kenney J, Taubenfeld SM, Zimmerman JM, Hanna J, Alberini C, Kelley AE, Maren S, Rudy JW, Yin JC, Sacktor TC, Fenton AA: PKMzeta maintains spatial, instrumental, and classically conditioned long-term memories. PLoS Biol 2008, 6: 2698–2706.CrossRef

17.

Shema R, Haramati S, Ron S, Hazvi S, Chen A, Sacktor TC, Dudai Y: Enhancement of consolidated long-term memory by overexpression of protein kinase Mzeta in the neocortex. Science 2011, 331: 1207–1210. 10.1126/science.1200215CrossRef

18.

Ji RR, Kohno T, Moore KA, Woolf CJ: Central sensitization and LTP: do pain and memory share similar mechanisms? Trends Neurosci 2003, 26: 696–705. 10.1016/j.tins.2003.09.017CrossRef

19.

Ben-Ari Y, Aniksztejn L, Bregestovski P: Protein kinase C modulation of NMDA currents: an important link for LTP induction. Trends Neurosci 1992, 15: 333–339. 10.1016/0166-2236(92)90049-ECrossRef

20.

Muller D, Buchs PA, Stoppini L, Boddeke H: Long-term potentiation, protein kinase C, and glutamate receptors. Mol Neurobiol 1991, 5: 277–288. 10.1007/BF02935551CrossRef

21.

Li XY, Ko HG, Chen T, Descalzi G, Koga K, Wang H, Kim SS, Shang Y, Kwak C, Park SW, Shim J, Lee K, Collingridge GL, Kaang BK, Zhuo M: Alleviating neuropathic pain hypersensitivity by inhibiting PKMzeta in the anterior cingulate cortex. Science 2010, 330: 1400–1404. 10.1126/science.1191792CrossRef

22.

Asiedu MN, Tillu DV, Melemedjian OK, Shy A, Sanoja R, Bodell B, Ghosh S, Porreca F, Price TJ: Spinal Protein Kinase M {zeta} Underlies the Maintenance Mechanism of Persistent Nociceptive Sensitization. J Neurosci 2011, 31: 6646–6653. 10.1523/JNEUROSCI.6286-10.2011PubMedCentralCrossRef

23.

Katz J, Seltzer Z: Transition from acute to chronic postsurgical pain: risk factors and protective factors. Expert Rev Neurother 2009, 9: 723–744. 10.1586/ern.09.20CrossRef

24.

Kehlet H, Jensen TS, Woolf CJ: Persistent postsurgical pain, risk factors and prevention. Lancet 2006, 367: 1618–1625. 10.1016/S0140-6736(06)68700-XCrossRef

25.

Sluka KA, Rees H, Chen PS, Tsuruoka M, Willis WD: Capsaicin-induced sensitization of primate spinothalamic tract cells is prevented by a protein kinase C inhibitor. Brain Res 1997, 772: 82–86. 10.1016/S0006-8993(97)00876-7CrossRef

26.

Sluka KA, Rees H, Chen PS, Tsuruoka M, Willis WD: Inhibitors of G-proteins and protein kinases reduce the sensitization to mechanical stimulation and the desensitization to heat of spinothalamic tract neurons induced by intradermal injection of capsaicin in the primate. Exp Brain Res 1997, 115: 15–24. 10.1007/PL00005675CrossRef

27.

Coderre TJ, Vaccarino AL, Melzack R: Central nervous system plasticity in the tonic pain response to subcutaneous formalin injection. Brain Res 1990, 535: 155–158. 10.1016/0006-8993(90)91835-5CrossRef

28.

Sullivan JP, Connor JR, Shearer BG, Burch RM: 2,6-Diamino-N-([1-(1-oxotridecyl)-2-piperidinyl] methyl)hexanamide (NPC 15437), a novel inhibitor of protein kinase C interacting at the regulatory domain. Mol Pharmacol 2002, 41: 38–44.

29.

LaMotte RH, Lundberg LE, Torebjörk HE: Central changes in processing of mechanoreceptive input in capsaicin-induced secondary hyperalgesia in humans. J Physiol 2002, 448: 749–764.CrossRef

30.

Gilchrist HD, Allard BL, Simone DA: Enhanced withdrawal responses to heat and mechanical stimuli following intraplantar injection of capsaicin in rats. Pain 1996, 67: 179–188. 10.1016/0304-3959(96)03104-1CrossRef

31.

Fisher K, Coderre TJ: Hyperalgesia and allodynia induced by intrathecal (RS)-dihydroxyphenylglycine in rats. Neuroreport 1998, 9: 1169–1172. 10.1097/00001756-199804200-00038CrossRef

32.

Kajander KC, Bennett GJ: Onset of a painful peripheral neuropathy in rat: a partial and differential deafferentation and spontaneous discharge in A beta and A delta primary afferent neurons. J Neurophysiol 1992, 68: 734–744.

33.

Devor M: Ectopic discharge in Abeta afferents as a source of neuropathic pain. Exp Brain Res 2009, 196: 115–28. 10.1007/s00221-009-1724-6CrossRef

34.

Laferrière A, Millecamps M, Xanthos DN, Xiao WH, Siau C, de Mos M, Sachot C, Ragavendran JV, Huygen FJ, Bennett GJ, Coderre TJ: Cutaneous tactile allodynia associated with microvascular dysfunction in muscle. Mol Pain 2008, 4: 49.PubMedCentralCrossRef

35.

Marchand F, D'Mello R, Yip PK, Calvo M, Muller E, Pezet S, Dickenson AH, McMahon SB: Specific involvement of atypical PKCzeta/PKMzeta in spinal persistent nociceptive processing following peripheral inflammation in rat. Mol Pain 2011, 7: 86. 10.1186/1744-8069-7-86PubMedCentralCrossRef

36.

Bennett GJ, Xie YK: A peripheral mononeuropathy in rat that produces disorders of pain sensation like those seen in man. Pain 1988, 33: 87–107. 10.1016/0304-3959(88)90209-6CrossRef

37.

Coderre TJ, Xanthos DN, Francis L, Bennett GJ: Chronic post-ischemia pain (CPIP): a novel animal model of complex regional pain syndrome-type I (CRPS-I; reflex sympathetic dystrophy) produced by prolonged hindpaw ischemia and reperfusion in the rat. Pain 2004, 112: 94–105. 10.1016/j.pain.2004.08.001CrossRef

38.

Pogatzki EM, Zahn PK, Brennan TJ: Lumbar catheterization of the subarachnoid space with a 32-gauge polyurethane catheter in the rat. Eur J Pain 2000, 4: 111–113. 10.1053/eujp.1999.0157CrossRef

39.

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. 10.1016/0304-3959(88)90026-7CrossRef

40.

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)90144-9CrossRef

41.

Kinnman E, Levine JD: Involvement of the sympathetic postganglionic neuron in capsaicin-induced secondary hyperalgesia in the rat. Neuroscience 1995, 65: 283–291. 10.1016/0306-4522(94)00474-JCrossRef

42.

Pitcher MH, Cervero F: Role of the NKCC1 co-transporter in sensitization of spinal nociceptive neurons. Pain 2010, 151: 756–762. 10.1016/j.pain.2010.09.008CrossRef

Title: PKMζ is essential for spinal plasticity underlying the maintenance of persistent pain
Authors: Andre Laferrière
Mark H Pitcher
Anne Haldane
Yue Huang
Virginia Cornea
Naresh Kumar
Todd C Sacktor
Fernando Cervero
Terence J Coderre
Publication date: 01-12-2011
Publisher: BioMed Central
Published in: Molecular Pain / Issue 1/2011
Electronic ISSN: 1744-8069
DOI: https://doi.org/10.1186/1744-8069-7-99

Keynote webinar | Spotlight on medication adherence

Springer Medicine

PKMζ is essential for spinal plasticity underlying the maintenance of persistent pain

Abstract

Background

Results

Conclusions

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Background

Results

Conclusions

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