Musculo-skeletal pain affects roughly half of the adult US population, resulting in enormous loss of productivity. Vitamin D deficiency is also extremely prevalent. Clinical studies suggest that populations prone to vitamin D deficiency, including the elderly and obese, are much more likely to experience muscle pain. Further, vitamin D repletion is reported to be effective in ameliorating muscle pain. However, the biological basis for hypovitaminosis D-induced pain is unclear. We've found that dorsal root ganglion sensory neurons express vitamin D receptors, and developed a rat model of vitamin D deficiency showing deep muscle sensitivity. Gastrocnemius muscle from these rats show increased indices of innervation, consistent with increased sensory axon density in a number of peripheral pain syndromes. The objective of this proposal is to explore the relation among vitamin D deficiency, sensory innervation and muscle pain. We hypothesize that vitamin D deficiency leads to sprouting of sensory nociceptor axons in skeletal muscle. In the first specific aim, we will characterize peripheral target innervation with regard to changes in innervation density, neuronal phenotype, and ability to activate spinal pathways in rats with normal or deficient vitamin D. In the second aim, we will determine direct effects of physiological and hypophysiological concentrations vitamin D on axon outgrowth from dissociated adult dorsal root ganglion neuronal cultures. We will also examine the role of target tissue by conducting explant cultures of ganglion and skeletal muscle from normal or vitamin D- deficient rats and assessing the muscle's ability to modulate neurite outgrowth. These studies represent the first systematic exploration of the biological basis of hypovitaminosis D-induced muscle pain. They are also the first to investigate a role of vitamin D in mature axonal outgrowth. Results from this exploratory study will provide a basis for additional mechanistic investigations using the rat model, and for clinical studies documenting the utility of vitamin D in preventing and reversing pain syndromes.

Public Health Relevance

Both musculo-skeletal pain and vitamin D deficiency are widespread within the US population, and clinical studies suggest that a causal relationship exists. However, the biological basis by which vitamin D deficiency leads to muscle pain is unclear. We propose the first systematic investigation concerning cellular mechanisms by which vitamin D deficiency leads to muscle pain. These studies will provide an evidence-based rationale for employing vitamin D supplementation as a preventative or therapeutic approach to a problem that costs the US economy in excess of $40 billion per year.

Agency
National Institute of Health (NIH)
Institute
National Center for Complementary & Alternative Medicine (NCCAM)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21AT006629-02
Application #
8244444
Study Section
Somatosensory and Chemosensory Systems Study Section (SCS)
Program Officer
Glowa, John R
Project Start
2011-04-01
Project End
2014-03-31
Budget Start
2012-04-01
Budget End
2014-03-31
Support Year
2
Fiscal Year
2012
Total Cost
$187,500
Indirect Cost
$62,500
Name
University of Kansas
Department
Physiology
Type
Schools of Medicine
DUNS #
016060860
City
Kansas City
State
KS
Country
United States
Zip Code
66160
Tague, S E; Smith, P G (2014) Vitamin D deficiency leads to sensory and sympathetic denervation of the rat synovium. Neuroscience 279:77-93
Tague, Sarah E; Clarke, Gwenaelle L; Winter, Michelle K et al. (2011) Vitamin D deficiency promotes skeletal muscle hypersensitivity and sensory hyperinnervation. J Neurosci 31:13728-38