Abstract
About 50 million of the U.S. adult population suffer from chronic pain. It is a complex disease in its own right for which currently available analgesics have been deemed woefully inadequate since ~20% of the sufferers derive no benefit. Vitamin D, known for its role in calcium homeostasis and bone metabolism, is thought to be of clinical benefit in treating chronic pain without the side-effects of currently available analgesics. A strong correlation between hypovitaminosis D and incidence of bone pain is known. However, the potential underlying mechanisms by which vitamin D might exert its analgesic effects are poorly understood. In this review, we discuss pathways involved in pain sensing and processing primarily at the level of dorsal root ganglion (DRG) neurons and the potential interplay between vitamin D, its receptor (VDR) and known specific pain signaling pathways including nerve growth factor (NGF), glial-derived neurotrophic factor (GDNF), epidermal growth factor receptor (EGFR), and opioid receptors. We also discuss how vitamin D/VDR might influence immune cells and pain sensitization as well as review the increasingly important topic of vitamin D toxicity. Further in vitro and in vivo experimental studies will be required to study these potential interactions specifically in pain models. Such studies could highlight the potential usefulness of vitamin D either alone or in combination with existing analgesics to better treat chronic pain.
Highlights
The newly proposed definition of pain by the International Association for the Study of Pain states—“An aversive sensory and emotional experience typically caused by, or resembling that caused by, actual or potential tissue injury1”
We discuss pathways involved in pain sensing and processing primarily at the level of dorsal root ganglion (DRG) neurons and the potential interplay between vitamin D/VDR and known specific pain signaling pathways including nerve growth factor (NGF), glial-derived neurotrophic factor (GDNF), epidermal growth factor receptor (EGFR), and opioid receptors
Further we showed that EGFR inhibition could prevent vascular dysfunction by normalizing up to 90% of the 1,100+ gene changes observed during the development of diabetes-induced microvascular dysfunction and that upregulation of EGFR appears to be a key early change leading to vascular pathology associated with diabetes [125, 129, 130]
Summary
The newly proposed definition of pain by the International Association for the Study of Pain states—“An aversive sensory and emotional experience typically caused by, or resembling that caused by, actual or potential tissue injury1”. The effect of VDR is dependent on several other, as yet unknown, factors including enzymatic activities such as, demethyltransferase and RNA polymerase that mediate the promotion or inhibition of gene expression. Some of these target genes include those that bind 1,25(OH)2D3 to activate it or that mark it for its degradation, suggesting a self-regulating mechanism [28] and perhaps restricting the possibility for vitamin D toxicity due to over-exposure to sunlight or dietary intake. In the proceeding sections we will discuss the interplay between vitamin D and different types of pain
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