Vitamin D and Its Potential Interplay With Pain Signaling Pathways

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.

Keywords: DRG; EGFR; GDNF; NGF; VDR; nociception; opioids; vitamin D toxicity.

Figure 1

Vitamin D and its receptor in pain signaling pathways. Vitamin D is synthesized in the skin. Vitamin D receptor (VDR) is expressed in neurons in the skin, dorsal root ganglia (DRG), spinal cord, brain, and the intestine. Nociceptors, from the specific area of the periphery and viscera respond to environmental nociceptive stimuli such as thermal, mechanical, or chemicals by converting the stimuli into a chemoelectrical signal (1). The signal travels as a nerve impulse through dorsal root ganglia (DRG) nerve fibers (c, β, and δ) from the skin to the spinal cord (2) where it gets transmitted to secondary neurons in the dorsal horns of the spinal cord (3). After modulating the signal, the secondary neurons relay it to the cortex where the message gets decoded and pain is perceived (4).

Figure 2

The potential cross-talk between vitamin D and EGFR pain signaling. (A) Highlights the known EREG/EGFR signaling pathways involved in pain sensing and processing including downstream PI3K/AKT, TRPV1, MAP kinases, and MMP-9 effector molecules. Vitamin D might exert its analgesic effect through direct inhibition of EGFR mRNA expression via binding to its VDRE in intron 1 (B). Alternatively, vitamin D can act indirectly through modulation of other intermediary signaling cascades that lead to inhibition/modulation of EGFR (B–D). This includes vitamin D-mediated regulation of known pain signals via opioid receptors, cannabinoid receptors, beta-adrenoceptors, sodium channels, cytokines, and NGF (C) as well as inhibiting the Ang II/AT1 receptor-mediated transactivation by the renin-angiotensin-aldosterone system (RAAS; D). In the RAAS, activation of the Ang-(1-7)/Mas receptor can counter-regulate the actions of Ang II/AT1 receptor and also inhibit EGFR signaling (113, 114) (D). Additionally, vitamin D can also inhibit EGFR by inhibiting ADAMs, SPROUTY-2, or by increasing E-cadherin (B; see main text for details).