Vitamin D deficiency exacerbates UV/endorphin and opioid addiction

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.

Gut feelings: the microbiota-gut-brain axis on steroids

“…Vitamin D 3 also targets opioid receptor signaling, as vitamin D 3 supplementation modulates expression of genes involved in the signaling pathway and reduces neuropathic pain (193). Vitamin D 3 deficiency is recently reported to increase risk for opioid dependence, possibly due to deficiencies in VDR signaling (115), suggesting interactions between VDR with other receptors that regulate nervous system function. Furthermore, vitamin D 3 is recently reported as an agonist of the calcium-selective channel TRPV1 which mediates pain sensation (142).…”

Transcriptional control of nucleus accumbens neuronal excitability by Retinoid X Receptor Alpha tunes sensitivity to drug rewards

“…Other promising candidate RXRα binding partners include 1) RXRγ, which is known to contribute to striatal- and dopamine-dependent locomotion 18 and depressive-like 19–21 behaviors, 2) NURR77/NR4A1, an IEG and orphan receptor associated with cocaine 52 and stress 53 behaviors that we here found positively correlated with RXRα expression (Fig. 2e), 3) RARs and PPARs because the enzymes that deliver retinoic acid to RAR/RXR or PPAR/RXR complexes – CRABP2 and FABP5 respectively – differentially contribute to addiction- 15, 16 and depression-related 17 behaviors, and 4) VDRs, as vitamin D deficiency was recently linked with opioid addiction 54 . Ultimately, a finer dissection of RXRα binding partners could better explain some of the cell-type-, region-, drug- and drug-regimen-specificity of drug-induced transcriptional programs, as these likely result not from the recruitment of one given transcription factor but rather of several factors that could be partly harmonized by RXRα, among others.…”

A Systematic Review of Opioid Use Disorder and Related Biomarkers

“…A study found that patients with a vitamin D deficiency were more likely to develop postoperative OUD and required a higher total opioid dose of an additional 98.7 morphine milligram equivalent dose, indicating that vitamin D may be a predictor for the onset of OUD ( 27 ). A recent study investigated retrospectively two separate populations, and found that vitamin D deficient or insufficient individuals are more likely to use opioids ( 28 ).…”