Vitamin D deficiency exacerbates UV/endorphin and opioid addiction.

Lajos Kemény ,Jennifer A Lo,Phillip D Rivera,David Kotler,Andrea L Hermann,Susan Regan,Staci D Bilbo,Joseph Kotler,Jennifer J Hsiao,Deena M Walker,William Sarnie,Yi Chun Lai,Matthew P Salomon,Yik Weng Yew,Weihua Ding,Sarah E Wakeman,Shiqian Shen,Maryam M Asgari,Mack Y Su,Nicholas Theodosakis,David E Fisher,Vanita Chopra,Liuyue Yang,Shinichiro Kato,Eric J Nestler,Anita A J Van Der Sande,Dave S B Hoon,Kathleen C Robinson,Yong-Hwee Eddie Loh ,Tobias A Beyer

doi:10.1126/sciadv.abe4577

Abstract

The current opioid epidemic warrants a better understanding of genetic and environmental factors that contribute to opioid addiction. Here we report an increased prevalence of vitamin D (VitD) deficiency in patients diagnosed with opioid use disorder and an inverse and dose-dependent association of VitD levels with self-reported opioid use. We used multiple pharmacologic approaches and genetic mouse models and found that deficiencies in VitD signaling amplify exogenous opioid responses that are normalized upon restoration of VitD signaling. Similarly, physiologic endogenous opioid analgesia and reward responses triggered by ultraviolet (UV) radiation are repressed by VitD signaling, suggesting that a feedback loop exists whereby VitD deficiency produces increased UV/endorphin-seeking behavior until VitD levels are restored by cutaneous VitD synthesis. This feedback may carry the evolutionary advantage of maximizing VitD synthesis. However, unlike UV exposure, exogenous opioid use is not followed by VitD synthesis (and its opioid suppressive effects), contributing to maladaptive addictive behavior.

Highlights

Opioid use disorder (OUD) is a major medical challenge that is continuing to increase in the United States
Previous studies have shown associations of vitamin D (VitD) deficiency with higher opioid doses among patients with opioid-consuming chronic pain [9] and patients with palliative cancer [10]. These studies are confounded by the presence of pain, which is associated with VitD deficiency [11]
The detrimental health effects of VitD deficiency have been suggested to contribute as an evolutionary driver for light skin pigmentation in humans [8], and it is plausible that additional mechanisms, like UV-seeking behavior, may further contribute to maintenance of VitD levels in humans and other species

Summary

Introduction

Opioid use disorder (OUD) is a major medical challenge that is continuing to increase in the United States. Causative but preventable environmental factors that contribute to opioid addiction are of great interest [3]. We hypothesized that UV-seeking behavior might be driven by VitD deficiency to maximize VitD synthesis and that VitD deficiency might sensitize individuals to exogenous (UV-independent) opioids, contributing to opioid addiction. A negative feedback loop might exist whereby UV/opioid-seeking behaviors are repressed when VitD levels are restored. This feedback might carry the evolutionary advantage of maximizing VitD synthesis. Unlike UV exposure, exogenous opioid use is not followed by VitD synthesis (and its opioid suppressive effects), contributing to a maladaptive addictive behavior cycle

Methods

Results

Conclusion