The Journal of Pain
Volume 12, Issue 1 , Pages 71-83 , January 2011

Progesterone Prevents Allodynia After Experimental Spinal Cord Injury

  • María F. Coronel

      Affiliations

    • Laboratorio de Bioquímica Neuroendócrina, Instituto de Biología y Medicina Experimental, CONICET, Buenos Aires, Argentina
    • Facultad de Ciencias Biomédicas, Universidad Austral, Buenos Aires, Argentina
    • ,
  • Florencia Labombarda

      Affiliations

    • Laboratorio de Bioquímica Neuroendócrina, Instituto de Biología y Medicina Experimental, CONICET, Buenos Aires, Argentina
    • Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires, Argentina
    • ,
  • Marcelo J. Villar

      Affiliations

    • Facultad de Ciencias Biomédicas, Universidad Austral, Buenos Aires, Argentina
    • ,
  • Alejandro F. De Nicola

      Affiliations

    • Laboratorio de Bioquímica Neuroendócrina, Instituto de Biología y Medicina Experimental, CONICET, Buenos Aires, Argentina
    • Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires, Argentina
    • ,
  • Susana L. González

      Affiliations

    • Laboratorio de Bioquímica Neuroendócrina, Instituto de Biología y Medicina Experimental, CONICET, Buenos Aires, Argentina
    • Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires, Argentina
    • Corresponding Author InformationAddress reprint requests to Susana Laura González, PhD, Instituto de Biología y Medicina Experimental, Vuelta de Obligado 2490, C1428ADN, Buenos Aires, Argentina.

Received 9 January 2010 ,Revised 18 March 2010 ,Accepted 29 April 2010.

References 

  1. Aloisi AM, Bonifazi M. Sex hormones, central nervous system and pain. Horm Behav. 2006;50:1–7
  2. Alonso G, Phan V, Guillemain I, Saunier M, Legrand A, Anoal M, et al. Immunocytochemical localization of the sigma(1) receptor in the adult rat central nervous system. Neuroscience. 2000;97:155–170
  3. Baastrup C, Finnerup NB. Pharmacological management of neuropathic pain following spinal cord injury. CNS Drugs. 2008;22:455–475
  4. Bajo M, Crawford EF, Roberto M, Madamba SG, Siggins GR. Chronic morphine treatment alters expression of N-methyl-D-aspartate receptor subunits in the extended amygdala. J Neurosci Res. 2006;83:532–537
  5. Balasubramanian B, Portillo W, Reyna A, Chen JZ, Moore AN, Dash PK, et al. Nonclassical mechanisms of progesterone action in the brain: I. Protein kinase C activation in the hypothalamus of female rats. Endocrinology. 2008;149:5509–5517
  6. Basbaum AI, Bautista DM, Scherrer G, Julius D. Cellular and molecular mechanisms of pain. Cell. 2009;139:267–284
  7. Baulieu EE. Neurosteroids, their role in brain physiology: Neurotrophycity, memory, aging. J Bull Acad Natl Med. 2001;185:349–372
  8. Bee LA, Dickenson AH. Rostral ventromedial medulla control of spinal sensory processing in normal and pathophysiological states. Neuroscience. 2007;147:786–793
  9. Burchiel KJ, Hsu FP. Pain and spasticity after spinal cord injury: Mechanisms and treatment. Spine. 2001;26:146–160
  10. Caudle RM, Perez FM, King C, Yu CG, Yezierski RP. N-methyl-D-aspartate receptor subunit expression and phosphorylation following excitotoxic spinal cord injury in rats. Neurosci Lett. 2003;349:37–40
  11. Chaplan S, Bach F, Pogrel J, Chung J, Yaksh T. Quantitative assessment of tactile allodynia in the rat paw. J Neurosci. 1994;16:7711–7724
  12. Charlet A, Lasbennes F, Darbon P, Poisbeau P. Fast non-genomic effects of progesterone-derived neurosteroids on nociceptive thresholds and pain symptoms. Pain. 2008;139:603–609
  13. Choi Y, Yoon YW, Na HS, Kim SH, Chung JM. Behavioral signs of ongoing pain and cold allodynia in a rat model of neuropathic pain. Pain. 1994;59:369–376
  14. Christensen MD, Everhart AW, Pickelman JT, Hulsebosch CE. Mechanical and thermal allodynia in chronic central pain following spinal cord injury. Pain. 1996;68:97–107
  15. Christensen MD, Hulsebosch CE. Chronic central pain after spinal cord injury. J Neurotrauma. 1997;14:517–537
  16. Coronel MF, Hernando-Insúa A, Rodriguez JM, Elías F, Chasseing NA, Montaner AD, et al. Oligonucleotide IMT504 reduces neuropathic pain after peripheral nerve injury. Neurosci Lett. 2008;444:69–73
  17. Costigan M, Scholz J, Woolf CJ. Neuropathic pain: A maladaptive response of the nervous system to damage. Annu Rev Neurosci. 2009;32:1–32
  18. Cutler SM, Cekic M, Miller DM, Wali B, VanLandingham JW, Stein DG. Progesterone improves acute recovery after traumatic brain injury in the aged rat. J Neurotrauma. 2007;24:1475–1486
  19. Dai D, Litman ES, Schonteich E, Leslie KK. Progesterone regulation of activating protein-1 transcriptional activity: A possible mechanism of progesterone inhibition of endometrial cancer cell growth. J Steroid Biochem Mol Biol. 2003;87:123–131
  20. Dawson-Basoa ME, Gintzler AR. Gestational and ovarian sex steroid antinociception: Synergy between spinal kappa and delta opioid systems. Brain Res. 1998;794:61–67
  21. De la Puente B, Nadal X, Portillo-Salido E, Sánchez-Arroyos R, Ovalle S, Palacios G, et al. Sigma-1 receptors regulate activity-induced spinal sensitization and neuropathic pain after peripheral nerve injury. Pain. 2009;145:294–303
  22. De Nicola AF, Labombarda F, Gonzalez Deniselle MC, Gonzalez SL, Garay L, Meyer M, et al. Progesterone neuroprotection in traumatic CNS injury and motoneuron degeneration. Front Neuroendocrinol. 2009;30:173–187
  23. Dogrul A, Ossipov MH, Porreca F. Differential mediation of descending pain facilitation and inhibition by spinal 5HT-3 and 5HT-7 receptors. Brain Res. 2009;1280:52–59
  24. Finnerup NB, Johannesen IL, Sindrup SH, Bach FW, Jensen TS. Pain and dysesthesia in patients with spinal cord injury: A postal survey. Spinal Cord. 2001;39:256–262
  25. Frye CA, Duncan JE. Progesterone metabolites, effective at the GABAA receptor complex, attenuate pain sensitivity in rats. Brain Res. 1994;643:194–203
  26. Gao X, Kim HK, Chung JM, Chung K. Enhancement of NMDA receptor phosphorylation of the spinal dorsal horn and nucleus gracilis neurons in neuropathic rats. Pain. 2005;116:62–72
  27. Gardell LR, Vanderah TW, Gardell SE, Wang R, Ossipov MH, Lai J, et al. Enhanced evoked excitatory transmitter release in experimental neuropathy requires descending facilitation. J Neurosci. 2003;23:8370–8379
  28. Gardell LR, Ibrahim M, Wang R, Wang Z, Ossipov MH, Malan TP, et al. Mouse strains that lack spinal dynorphin upregulation after peripheral nerve injury do not develop neuropathic pain. Neuroscience. 2004;123:43–52
  29. Gintzler AR, Liu NJ. The maternal spinal cord: Biochemical and physiological correlates of steroid-activated antinociceptive processes. Prog Brain Res. 2001;133:83–97
  30. Grossman SD, Wolfe BB, Yasuda RP, Wrathall JR. Changes in NMDA receptor subunit expression in response to contusive spinal cord injury. J Neurochem. 2000;75:174–184
  31. Guennoun R, Meffre D, Labombarda F, Gonzalez SL, Gonzalez Deniselle MC, Stein DG, et al. The membrane-associated progesterone-binding protein 25-Dx: Expression, cellular localization and up-regulation after brain and spinal cord injuries. Brain Res Rev. 2008;57:493–505
  32. Guo W, Wang H, Watanabe M, Shimizu K, Zou S, LaGraize SC, et al. Glial-cytokine-neuronal interactions underlying the mechanisms of persistent pain. J Neurosci. 2007;27:6006–6018
  33. Gwak YS, Hulsebosch CE. Remote astrocytic and microglial activation modulates neuronal hyperexcitability and below-level neuropathic pain after spinal injury in rat. Neuroscience. 2009;161:895–903
  34. Haberny SL, Carr KD. Comparison of basal and D-1 dopamine receptor agonist-stimulated neuropeptide gene expression in caudate-putamen and nucleus accumbens of ad libitum fed and food-restricted rats. Brain Res Mol Brain Res. 2005;141:121–127
  35. Hains BC, Waxman SG. Activated microglia contribute to the maintenance of chronic pain after spinal cord injury. J Neurosci. 2006;26:4308–4317
  36. Heinricher MM, Tavares I, Leith JL, Lumb BM. Descending control of nociception: Specificity, recruitment and plasticity. Brain Res Rev. 2009;60:214–225
  37. Hulsebosch CE, Hains BC, Crown ED, Carlton SM. Mechanisms of chronic central neuropathic pain after spinal cord injury. Brain Res Rev. 2009;60:202–213
  38. Jing H, Iwasaki Y, Nishiyama M, Taguchi T, Tsugita M, Taniguchi Y, et al. Multisignal regulation of the rat NMDA1 receptor subunit gene–a pivotal role of glucocorticoid-dependent transcription. Life Sci. 2008;82:1137–1141
  39. Kibaly C, Meyer L, Patte-Mensah C, Mensah-Nyagan AG. Biochemical and functional evidence for the control of pain mechanisms by dehydroepiandrosterone endogenously synthesized in the spinal cord. FASEB J. 2008;22:93–104
  40. Kim HW, Roh DH, Yoon SY, Seo HS, Kwon YB, Han HJ, et al. Activation of the spinal sigma-1 receptor enhances NMDA-induced pain via PKC- and PKA-dependent phosphorylation of the NR1 subunit in mice. Br J Pharmacol. 2008;154:1125–1134
  41. Kondo D, Yabe R, Kurihara T, Saegusa H, Zong S, Tanabe T. Progesterone receptor antagonist is effective in relieving neuropathic pain. Eur J Pharmacol. 2006;541:44–48
  42. Labombarda F, Pianos A, Liere P, Eychenne B, González S, Cambourg A, et al. Injury elicited increase in spinal cord neurosteroid content analyzed by gas chromatography mass spectrometry. Endocrinology. 2006;147:1847–1859
  43. Labombarda F, Coronel MF, Villar MJ, De Nicola AF, Gonzalez SL. Neuropathic pain and temporal expression of preprodynorphin, protein kinase C and N-methyl-D-aspartate receptor subunits after spinal cord injury. Neurosci Lett. 2008;447:115–119
  44. Labombarda F, Gonzalez SL, Lima A, Roig P, Guennoun R, Schumacher M, et al. Effects of progesterone on oligodendrocyte progenitors, oligodendrocyte transcription factors and myelin proteins following spinal cord injury. Glia. 2009;57:884–897
  45. Lacroix-Fralish ML, Tawfik VL, Nutile-McMenemy N, DeLeo JA. Progesterone mediates gonadal hormone differences in tactile and thermal hypersensitivity following L5 nerve root ligation in female rats. Neuroscience. 2006;138:601–608
  46. Lacroix-Fralish ML, Tawfik VL, Nutile-McMenemy N, Deleo JA. Neuregulin 1 is a pronociceptive cytokine that is regulated by progesterone in the spinal cord: Implications for sex specific pain modulation. Eur J Pain. 2008;12:94–103
  47. Lai J, Ossipov MH, Vanderah TW, Malan TP, Porreca F. Neuropathic pain: The paradox of dynorphin. Mol Interv. 2001;1:160–167
  48. Lan JY, Skeberdis VA, Jover T, Grooms SY, Lin Y, Araneda RC, et al. Protein kinase C modulates NMDA receptor traffiking and gating. Nat Neurosci. 2001;4:382–390
  49. Latremoliere A, Woolf CJ. Central sensitization: A generator of pain hypersensitivity by central neural plasticity. J Pain. 2009;10:895–926
  50. Laughlin TM, Vanderah TW, Lashbrook J, Nichols ML, Ossipov M, Porreca F, et al. Spinally administered dynorphin A produces long-lasting allodynia: Involvement of NMDA but not opioid receptors. Pain. 1997;72:253–260
  51. Leonelli E, Bianchi R, Cavaletti G, Caruso D, Crippa D, García-Segura LM, et al. Progesterone and its derivatives are neuroprotective agents in experimental diabetic neuropathy: A multimodal analysis. Neurscience. 2007;144:1293–1304
  52. Lim G, Wang S, Zeng Q, Sung B, Yang L, Mao J. Expression of spinal NMDA receptor and PKCgamma after chronic morphine is regulated by spinal glucocorticoid receptor. J Neurosci. 2005;25:11145–11154
  53. Liu A, Hoffman PW, Lu W, Bai G. NF-kappaB site interacts with Sp factors and up-regulates the NR1 promoter during neuronal differentiation. J Biol Chem. 2004;279:17449–17458
  54. Liu NJ, Gintzler AR. Prolonged ovarian sex steroid treatment of male rats produces antinociception: Identification of sex-based divergent analgesic mechanisms. Pain. 2000;85:273–281
  55. Liu NJ, von Gizycki H, Gintzler AR. Sexually dimorphic recruitment of spinal opioid analgesic pathways by the spinal application of morphine. J Pharmacol Exp Ther. 2007;322:654–660
  56. Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-ΔΔCT) method. Methods. 2001;25:402–408
  57. Lovick TA, Devall AJ. Progesterone withdrawal-evoked plasticity of neural function in the female periaqueductal grey matter. Neural Plast. 2008 Dec 2;[Epub ahead of print]
  58. Martin WJ, Malmberg AB, Basbaum AI. PKCgamma contributes to a subset of the NMDA-dependent spinal circuits that underlie injury-induced persistent pain. J Neurosci. 2001;21:5321–5327
  59. Maurice T, Grégoire C, Espallergues J. Neuro(active)steroids actions at the neuromodulatory sigma1 (sigma1) receptor: Biochemical and physiological evidences, consequences in neuroprotection. Pharmacol Biochem Behav. 2006;84:581–597
  60. McBain CJ, Mayer ML. N-methyl-D-aspartic acid receptor structure and function. Physiol Rev. 1994;74:723–760
  61. Mensah-Nyagan AG, Kibaly C, Schaeffer V, Venard C, Meyer L, Patte-Mensah C. Endogenous steroid production in the spinal cord and potential involvement in neuropathic pain modulation. J Steroid Biochem Mol Biol. 2008;109:286–293
  62. Mensah-Nyagan AG, Meyer L, Schaeffer V, Kibaly C, Patte-Mensah C. Evidence for a key role of steroids in the modulation of pain. Psychoneuroendocrinology. 2009;34(Suppl 1):S169–S177
  63. Miraucourt LS, Dallel R, Voisin DL. Glycine inhibitory dysfunction turns touch into pain through PKCgamma interneurons. PLoS One. 2007;2:1116
  64. Molander C, Grant G. Spinal Cord Cytoarchitecture. In: The Rat Nervous System. 2nd ed.. San Diego, CA: Academic Press; 1995;p. 39–45
  65. Monnet FP, Maurice T. The sigma1 protein as a target for the non-genomic effects of neuro(active)steroids: Molecular, physiological, and behavioral aspects. J Pharmacol Sci. 2006;100:93–118
  66. Nagy GG, Watanabe M, Fukaya M, Todd AJ. Synaptic distribution of the NR1, NR2A and NR2B subunits of the N-methyl-d-aspartate receptor in the rat lumbar spinal cord revealed with an antigen-unmasking technique. Eur J Neurosci. 2004;20:3301–3312
  67. Neumann S, Braz JM, Skinner K, Llewellyn-Smith IJ, Basbaum AI. Innocuous, not noxious, input activates PKCgamma interneurons of the spinal dorsal horn via myelinated afferent fibers. J Neurosci. 2008;28:7936–7944
  68. Pathirathna S, Brimelow BC, Jagodic MM, Krishnan K, Jiang X, Zorumski CF, et al. New evidence that both T-type calcium channels and GABAA channels are responsible for the potent peripheral analgesic effects of 5alpha-reduced neuroactive steroids. Pain. 2005;114:429–443
  69. Patte-Mensah C, Li S, Mensah-Nyagan AG. Impact of neuropathic pain on the gene expression and activity of cytochrome P450side-chain-cleavage in sensory neural networks. Cell Mol Life Sci. 2004;61:2274–2284
  70. Patte-Mensah C, Kibaly C, Mensah-Nyagan AG. Substance P inhibits progesterone conversion to neuroactive metabolites in spinal sensory circuit: A potential component of nociception. PNAS. 2005;102:9044–9049
  71. Peinnequin A, Mouret C, Birot O, Alonso A, Mathieu J, Clarençon D, et al. Rat pro-inflammatory cytokine and cytokine related mRNA quantification by real-time polymerase chain reaction using SYBR green. BMC Immunol. 2004;5:3
  72. Peng HY, Chen GD, Lee SD, Lai CY, Chiu CH, Cheng CL, et al. Neuroactive steroids inhibit spinal reflex potentiation by selectively enhancing specific spinal GABA(A) receptor subtypes. Pain. 2009;143:12–20
  73. Pettus EH, Wright DW, Stein DG, Hoffman SW. Progesterone treatment inhibits the inflammatory agents that accompany traumatic brain injury. Brain Res. 2005;1049:112–119
  74. Pluchino N, Luisi M, Lenzi E, Centofanti M, Begliuomini S, Freschi L, et al. Progesterone and progestins: Effects on brain, allopregnanolone and beta-endorphin. J Steroid Biochem Mol Biol. 2006;102:205–213
  75. Poisbeau P, Patte-Mensah C, Keller AF, Barrot M, Breton JD, Luis-Delgado OE, et al. Inflammatory pain upregulates spinal inhibition via endogenous neurosterois production. J Neurosci. 2005;25:11768–11776
  76. Porreca F, Ossipov MH, Gebhart GF. Chronic pain and medullary descending facilitation. Trends Neurosci. 2002;25:319–325
  77. Qiang M, Ticku MK. Role of AP-1 in ethanol-induced N-methyl-D-aspartate receptor 2B subunit gene up-regulation in mouse cortical neurons. J Neurochem. 2005;95:1332–1341
  78. Ren K, Dubne R, Murphy A, Hoffman GE. Progesterone attenuates persistent inflammatory hyperalgesia in females rats: Involvement of spinal NMDA receptor mechanism. Brain Res. 2000;865:272–277
  79. Ren K, Dubner R. Descending modulation in persistent pain: An update. Pain. 2002;100:1–6
  80. Roberts J, Ossipov MH, Porreca F. Glial activation in the rostroventromedial medulla promotes descending facilitation to mediate inflammatory hypersensitivity. Eur J Neurosci. 2009;30:229–241
  81. Rodriguez Parkitna JM, Bilecki W, Mierzejewski P, Stefanski R, Ligeza A, Bargiela A, et al. Effects of morphine on gene expression in the rat amygdala. J Neurochem. 2004;91:38–48
  82. Roglio I, Bianchi R, Gotti S, Scurati S, Giatti S, Pesaresi M, et al. Neuroprotective effects of dihydroprogesterone and progesterone in an experimental model of nerve crush injury. Neuroscience. 2008;155:673–685
  83. Roh DH, Kim HW, Yoon SY, Seo HS, Kwon YB, Han HJ, et al. Depletion of capsaicin-sensitive afferents prevents lamina-dependent increases in spinal N-methyl-D-aspartate receptor subunit 1 expression and phosphorylation associated with thermal hyperalgesia in neuropathic rats. Eur J Pain. 2008;12:552–563
  84. Rometo AM, Rance NE. Changes in prodynorphin gene expression and neuronal morphology in the hypothalamus of postmenopausal women. J Neuroendocrinol. 2008;20:1376–1381
  85. Schumacher M, Guennoun R, Ghoumari A, Massaad C, Robert F, El-Etr M, et al. Novel perspectives for progesterone in hormone replacement therapy, with special reference to the nervous system. Endocr Rev. 2007;28:387–439
  86. Schumacher M, Sitruk-Ware R, De Nicola AF. Progesterone and progestins: Neuroprotection and myelin repair. Curr Opin Pharmacol. 2008;8:740–746
  87. Thomas AJ, Nockels RP, Pan HQ, Shaffrey CI, Chopp M. Progesterone is neuroprotective after experimental acute spinal cord trauma in rats. Spine. 1999;24:2134–2138
  88. Tomiyama M, Furusawa K, Kamijo M, Kimura T, Matsunaga M, Baba M. Upregulation of mRNAs coding for AMPA and NMDA receptor subunits and metabotropic glutamate receptors in the dorsal horn of the spinal cord in a rat model of diabetes mellitus. Brain Res Mol Brain Res. 2005;136:275–281
  89. Ultenius C, Linderoth B, Meyerson BA, Wallin J. Spinal NMDA receptor phosphorylation correlates with the presence of neuropathic signs following peripheral nerve injury in the rat. Neurosci Lett. 2006;399:85–90
  90. Vats ID, Dolt KS, Kumar K, Karar J, Nath M, Mohan A, et al. YFa, a chimeric opioid peptide, induces kappa-specific antinociception with no tolerance development during 6 days of chronic treatment. J Neurosci Res. 2008;86:1599–1607
  91. Wang Z, Gardell LR, Ossipov MH, Vanderah TW, Brennan MB, Hochgeschwender U, et al. Pronociceptive actions of dynorphin maintain chronic neuropathic pain. J Neurosci. 2001;21:1779–1786
  92. Wei F, Guo W, Zou S, Ren K, Dubner R. Supraspinal glial-neuronal interactions contribute to descending pain facilitation. J Neurosci. 2008;28:10482–10495
  93. Weyerbacher AR, Xu Q, Tamasdan C, Shin SJ, Inturrisi CE. N-Methyl-d-aspartate receptor (NMDAR) independent maintenance of inflammatory pain. Pain. 2010;148(2):237–246
  94. Woods AS, Kaminski R, Oz M, Wang Y, Hauser K, Goody R, et al. Decoy peptides that bind dynorphin noncovalently prevent NMDA receptor-mediated neurotoxicity. J Proteome Res. 2006;5:1017–1023
  95. Wright DW, Kellermann AL, Hertzberg VS, Clark PL, Frankel M, Goldstein FC, et al. ProTECT: A randomized clinical trial of progesterone for acute traumatic brain injury. Ann Emerg Med. 2007;49:391–402
  96. Xiao G, Wei J, Yan W, Wang W, Lu Z. Improved outcomes from the administration of progesterone for patients with acute severe traumatic brain injury: A randomized controlled trial. Crit Care. 2008;12(2):R61
  97. Yezierski RP. Spinal cord injury pain: Spinal and supraspinal mechanisms. J Rehabil Res Dev. 2009;46:95–107

 Supported by the University of Buenos Aires (M808) and the National Research Council of Argentina (CONICET, PIP 5542).

PII: S1526-5900(10)00533-X

doi: 10.1016/j.jpain.2010.04.013

The Journal of Pain
Volume 12, Issue 1 , Pages 71-83 , January 2011

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