VITAMIN D DEFICIENCY CAUSES MUSCULOSKELETAL HYPERSENSITIVITY: THE ROLE OF NOCICEPTOR HYPERINNERVATION

Abstract

Clinical studies link vitamin D deficiency and musculoskeletal pain, both of which occur more frequently in women. However, a causal relationship has been difficult to establish and it is not clear whether vitamin D metabolites directly influence nociceptors (`pain-sensing' neurons). It was shown here, via immunohistochemistry and western blot, that rat putative nociceptors contain vitamin D receptors (VDRs) and metabolic enzymes, whose expression is regulated by ovarian hormones. In ovariectomized rats a vitamin D deficient diet induces balance deficits and deep tissue mechanical hyperalgesia, concurrent with muscle hyperinnervation by presumed nociceptors. Balance deficits, muscle mechanical hypersensitivity, and hyperinnervation are not corrected by elevated dietary calcium. In primary sensory cultures, VDR is enriched in c-fiber growth cones and regulates neurite outgrowth through VDR rapid response pathways. Therefore, vitamin D metabolites act directly on nociceptive neurons to inhibit axonal sprouting, accounting for hypovitaminosis D-induced muscle hyperinnervation, and possibly contributing to hypersensitivity.