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Cholecalciferol (Vitamin D3) Reduces Rat Neuropathic Pain by Modulating Opioid Signaling

  • Pierrick PoisbeauEmail author
  • Maya Aouad
  • Géraldine Gazzo
  • Adrien Lacaud
  • Véronique Kemmel
  • Véréna Landel
  • Vincent Lelievre
  • François FeronEmail author
Article

Abstract

The impact of vitamin D on sensory function, including pain processing, has been receiving increasing attention. Indeed, vitamin D deficiency is associated with various chronic pain conditions, and several lines of evidence indicate that vitamin D supplementation may trigger pain relief. However, the underlying mechanisms of action remain poorly understood. We used inflammatory and non-inflammatory rat models of chronic pain to evaluate the benefits of vitamin D3 (cholecalciferol) on pain symptoms. We found that cholecalciferol supplementation improved mechanical nociceptive thresholds in monoarthritic animals and reduced mechanical hyperalgesia and cold allodynia in a model of mononeuropathy. Transcriptomic analysis of cerebrum, dorsal root ganglia, and spinal cord tissues indicate that cholecalciferol supplementation induces a massive gene dysregulation which, in the cerebrum, is associated with opioid signaling (23 genes), nociception (14), and allodynia (8), and, in the dorsal root ganglia, with axonal guidance (37 genes) and nociception (17). Among the identified cerebral dysregulated nociception-, allodynia-, and opioid-associated genes, 21 can be associated with vitamin D metabolism. However, it appears that their expression is modulated by intermediate regulators such as diverse protein kinases and not, as expected, by the vitamin D receptor. Overall, several genes—Oxt, Pdyn, Penk, Pomc, Pth, Tac1, and Tgfb1—encoding for peptides/hormones stand out as top candidates to explain the therapeutic benefit of vitamin D3 supplementation. Further studies are now warranted to detail the precise mechanisms of action but also the most favorable doses and time windows for pain relief.

Keywords

Cholecalciferol Analgesia Steroid Sciatic nerve constriction Gene regulation Opioid 

Notes

Acknowledgments

This work was supported by the following French institutions: Centre National de la Recherche Scientifique, Fondation de l’Avenir, Université de Strasbourg, and Institut Universitaire de France. MA and GG received PhD scholarship from the French Ministère de la Recherche et de l’Enseignement Supérieur. We thank the following research programs of excellence for their support: FHU Neurogenycs, French National Research Agency (ANR) through the Programme d’Investissement d’Avenir (contract ANR-17-EURE-0022, EURIDOL graduate school of pain).

Compliance with Ethical Standards

Conflict of Interest Statement

The authors declare that they have no conflict of interest.

Supplementary material

12035_2019_1582_Fig7_ESM.png (391 kb)
Supplementary Fig. 1

RT-qPCR validation of several dysregulated transcripts in the dorsal root ganglia (DRG) and cerebrum of animals that received sham or cuff surgery with or without vitamin D3 supplementation. Relative expression of transcripts coding for diverse neurotransmitters, neuropeptides and neurotrophic factors. Statistical code for Sidak’s multiple comparisons test: *** p < 0.001. (PNG 390 kb)

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High Resolution Image (TIF 10072 kb)
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Supplementary Fig. 2

RT-qPCR validation of several dysregulated transcripts in the dorsal root ganglia (DRG) and cerebrum of animals that received sham or cuff surgery with or without vitamin D3 supplementation. Relative expression of transcripts coding for proteins of the extracellular matrix and some chemokines. Statistical code for Sidak’s multiple comparisons test: *** p < 0.001. (PNG 360 kb)

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High Resolution Image (TIF 10239 kb)
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Supplementary Fig. 3

Schematic view of the putative mechanisms of cholecalciferol action in the cerebrum (a), dorsal root ganglia (DRG) (b) and spinal cord (c). Five common regulators – Erk1/2 (i.e. Mapk3/1), Jnk (i.e. Mapk8), P38mapk, Prkca, Smad – are identified, although dysregulated genes differ greatly from one tissue to another. Regulators are either activated (brown) or inhibited (blue); genes are either up- (red) or downregulated (green). (PNG 2067 kb)

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High Resolution Image (TIF 580 kb)
12035_2019_1582_Fig10_ESM.png (301 kb)
Supplementary Table 1

List of primer sequences used to amplify genes of interest by RT-qPCR. (PNG 301 kb)

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High Resolution Image (TIF 21884 kb)
12035_2019_1582_MOESM5_ESM.docx (39 kb)
Supplementary Table 2 Alphabetical list of over- (in red) and under-expressed genes (in green) in the dorsal root ganglia (DRG; yellow boxes), the spinal cord (blue boxes) and the cerebrum (green boxes) of cuff-operated rats supplemented with vitamin D3 compared with unsupplemented animals. (DOCX 39 kb)

References

  1. 1.
    Cui X, Gooch H, Petty A, McGrath JJ, Eyles D (2017) Vitamin D and the brain: genomic and non-genomic actions. Mol Cell Endocrinol 453:131–143PubMedCrossRefGoogle Scholar
  2. 2.
    Landel V, Stephan D, Cui X, Eyles D, Feron F (2017) Differential expression of vitamin D-associated enzymes and receptors in brain cell subtypes. J Steroid Biochem Mol Biol 177:129–134PubMedCrossRefGoogle Scholar
  3. 3.
    Landel V, Annweiler C, Millet P, Morello M, Feron F (2016) Vitamin D, cognition and Alzheimer's disease: the therapeutic benefit is in the D-tails. J Alzheimers Dis 53(2):419–444PubMedPubMedCentralCrossRefGoogle Scholar
  4. 4.
    Cheng JB, Motola DL, Mangelsdorf DJ, Russell DW (2003) De-orphanization of cytochrome P450 2R1: a microsomal vitamin D 25-hydroxilase. J Biol Chem 278(39):38084–380093PubMedCrossRefGoogle Scholar
  5. 5.
    Schuster I (2011) Cytochromes P450 are essential players in the vitamin D signaling system. Biochim Biophys Acta 1814(1):186–199CrossRefGoogle Scholar
  6. 6.
    Holick MF (2007) Vitamin D deficiency. N Engl J Med 357(3):266–281PubMedCrossRefGoogle Scholar
  7. 7.
    Plotnikoff GA, Quigley JM (2003) Prevalence of severe hypovitaminosis D in patients with persistent, nonspecific musculoskeletal pain. Mayo Clin Proc 78(12):1463–1470CrossRefPubMedGoogle Scholar
  8. 8.
    Lotfi A, Abdel-Nasser AM, Hamdy A, Omran AA, El-Rehany MA (2007) Hypovitaminosis D in female patients with chronic low back pain. Clin Rheumatol 26(11):1895–1901PubMedCrossRefGoogle Scholar
  9. 9.
    Mouyis M, Ostor AJ, Crisp AJ, Ginawi A, Halsall DJ, Shenker N, Poole KE (2008) Hypovitaminosis D among rheumatology outpatients in clinical practice. Rheumatology (Oxford) 47(9):1348–1351CrossRefGoogle Scholar
  10. 10.
    Atherton K, Berry DJ, Parsons T, Macfarlane GJ, Power C, Hypponen E (2009) Vitamin D and chronic widespread pain in a white middle-aged British population: evidence from a cross-sectional population survey. Ann Rheum Dis 68(6):817–822PubMedCrossRefGoogle Scholar
  11. 11.
    Tague SE, Clarke GL, Winter MK, McCarson KE, Wright DE, Smith PG (2011) Vitamin D deficiency promotes skeletal muscle hypersensitivity and sensory hyperinnervation. J Neurosci 31(39):13728–13738PubMedPubMedCentralCrossRefGoogle Scholar
  12. 12.
    Wepner F, Scheuer R, Schuetz-Wieser B, Machacek P, Pieler-Bruha E, Cross HS, Hahne J, Friedrich M (2014) Effects of vitamin D on patients with fibromyalgia syndrome: a randomized placebo-controlled trial. Pain 155(2):261–268PubMedCrossRefGoogle Scholar
  13. 13.
    Schreuder F, Bernsen RM, van der Wouden JC (2012) Vitamin D supplementation for nonspecific musculoskeletal pain in non-Western immigrants: a randomized controlled trial. Ann Fam Med 10(6):547–555PubMedPubMedCentralCrossRefGoogle Scholar
  14. 14.
    Straube S, Andrew Moore R, Derry S, McQuay HJ (2009) Vitamin D and chronic pain. Pain 141(1–2):10–13PubMedCrossRefGoogle Scholar
  15. 15.
    Shipton EE, Shipton EA (2015) Vitamin D deficiency and pain: clinical evidence of low levels of vitamin D and supplementation in chronic pain states. Pain Ther 4(1):67–87PubMedPubMedCentralCrossRefGoogle Scholar
  16. 16.
    Straube S, Derry S, Straube C, Moore RA (2015) Vitamin D for the treatment of chronic painful conditions in adults. Cochrane Database Syst Rev 5:CD007771Google Scholar
  17. 17.
    Wu Z, Malihi Z, Stewart AW, Lawes CM, Scragg R (2016) Effect of vitamin D supplementation on pain: a systematic review and meta-analysis. Pain Physician 19(7):415–427PubMedGoogle Scholar
  18. 18.
    de Oliveira DL, Hirotsu C, Tufik S, Andersen ML (2017) The interfaces between vitamin D, sleep and pain. J Endocrinol 234(1):R23–R36PubMedCrossRefGoogle Scholar
  19. 19.
    Yong WC, Sanguankeo A, Upala S (2017) Effect of vitamin D supplementation in chronic widespread pain: a systematic review and meta-analysis. Clin Rheumatol 36(12):2825–2833PubMedCrossRefGoogle Scholar
  20. 20.
    Helde-Frankling M, Bjorkhem-Bergman L (2017) Vitamin D in pain management. Int J Mol Sci 18(10):2170–2179PubMedCentralCrossRefGoogle Scholar
  21. 21.
    Colotta F, Jansson B, Bonelli F (2017) Modulation of inflammatory and immune responses by vitamin D. J Autoimmun 85:78–97PubMedCrossRefGoogle Scholar
  22. 22.
    Sassi F, Tamone C, D’Amelio P (2018) Vitamin D: nutrient, hormone, and immunomodulator. Nutrients 10(11):1656–1670PubMedCentralCrossRefGoogle Scholar
  23. 23.
    Liu X, Nelson A, Wang X, Farid M, Gunji Y, Ikari J, Iwasawa S, Basma H et al (2014) Vitamin D modulates prostaglandin E2 synthesis and degradation in human lung fibroblasts. Am J Respir Cell Mol Biol 50(1):40–50PubMedGoogle Scholar
  24. 24.
    Gendelman O, Itzhaki D, Makarov S, Bennun M, Amital H (2015) A randomized double-blind placebo-controlled study adding high dose vitamin D to analgesic regimens in patients with musculoskeletal pain. Lupus 24(4–5):483–489PubMedCrossRefGoogle Scholar
  25. 25.
    Huang W, Shah S, Long Q, Crankshaw AK, Tangpricha V (2013) Improvement of pain, sleep, and quality of life in chronic pain patients with vitamin D supplementation. Clin J Pain 29(4):341–347PubMedCrossRefGoogle Scholar
  26. 26.
    Banafshe HR, Khoshnoud MJ, Abed A, Saghazadeh M, Mesdaghinia A (2018) Vitamin D supplementation attenuates the behavioral scores of neuropathic pain in rats. Nutr Neurosci 12:1–6Google Scholar
  27. 27.
    Chabas JF, Stephan D, Marqueste T, Garcia S, Lavaut MN, Nguyen C, Legre R, Khrestchatisky M et al (2013) Cholecalciferol (vitamin D(3)) improves myelination and recovery after nerve injury. PLoS One 8(5):e65034PubMedPubMedCentralCrossRefGoogle Scholar
  28. 28.
    Montava M, Garcia S, Mancini J, Jammes Y, Courageot J, Lavieille JP, Feron F (2015) Vitamin D3 potentiates myelination and recovery after facial nerve injury. Eur Arch Otorhinolaryngol 272(10):2815–2823PubMedCrossRefGoogle Scholar
  29. 29.
    Aouad M, Zell V, Juif PE, Lacaud A, Goumon Y, Darbon P, Lelievre V, Poisbeau P (2014) Etifoxine analgesia in experimental monoarthritis: a combined action that protects spinal inhibition and limits central inflammatory processes. Pain 155(2):403–412PubMedCrossRefGoogle Scholar
  30. 30.
    Aouad M, Petit-Demouliere N, Goumon Y, Poisbeau P (2014) Etifoxine stimulates allopregnanolone synthesis in the spinal cord to produce analgesia in experimental mononeuropathy. Eur J Pain 18(2):258–268PubMedCrossRefGoogle Scholar
  31. 31.
    Luis-Delgado OE, Barrot M, Rodeau JL, Schott G, Benbouzid M, Poisbeau P, Freund-Mercier MJ, Lasbennes F (2006) Calibrated forceps: a sensitive and reliable tool for pain and analgesia studies. J Pain 7(1):32–39PubMedCrossRefGoogle Scholar
  32. 32.
    Aouad M, Charlet A, Rodeau JL, Poisbeau P (2009) Reduction and prevention of vincristine-induced neuropathic pain symptoms by the non-benzodiazepine anxiolytic etifoxine are mediated by 3alpha-reduced neurosteroids. Pain 147(1–3):54–59PubMedCrossRefGoogle Scholar
  33. 33.
    Chomczynski P, Sacchi N (1987) Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal Biochem 162(1):156–159PubMedPubMedCentralCrossRefGoogle Scholar
  34. 34.
    Lelievre V, Hu Z, Byun JY, Ioffe Y, Waschek JA (2002) Fibroblast growth factor-2 converts PACAP growth action on embryonic hindbrain precursors from stimulation to inhibition. J Neurosci Res 67(5):566–573PubMedCrossRefGoogle Scholar
  35. 35.
    Fernandes de Abreu DA, Eyles D, Feron F (2009) Vitamin D, a neuro-immunomodulator: implications for neurodegenerative and autoimmune diseases. Psychoneuroendocrinology 34(Suppl 1):S265–S277PubMedCrossRefGoogle Scholar
  36. 36.
    Lemire JM, Archer DC, Beck L, Spiegelberg HL (1995) Immunosuppressive actions of 1,25-dihydroxyvitamin D3: preferential inhibition of Th1 functions. J Nutr 125(6 Suppl):1704S–1708SPubMedGoogle Scholar
  37. 37.
    Boonstra A, Barrat FJ, Crain C, Heath VL, Savelkoul HF, O'Garra A (2001) 1alpha,25-Dihydroxyvitamin d3 has a direct effect on naive CD4(+) T cells to enhance the development of Th2 cells. J Immunol 167(9):4974–4980CrossRefPubMedGoogle Scholar
  38. 38.
    Jeffery LE, Burke F, Mura M, Zheng Y, Qureshi OS, Hewison M, Walker LS, Lammas DA et al (2009) 1,25-Dihydroxyvitamin D3 and IL-2 combine to inhibit T cell production of inflammatory cytokines and promote development of regulatory T cells expressing CTLA-4 and FoxP3. J Immunol 183(9):5458–5467PubMedPubMedCentralCrossRefGoogle Scholar
  39. 39.
    Cantorna MT, Waddell A (2014) The vitamin D receptor turns off chronically activated T cells. Ann N Y Acad Sci 1317:70–75PubMedCrossRefGoogle Scholar
  40. 40.
    Bivona G, Agnello L, Ciaccio M (2018) The immunological implication of the new vitamin D metabolism. Cent Eur J Immunol 43(3):331–334PubMedPubMedCentralCrossRefGoogle Scholar
  41. 41.
    Navarro S, Soletto L, Puchol S, Rotllant J, Soengas JL, Cerda-Reverter JM (2016) 60 years of POMC: POMC: an evolutionary perspective. J Mol Endocrinol 56(4):T113–T118PubMedCrossRefGoogle Scholar
  42. 42.
    Staszkiewicz J, Skowronski MT, Siawrys G, Kaminski T, Krazinski BE, Plonka KJ, Wylot B, Przala J et al (2007) Expression of proopiomelanocortin, proenkephalin and prodynorphin genes in porcine luteal cells. Acta Vet Hung 55(4):435–449PubMedCrossRefGoogle Scholar
  43. 43.
    Wylot B, Staszkiewicz J, Okrasa S (2008) The expression of genes coding for opioid precursors, opioid receptors, beta-LH subunit and GnRH receptor in the anterior pituitary of cyclic gilts. J Physiol Pharmacol 59(4):745–758PubMedGoogle Scholar
  44. 44.
    Xu K, Bastia E, Schwarzschild M (2005) Therapeutic potential of adenosine A(2A) receptor antagonists in Parkinson's disease. Pharmacol Ther 105(3):267–310PubMedCrossRefGoogle Scholar
  45. 45.
    van de Pavert SA, Clarke IJ, Rao A, Vrana KE, Schwartz J (1997) Effects of vasopressin and elimination of corticotropin-releasing hormone-target cells on pro-opiomelanocortin mRNA levels and adrenocorticotropin secretion in ovine anterior pituitary cells. J Endocrinol 154(1):139–147PubMedCrossRefGoogle Scholar
  46. 46.
    Bousquet C, Zatelli MC, Melmed S (2000) Direct regulation of pituitary proopiomelanocortin by STAT3 provides a novel mechanism for immuno-neuroendocrine interfacing. J Clin Invest 106(11):1417–1425PubMedPubMedCentralCrossRefGoogle Scholar
  47. 47.
    Bian JM, Wu N, Su RB, Li J (2012) Opioid receptor trafficking and signaling: what happens after opioid receptor activation? Cell Mol Neurobiol 32(2):167–184PubMedCrossRefGoogle Scholar
  48. 48.
    Koch T, Hollt V (2008) Role of receptor internalization in opioid tolerance and dependence. Pharmacol Ther 117(2):199–206PubMedCrossRefGoogle Scholar
  49. 49.
    El-Shewy HM, Abdel-Samie SA, Al Qalam AM, Lee MH, Kitatani K, Anelli V, Jaffa AA, Obeid LM et al (2011) Phospholipase C and protein kinase C-beta 2 mediate insulin-like growth factor II-dependent sphingosine kinase 1 activation. Mol Endocrinol 25(12):2144–2156PubMedPubMedCentralCrossRefGoogle Scholar
  50. 50.
    Farnsworth NL, Walter RL, Hemmati A, Westacott MJ, Benninger RK (2016) Low level pro-inflammatory cytokines decrease connexin36 gap junction coupling in mouse and human islets through nitric oxide-mediated protein kinase Cdelta. J Biol Chem 291(7):3184–3196PubMedCrossRefGoogle Scholar
  51. 51.
    Fell GL, Robinson KC, Mao J, Woolf CJ, Fisher DE (2014) Skin beta-endorphin mediates addiction to UV light. Cell 157(7):1527–1534PubMedPubMedCentralCrossRefGoogle Scholar
  52. 52.
    Souza GR, Talbot J, Lotufo CM, Cunha FQ, Cunha TM, Ferreira SH (2013) Fractalkine mediates inflammatory pain through activation of satellite glial cells. Proc Natl Acad Sci U S A 110(27):11193–11198PubMedPubMedCentralCrossRefGoogle Scholar
  53. 53.
    Ledent C, Vaugeois JM, Schiffmann SN, Pedrazzini T, El Yacoubi M, Vanderhaeghen JJ, Costentin J, Heath JK et al (1997) Aggressiveness, hypoalgesia and high blood pressure in mice lacking the adenosine A2a receptor. Nature 388(6643):674–678PubMedCrossRefGoogle Scholar
  54. 54.
    Inoue M, Shimohira I, Yoshida A, Zimmer A, Takeshima H, Sakurada T, Ueda H (1999) Dose-related opposite modulation by nociceptin/orphanin FQ of substance P nociception in the nociceptors and spinal cord. J Pharmacol Exp Ther 291(1):308–313PubMedGoogle Scholar
  55. 55.
    Yang J, Yang Y, Chen JM, Liu WY, Wang CH, Lin BC (2007) Effect of oxytocin on acupuncture analgesia in the rat. Neuropeptides 41(5):285–292PubMedCrossRefGoogle Scholar
  56. 56.
    Ho YC, Lee HJ, Tung LW, Liao YY, Fu SY, Teng SF, Liao HT, Mackie K et al (2011) Activation of orexin 1 receptors in the periaqueductal gray of male rats leads to antinociception via retrograde endocannabinoid (2-arachidonoylglycerol)-induced disinhibition. J Neurosci 31(41):14600–14610PubMedPubMedCentralCrossRefGoogle Scholar
  57. 57.
    Savelieva KV, Zhao S, Pogorelov VM, Rajan I, Yang Q, Cullinan E, Lanthorn TH (2008) Genetic disruption of both tryptophan hydroxylase genes dramatically reduces serotonin and affects behavior in models sensitive to antidepressants. PLoS One 3(10):e3301PubMedPubMedCentralCrossRefGoogle Scholar
  58. 58.
    Gregus AM, Dumlao DS, Wei SC, Norris PC, Catella LC, Meyerstein FG, Buczynski MW, Steinauer JJ et al (2013) Systematic analysis of rat 12/15-lipoxygenase enzymes reveals critical role for spinal eLOX3 hepoxilin synthase activity in inflammatory hyperalgesia. FASEB J 27(5):1939–1949PubMedPubMedCentralCrossRefGoogle Scholar
  59. 59.
    Yoshida A, Mobarakeh JI, Sakurai E, Sakurada S, Orito T, Kuramasu A, Kato M, Yanai K (2005) Intrathecally-administered histamine facilitates nociception through tachykinin NK1 and histamine H1 receptors: A study in histidine decarboxylase gene knockout mice. Eur J Pharmacol 522(1–3):55–62PubMedCrossRefGoogle Scholar
  60. 60.
    Oshio K, Watanabe H, Yan D, Verkman AS, Manley GT (2006) Impaired pain sensation in mice lacking Aquaporin-1 water channels. Biochem Biophys Res Commun 341(4):1022–1028PubMedCrossRefGoogle Scholar
  61. 61.
    Roh DH, Seo HS, Yoon SY, Song S, Han HJ, Beitz AJ, Lee JH (2010) Activation of spinal alpha-2 adrenoceptors, but not mu-opioid receptors, reduces the intrathecal N-methyl-D-aspartate-induced increase in spinal NR1 subunit phosphorylation and nociceptive behaviors in the rat. Anesth Analg 110(2):622–629PubMedCrossRefGoogle Scholar
  62. 62.
    Liu HX, Brumovsky P, Schmidt R, Brown W, Payza K, Hodzic L, Pou C, Godbout C et al (2001) Receptor subtype-specific pronociceptive and analgesic actions of galanin in the spinal cord: selective actions via GalR1 and GalR2 receptors. Proc Natl Acad Sci U S A 98(17):9960–9964PubMedPubMedCentralCrossRefGoogle Scholar
  63. 63.
    Lantero A, Tramullas M, Pilar-Cuellar F, Valdizan E, Santillan R, Roques BP, Hurle MA (2014) TGF-beta and opioid receptor signaling crosstalk results in improvement of endogenous and exogenous opioid analgesia under pathological pain conditions. J Neurosci 34(15):5385–5395PubMedCrossRefGoogle Scholar
  64. 64.
    Gillespie CS, Sherman DL, Fleetwood-Walker SM, Cottrell DF, Tait S, Garry EM, Wallace VC, Ure J et al (2000) Peripheral demyelination and neuropathic pain behavior in periaxin-deficient mice. Neuron 26(2):523–531PubMedCrossRefGoogle Scholar
  65. 65.
    Chillingworth NL, Morham SG, Donaldson LF (2006) Sex differences in inflammation and inflammatory pain in cyclooxygenase-deficient mice. Am J Physiol Regul Integr Comp Physiol 291(2):R327–R334PubMedCrossRefGoogle Scholar
  66. 66.
    Milligan ED, Twining C, Chacur M, Biedenkapp J, O'Connor K, Poole S, Tracey K, Martin D et al (2003) Spinal glia and proinflammatory cytokines mediate mirror-image neuropathic pain in rats. J Neurosci 23(3):1026–1040PubMedCrossRefGoogle Scholar
  67. 67.
    Kim DS, Li KW, Boroujerdi A, Peter Yu Y, Zhou CY, Deng P, Park J, Zhang X et al (2012) Thrombospondin-4 contributes to spinal sensitization and neuropathic pain states. J Neurosci 32(26):8977–8987PubMedPubMedCentralCrossRefGoogle Scholar
  68. 68.
    Shi TJ, Zhang MD, Zeberg H, Nilsson J, Grunler J, Liu SX, Xiang Q, Persson J et al (2013) Coenzyme Q10 prevents peripheral neuropathy and attenuates neuron loss in the db−/db- mouse, a type 2 diabetes model. Proc Natl Acad Sci U S A 110(2):690–695PubMedCrossRefGoogle Scholar
  69. 69.
    Pareek TK, Keller J, Kesavapany S, Pant HC, Iadarola MJ, Brady RO, Kulkarni AB (2006) Cyclin-dependent kinase 5 activity regulates pain signaling. Proc Natl Acad Sci U S A 103(3):791–796PubMedPubMedCentralCrossRefGoogle Scholar
  70. 70.
    Bautista DM, Siemens J, Glazer JM, Tsuruda PR, Basbaum AI, Stucky CL, Jordt SE, Julius D (2007) The menthol receptor TRPM8 is the principal detector of environmental cold. Nature 448(7150):204–208CrossRefPubMedGoogle Scholar
  71. 71.
    Jiang M, Gold MS, Boulay G, Spicher K, Peyton M, Brabet P, Srinivasan Y, Rudolph U et al (1998) Multiple neurological abnormalities in mice deficient in the G protein Go. Proc Natl Acad Sci U S A 95(6):3269–3274PubMedPubMedCentralCrossRefGoogle Scholar
  72. 72.
    Sakai A, Asada M, Seno N, Suzuki H (2008) Involvement of neural cell adhesion molecule signaling in glial cell line-derived neurotrophic factor-induced analgesia in a rat model of neuropathic pain. Pain 137(2):378–388PubMedCrossRefGoogle Scholar
  73. 73.
    Li L, Qin H, Shi W, Gao G (2007) Local Nogo-66 administration reduces neuropathic pain after sciatic nerve transection in rat. Neurosci Lett 424(3):145–148PubMedCrossRefGoogle Scholar
  74. 74.
    Chao MV (1994) The p75 neurotrophin receptor. J Neurobiol 25(11):1373–1385PubMedCrossRefGoogle Scholar
  75. 75.
    Wang Y, Zhu J, DeLuca HF (2012) Where is the vitamin D receptor? Arch Biochem Biophys 523(1):123–133PubMedCrossRefGoogle Scholar
  76. 76.
    Eyles DW, Liu PY, Josh P, Cui X (2014) Intracellular distribution of the vitamin D receptor in the brain: comparison with classic target tissues and redistribution with development. Neuroscience 268:1–9PubMedCrossRefGoogle Scholar
  77. 77.
    Wang TT, Tavera-Mendoza LE, Laperriere D, Libby E, MacLeod NB, Nagai Y, Bourdeau V, Konstorum A et al (2005) Large-scale in silico and microarray-based identification of direct 1,25-dihydroxyvitamin D3 target genes. Mol Endocrinol 19(11):2685–2695PubMedCrossRefGoogle Scholar
  78. 78.
    Han S, Li T, Ellis E, Strom S, Chiang JY (2010) A novel bile acid-activated vitamin D receptor signaling in human hepatocytes. Mol Endocrinol 24(6):1151–1164PubMedPubMedCentralCrossRefGoogle Scholar
  79. 79.
    Schwartz Z, Ehland H, Sylvia VL, Larsson D, Hardin RR, Bingham V, Lopez D, Dean DD et al (2002) 1alpha,25-dihydroxyvitamin D(3) and 24R,25-dihydroxyvitamin D(3) modulate growth plate chondrocyte physiology via protein kinase C-dependent phosphorylation of extracellular signal-regulated kinase 1/2 mitogen-activated protein kinase. Endocrinology 143(7):2775–2786PubMedCrossRefGoogle Scholar
  80. 80.
    Peric M, Koglin S, Kim SM, Morizane S, Besch R, Prinz JC, Ruzicka T, Gallo RL et al (2008) IL-17A enhances vitamin D3-induced expression of cathelicidin antimicrobial peptide in human keratinocytes. J Immunol 181(12):8504–8512PubMedPubMedCentralCrossRefGoogle Scholar
  81. 81.
    Shen M, Yen A (2009) Nicotinamide cooperates with retinoic acid and 1,25-dihydroxyvitamin D(3) to regulate cell differentiation and cell cycle arrest of human myeloblastic leukemia cells. Oncology 76(2):91–100PubMedPubMedCentralCrossRefGoogle Scholar
  82. 82.
    Gniadecki R (1998) Nongenomic signaling by vitamin D: a new face of Src. Biochem Pharmacol 56(10):1273–1277PubMedCrossRefGoogle Scholar
  83. 83.
    Gold ES, Diercks AH, Podolsky I, Podyminogin RL, Askovich PS, Treuting PM, Aderem A (2014) 25-Hydroxycholesterol acts as an amplifier of inflammatory signaling. Proc Natl Acad Sci U S A 111(29):10666–10671PubMedPubMedCentralCrossRefGoogle Scholar

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Authors and Affiliations

  1. 1.Centre National de la Recherche ScientifiqueUniversité de Strasbourg, Institut des Neurosciences Cellulaires et IntégrativesStrasbourgFrance
  2. 2.Faculté de Médecine, Laboratoire de Biochimie et Biologie MoléculaireCentre Hospitalier Universitaire de StrasbourgStrasbourgFrance
  3. 3.Institut de NeuroPhysioPathologie, CNRS UMR 7051Aix-Marseille Université - Faculté de Médecine NordMarseille Cedex 15France

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