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

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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.

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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).

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  1. Pierrick Poisbeau and Maya Aouad contributed equally to this work.

Authors and Affiliations

  1. Centre National de la Recherche Scientifique, Université de Strasbourg, Institut des Neurosciences Cellulaires et Intégratives, F-67000, Strasbourg, France

    Pierrick Poisbeau, Maya Aouad, Géraldine Gazzo, Adrien Lacaud & Vincent Lelievre

  2. Faculté de Médecine, Laboratoire de Biochimie et Biologie Moléculaire, Centre Hospitalier Universitaire de Strasbourg, Strasbourg, France

    Véronique Kemmel

  3. Institut de NeuroPhysioPathologie, CNRS UMR 7051, Aix-Marseille Université - Faculté de Médecine Nord, CS 811. 51 Bd P. Dramard, 13344, Marseille Cedex 15, France

    Véréna Landel & François Feron

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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)

High Resolution Image (TIF 10072 kb)

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)

High Resolution Image (TIF 10239 kb)

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)

High Resolution Image (TIF 580 kb)

Supplementary Table 1

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

High Resolution Image (TIF 21884 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)

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Poisbeau, P., Aouad, M., Gazzo, G. et al. Cholecalciferol (Vitamin D3) Reduces Rat Neuropathic Pain by Modulating Opioid Signaling. Mol Neurobiol 56, 7208–7221 (2019). https://doi.org/10.1007/s12035-019-1582-6

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