Pain Processing:
How Vitamin D Impacts Pain Processing
Vitamin D3 occupies a distinctive position in the nutraceutical paradigm as a hormone with multiple effects extending far beyond its classical role in calcium homeostasis.
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Definitions and Terms Related to Pain
How Vitamin D Impacts Pain Processing
Vitamin D3 occupies a distinctive position in the nutraceutical paradigm as a hormone with multiple effects extending far beyond its classical role in calcium homeostasis. Unlike other nutraceuticals that act primarily through antioxidant or anti-inflammatory mechanisms, vitamin D3 exerts analgesic effects through a unique dual receptor system—the nuclear vitamin D receptor (VDR) for genomic effects and the recently discovered direct modulation of TRPV1 channels for rapid non-genomic effects.[1][2] This dual mechanism allows vitamin D to influence pain processing at multiple levels, from peripheral nociceptor sensitization to supraspinal opioid signaling.
These mechanisms address four pathological processes central to the Pain Processing treatment paradigm: Systemic Inflammation, Neuroinflammation, Oxidative Stress and Mitochondrial Dysfunction.
Vitamin D3 provides unique analgesic properties distinct from other nutraceuticals.
The Levels of Pain Processing can be organized as follows:
Level 1: Peripheral Nociception (Pain Receptor Transduction): Activation and Sensitization
Level 2: Primary Afferent Transmission to Spinal Cord
Level 3: Spinal Cord Dorsal Horn Processing (First Synapse)
Level 4: Ascending Spinal Pathways and Supraspinal Processing
Level 5: Thalamic and Cortical Processing and Pain Perception
Level 6: Descending Pain Modulation
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Level 1: Peripheral Nociceptor Activation and Sensitization
TRPV1 Channel Modulation:
A groundbreaking discovery reveals that vitamin D is an endogenous partial agonist of the TRPV1 (capsaicin) receptor. 25-hydroxyvitamin D (25OHD) can weakly activate TRPV1 yet antagonize the stimulatory effects of full TRPV1 agonists capsaicin and oleoyl dopamine. Both 25OHD and 1,25OHD can inhibit capsaicin-induced TRPV1 activity. Structural modeling places 25OHD in the same vanilloid binding pocket as capsaicin. Furthermore, 25OHD inhibits the potentiating effects of PKC-mediated TRPV1 activity and reduces capsaicin-induced calcium activity in trigeminal neurons.[1]
Prostaglandin E2 Inhibition:
Vitamin D-mediated inhibition of Prostaglandin E2 (PGE2) exhibits a credible mechanistic explanation for peripheral analgesic effects. PGE2 is a key mediator of peripheral sensitization, and its reduction by vitamin D may decrease nociceptor excitability at the site of tissue injury.[2]
Peripheral Nerve Function:
Vitamin D is involved in myelination, axonal homogeneity of peripheral nerves, and neuronal-cell differentiation. Calcitriol supplementation may be a simple means to avoid the onset and/or development of peripheral nervous-system disorders.[3] In diabetic neuropathy patients, vitamin D is associated with the conduction ability of peripheral nerves and may have a nerve- and threshold-selective relationship with the prevalence and severity of diabetic peripheral neuropathy.[4]
VDR Expression in Sensory Neurons:
Nuclear VDR immunoreactivity is present within nearly all DRG neurons, while cytoplasmic VDR is found preferentially in unmyelinated calcitonin gene-related peptide (CGRP)-positive neurons, colocalizing with the vitamin D metabolizing enzymes CYP27B1 and CYP24. These unmyelinated CGRP-positive neurons appear to have a distinct vitamin D phenotype, implying that vitamin D signaling may play a specialized role in a neural cell population that is primarily nociceptive.[5]
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Level 2: Primary Afferent Transmission to Spinal Cord
DRG Gene Expression Modulation:
Transcriptomic analysis of dorsal root ganglia following cholecalciferol supplementation reveals massive gene dysregulation associated with axonal guidance (37 genes) and nociception (17 genes). This suggests that vitamin D influences the fundamental properties of primary afferent neurons, including their capacity for signal transmission.[6]
Neurotrophic Factor Interactions:
Vitamin D/VDR interacts with known specific pain signaling pathways including nerve growth factor (NGF), glial-derived neurotrophic factor (GDNF), and epidermal growth factor receptor (EGFR). These interactions may modulate the sensitivity and function of primary afferent neurons.[2]
Hormonal Regulation of VDR in DRG:
Ovarian hormones regulate vitamin D-related proteins in DRG neurons. Following ovariectomy, total VDR expression drops significantly, predominantly due to decreased expression within unmyelinated CGRP-positive neurons. This finding may explain why vitamin D deficiency appears to exacerbate some peri-menopausal pain syndromes.[5]
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Level 3: Spinal Cord Dorsal Horn Processing
GABAergic Interneuron Preservation:
A critical mechanism for vitamin D’s spinal analgesic effects involves preservation of inhibitory interneurons. Intrathecal administration of VitD3 preserved spinal GABAergic interneurons through suppression of mitochondria-associated ferroptosis. The neuroprotective effects were eliminated by the ferroptosis inducer RSL3, confirming the mechanistic link.[7]
Ferroptosis Suppression:
Ferroptosis cell death associated with free radical toxicity) was observed in the spinal cord following spared nerve injury (SNI). VitD3 treatment suppressed ferroptosis and alleviated mechanical nociceptive behaviors. Mechanistically, VitD3 inhibited SNI-induced activation of spinal PKCα/NOX4 signaling. Inhibition of PKCα/NOX4 signaling alleviated mechanical pain hypersensitivity, accompanied by reduced ferroptosis and mitochondrial dysfunction.[7]
Spinal Mitochondrial Protection:
VitD3 mitigated aberrant mitochondrial morphology and oxidative metabolism in the spinal cord. Activation of PKCα/NOX4 signaling in naïve rats induced hyperalgesia, ferroptosis, loss of GABAergic interneurons, and mitochondrial dysfunction in the spinal cord—all of which were reversed by VitD3 treatment.[7]
Microglial Modulation in Spinal Cord:
Vitamin D deficiency produces profound modifications in spinal microglia. Morphological analysis of ex-vivo microglia obtained from vitamin-D-deficient adult mice revealed an increased number of activated microglia in the spinal cord. Remarkably, activated spinal microglia were detected in a prominent manner in females, suggesting sex-specific effects.[8]
Endocannabinoid System Modulation:
Vitamin D deficiency induced tactile allodynia associated with neuronal hyperexcitability and alterations of endocannabinoid system members (endogenous mediators and their receptors) at the spinal cord level. Palmitoylethanolamide (PEA) counteracted both the pain behavior and spinal biochemical changes in vitamin D deficient mice.[8]
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Level 4: Ascending Pathways and Supraspinal Processing
Cerebral Opioid Signaling Modulation:
Transcriptomic analysis of cerebrum following cholecalciferol supplementation reveals massive gene dysregulation associated with opioid signaling (23 genes), nociception (14 genes), and allodynia (8 genes). Among the identified cerebral dysregulated genes, 21 can be associated with vitamin D metabolism. Several genes—Oxt, Pdyn, Penk, Pomc, Pth, Tac1, and Tgfb1—encoding for peptides/hormones stand out as top candidates to explain the therapeutic benefit of vitamin D supplementation.[6]
Brain iNOS and COX-2 Reduction:
VD3 significantly decreased iNOS and COX-2 expressions in brain areas, such as hippocampus and prefrontal cortex. This central anti-inflammatory effect may contribute to reduced pain perception at supraspinal levels.[9]
Dystrophic Microglial Phenotype in Brain:
While spinal microglia showed activation in vitamin D deficiency, brain microglia appeared in a dystrophic phenotype—suggesting region-specific effects of vitamin D on glial function that may differentially impact pain processing at various CNS levels.[8]
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Level 5: Descending Modulatory Systems
Opioid Peptide Gene Regulation:
Vitamin D supplementation modulates genes encoding endogenous opioid peptides including prodynorphin (Pdyn), proenkephalin (Penk), and proopiomelanocortin (Pomc). These peptides are critical components of descending inhibitory pain pathways originating in the periaqueductal gray and rostral ventromedial medulla.[6]
Oxytocin System Modulation:
The oxytocin gene (Oxt) is among the top candidates dysregulated by vitamin D supplementation. Oxytocin has established analgesic properties and modulates descending pain inhibition, suggesting another mechanism by which vitamin D may enhance endogenous pain control.[6]
Vitamin D Deficiency and Opioid Sensitivity:
Vitamin D deficiency exacerbates opioid responses. Research demonstrates an increased prevalence of vitamin D deficiency in patients diagnosed with opioid use disorder and an inverse and dose-dependent association of vitamin D levels with self-reported opioid use. Deficiencies in vitamin D signaling amplify exogenous opioid responses that are normalized upon restoration of vitamin D signaling.[10]
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Level 6: Cortical Processing and Pain Perception
Neurocognitive Effects:
Vitamin D deficiency is associated with neuroinflammation and neurocognitive deficits. Vit D treatment not only effectively alleviated neurocognitive deficits but also promoted hippocampal neuronal survival. These effects may influence the cognitive and emotional dimensions of pain perception.[9]
Neuroplasticity and Synaptic Function:
Vitamin D impacts neurotransmitter synthesis and brain plasticity. It adjusts inflammatory mediators and antioxidants, resulting in neuroprotective effects. Additionally, vitamin D influences serotonin synthesis, which may contribute to both analgesic and antidepressant effects relevant to chronic pain states.[11]
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Targeting the Four Pathological Processes
1. Systemic Inflammation:
Vitamin D comprehensively addresses systemic inflammation through multiple mechanisms:
NF-κB Inhibition:
The vitamin D receptor (VDR) physically interacts with IκB kinase β (IKKβ) to block NF-κB activation. 1,25(OH)₂D₃ rapidly attenuates TNFα-induced p65 nuclear translocation and NF-κB activity in a VDR-dependent manner. VDR-IKKβ interaction disrupts the formation of the IKK complex and abolishes IKK activity to phosphorylate IκBα, consequently stabilizing IκBα and arresting p65/p50 nuclear translocation.[12]
Pro-inflammatory Cytokine Reduction:
VD3 reduced the edema volume and the number of polymorphonuclear (PMN) cells, as well as the TNF-alpha expression in edematous paws compared with control groups.[9] High-dose vitamin D supplementation (40,000 IU/week) produced a significant decrease in IL-6 level (2.5 pg/mL vs. 0.6 pg/mL, P 0.001) and an increase in IL-10 level (2.5 pg/mL vs. 4.5 pg/mL, P 0.001) in diabetic neuropathy patients.[13]
Umbrella Meta-Analysis Evidence:
An umbrella meta-analysis of 23 meta-analyses revealed that vitamin D supplementation significantly reduced serum C-reactive protein (CRP), tumor necrosis factor-α (TNF-α), confirming anti-inflammatory effects across various health conditions.[14]
2. Neuroinflammation:
Vitamin D potently modulates neuroinflammatory processes:
Microglial Modulation:
Vitamin D3 may upregulate microglial Sirt6 to reduce H3K9ac and inhibit microglial activation, thereby antagonizing neuroinflammation. Vitamin D3 promoted microglial Sirt6 distribution and attenuated microglia displaying an activated morphology in the hippocampus of LPS-stimulated mice.[15]
IL-10/SOCS3 Mechanism:
Vitamin D3 alters microglia immune activation by an IL-10 dependent SOCS3 mechanism. Activated microglia exposed to vitamin D3 had reduced expression of pro-inflammatory cytokines IL-6, IL-12, and TNFα, and increased expression of IL-10. The reduction in pro-inflammatory cytokines was dependent on IL-10 induction of suppressor of cytokine signaling-3 (SOCS3), creating a feedback loop that downregulates the pro-inflammatory immune response.[16]
TLR4/MyD88/NF-κB Pathway:
Vitamin D protects against neuroinflammation via modulating the TLR4/MyD88/NF-κB pathway-mediated microglial polarization. VD therapy prevented excessive neuroinflammation and oxidative stress, promoting hippocampal microglial M2 polarization.[9]
ERK and NF-κB Inhibition in Microglia:
VD3 inhibited LPS-induced activation of extracellular signal-regulated kinase (ERK) and nuclear translocation of NF-κB in microglial cells. VD3 can inhibit production of several pro-inflammatory molecules from microglia, and suppression of ERK activation is at least in part involved in the anti-inflammatory effect.[17]
3. Oxidative Stress:
Vitamin D addresses oxidative stress through multiple pathways:
Nrf2 Pathway Activation:
Vitamin D can attenuate oxidative stress and delay cellular senescence, mainly by inducing the expression of nuclear factor erythroid 2-related factor 2 (Nrf2) and Klotho and improving mitochondrial homeostasis. The antioxidative effects of 1,25(OH)₂D are carried out via VDR by activation of the Nrf2 oxidative stress response pathway through transcriptional or posttranscriptional activation of Nrf2 or transcriptional upregulation of Sirt1 and Bmi1 expression.[18]
AMPK/SIRT1 Activation:
1,25(OH)₂D decreases oxidative stress and increases AMPK/SIRT1 activation in muscle cells. Significant incremental changes in NAD levels, activities of AMPK/SIRT1, and SIRT1 expression were noted in 1,25(OH)₂D-treated cells, suggesting potent inhibitory effects on oxidative stress through metabolic regulation.[19]
Clinical Antioxidant Effects:
A meta-analysis of clinical trials found that vitamin D supplementation increased serum levels of total antioxidant capacity (TAC) and glutathione (GSH). Additionally, malondialdehyde (MDA) concentration decreased significantly following vitamin D supplementation.[14]
4. Mitochondrial Dysfunction:
Vitamin D provides comprehensive mitochondrial support:
Mitochondrial Morphology Protection:
1,25(OH)₂D improves oxidative stress-induced mitochondrial morphological changes such as swelling, irregular cristae, and smaller size and number. VitD3 mitigated aberrant mitochondrial morphology and oxidative metabolism in the spinal cord following nerve injury.[7][19]
Mitochondrial Biogenesis:
1,25(OH)₂D treatment increases mtDNA contents as well as gene expression involved in mitochondrial biogenesis such as PGC1α, NRF1, and Tfam.[19]
Direct VDR-Mitochondrial Interaction:
A groundbreaking discovery reveals that the vitamin D receptor (VDR) directly binds to mitochondrial DNA and regulates transcription of mtDNA-encoded oxidative phosphorylation (OXPHOS) subunits. VDR was shown to bind to the mtDNA D-loop site in several locations, with a consensus sequence “MMHKCA.” Furthermore, VDR interacts with mitochondrial transcription factor A (TFAM), and their binding sites are located in close proximity in mtDNA. This demonstrates that VDR is indispensable for energy-demanding cells.[20]
Mitochondrial Oxygen Consumption:
The mitochondrial oxygen consumption rate (OCR) increased in 1,25(OH)₂D₃-treated cells. In treated cells, mitochondrial volume and branching and expression of the pro-fusion protein OPA1 increased, whereas expression of the pro-fission proteins Fis1 and Drp1 decreased. Phosphorylated pyruvate dehydrogenase (PDH) and PDH kinase 4 (PDK4) decreased, indicating enhanced mitochondrial substrate utilization.[19]
Ferroptosis Prevention:
VitD3 attenuates neuropathic pain by suppression of mitochondria-associated ferroptosis mediated by PKCα/NOX4 signaling. Ferroptosis was observed in the spinal cord following nerve injury, and VitD3 treatment suppressed ferroptosis and alleviated mechanical nociceptive behaviors. The neuroprotective effects were eliminated by the ferroptosis inducer RSL3, confirming the mechanistic link.[7]
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Clinical Evidence Supporting Pain Pathway Effects
Diabetic Peripheral Neuropathy:
A systematic review of vitamin D supplementation on diabetic peripheral neuropathy included four studies with 364 patients. Meta-analytical results showed a McGill Pain Questionnaire score improvement in favor of vitamin D supplementation. Non-meta-analytical results of all individual studies showed significant amelioration of pain scores. Pain improvement was not correlated to baseline or change in serum vitamin D level, suggesting the absolute value attained may be more important.[21]
High-dose vitamin D supplementation (40,000 IU/week for 24 weeks) in diabetic neuropathy patients produced a significant decrease in neuropathy severity scores and improvement of cutaneous microcirculation. Additionally, IL-6 decreased and IL-10 increased. No changes were detected in the 5000 IU/week group, suggesting a dose-response relationship.[13]
Fibromyalgia Syndrome:
A meta-analysis found that vitamin D supplementation had significant positive effects on physical function, role limitations due to emotional health, social function, and general health Improvement of FIQ scores was noted[22]
A randomized placebo-controlled trial in fibromyalgia patients with serum calcifediol 32 ng/mL found that achieving levels between 32-48 ng/mL produced a marked reduction in pain over the treatment period, with significant group effects on VAS scores and physical role functioning.[23]
Chronic Widespread Pain:
A meta-analysis of four RCTs involving 287 subjects demonstrated a significantly lower VAS in chronic widespread pain patients who received vitamin D treatment compared with placebo.[24]
Neuropathic Pain (Preclinical):
Cholecalciferol supplementation improved mechanical nociceptive thresholds in monoarthritic animals and reduced mechanical hyperalgesia and cold allodynia in a model of mononeuropathy. Transcriptomic analysis revealed massive gene dysregulation associated with opioid signaling (23 genes), nociception (14 genes), and allodynia (8 genes) in the cerebrum.[6]
Important Negative Evidence:
Large population-based trials have shown limited benefit in vitamin D-replete individuals. The D-Health Trial (n=21,315) found that supplementation with 60,000 IU/month had negligible effect on bodily pain in a population where 76% were predicted to have 25(OH)D >50 nmol/L at baseline.[25] Similarly, the ViDA study (n=5,108) found no difference in mean PIQ-6 scores with monthly 100,000 IU vitamin D3 over 3.3 years, though vitamin D-deficient participants showed lower risk of NSAID dispensing.[26]
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Safety Profile
Vitamin D demonstrates a favorable safety profile at recommended doses:
General Safety:
Vitamin D supplementation at doses recommended by the National Academy of Medicine is generally safe. Up to 4000 IU of vitamin D per day is safe for adults, but higher doses are associated with increased risk of kidney stones, weakness, and gastrointestinal problems. Vitamin D3 supplementation leads to greater and more sustained increases in serum 25-hydroxyvitamin D levels than does vitamin D2 supplementation.[27]
High-Dose Safety Data:
The Calgary Vitamin D Study (n=373, 3-year follow-up) compared 400, 4000, and 10,000 IU/day. The safety profile was similar across all dose groups for clinical adverse events (97.9% experienced some adverse event, balanced across arms). Mild hypercalcemia occurred in 15 (4%) participants; all cases resolved on repeat testing. Hypercalciuria occurred in 87 (23%) participants.[28]
Dosing Considerations:
Clinical evidence supports that patients with deficient levels (30 nmol/L) are most likely to benefit from supplementation, while individuals with 25-OHD >50 nmol/L probably have little benefit. For pain conditions, achieving serum levels of 32-48 ng/mL (80-120 nmol/L) appears optimal. Higher doses (40,000 IU/week) may be needed for diabetic neuropathy, while lower maintenance doses (24,000 IU/month) may be sufficient for chronic pain in vitamin D-replete individuals.[23][26]
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Unique Mechanistic Contributions of Vitamin D3
Vitamin D3 offers several unique mechanisms not shared by other nutraceuticals in the paradigm:
1. Dual Receptor System:
Vitamin D is unique among your selected nutraceuticals in acting through both a nuclear receptor (VDR) for genomic effects and direct modulation of TRPV1 channels for rapid non-genomic effects. This dual mechanism allows vitamin D to influence pain processing through both long-term transcriptional changes and immediate effects on nociceptor excitability.[1][2]
2. Direct VDR-Mitochondrial DNA Interaction:
The discovery that VDR directly binds to mitochondrial DNA and regulates transcription of OXPHOS subunits represents a unique mechanism not shared by other nutraceuticals. This direct mitochondrial transcriptional regulation may explain vitamin D’s profound effects on cellular energetics.[20]
3. Opioid Peptide Gene Regulation:
Vitamin D supplementation modulates genes encoding endogenous opioid peptides including prodynorphin, proenkephalin, and proopiomelanocortin. This regulation of descending inhibitory pain pathways is unique among your selected nutraceuticals and may explain vitamin D’s effects on opioid sensitivity.[6]
4. Ferroptosis Prevention in Spinal Cord:
Vitamin D’s ability to preserve spinal GABAergic interneurons through suppression of mitochondria-associated ferroptosis via PKCα/NOX4 signaling represents a unique neuroprotective mechanism that directly addresses the loss of inhibitory tone in chronic pain states.[7]
5. Deficiency-Dependent Efficacy:
Unlike other nutraceuticals in your paradigm, vitamin D’s analgesic efficacy is strongly dependent on baseline vitamin D status. Patients with deficiency (30 nmol/L) show the most robust responses, while vitamin D-replete individuals show minimal benefit. This suggests vitamin D supplementation is most appropriately viewed as correction of a deficiency state rather than pharmacological intervention.[25][26]
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Synergistic Potential with Other Nutraceuticals
Vitamin D demonstrates significant potential for synergy with other agents in the paradigm:
With Palmitoylethanolamide (PEA):
Vitamin D deficiency induced tactile allodynia associated with alterations of endocannabinoid system members at the spinal cord level. PEA counteracted both the pain behavior and spinal biochemical changes in vitamin D-deficient mice, suggesting complementary mechanisms through the endocannabinoid system.[8]
With Nicotinamide Riboside:
Both vitamin D and NR activate AMPK/SIRT1 signaling. Vitamin D treatment increases NAD levels and SIRT1 expression in muscle cells, suggesting convergent mechanisms on the NAD+/sirtuin axis that may provide enhanced mitochondrial protection when combined.[19]
With CoQ10:
Vitamin D’s direct regulation of mtDNA-encoded OXPHOS subunits complements CoQ10’s role as an electron carrier in the ETC. This combination may provide comprehensive mitochondrial support addressing both transcriptional regulation and electron transport efficiency.[20]
With Alpha-Lipoic Acid:
Both vitamin D and ALA have demonstrated efficacy in diabetic neuropathy through distinct mechanisms. Vitamin D’s effects on nerve function and myelination complement ALA’s antioxidant and metabolic effects, suggesting potential for additive benefits in diabetic peripheral neuropathy.[21]
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Summary
Vitamin D3 provides a unique contribution to your pain processing paradigm through its dual receptor system (nuclear VDR and membrane TRPV1), direct mitochondrial DNA regulation, and modulation of endogenous opioid peptide genes. Its mechanisms span all six levels of pain processing, from peripheral TRPV1 modulation to supraspinal opioid signaling regulation. Vitamin D comprehensively addresses your four pathological processes—systemic inflammation (NF-κB inhibition, cytokine modulation), neuroinflammation (microglial polarization, IL-10/SOCS3 pathway), oxidative stress (Nrf2 activation, glutathione enhancement), and mitochondrial dysfunction (direct VDR-mtDNA binding, ferroptosis prevention, biogenesis promotion).
The critical clinical consideration is that vitamin D’s analgesic efficacy is strongly deficiency-dependent, making baseline 25(OH)D assessment essential for patient selection. In deficient patients, vitamin D supplementation produces meaningful pain reduction across multiple conditions including diabetic neuropathy, fibromyalgia, and chronic widespread pain. Its synergistic potential with other nutraceuticals in your paradigm—particularly PEA (endocannabinoid system), NR (NAD+/SIRT1 axis), CoQ10 (mitochondrial ETC), and magnesium (vitamin D metabolism)—supports its inclusion in a comprehensive multimodal approach to pain processing pathology.
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References
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- Increased NF-kappaB Activity in Fibroblasts Lacking the Vitamin D Receptor. Sun J, Kong J, Duan Y, et al. American Journal of Physiology. Endocrinology and Metabolism. 2006;291(2):E315-22. doi:10.1152/ajpendo.00590.2005.
- Vitamin D Receptor Deletion Leads to Reduced Level of IkappaBalpha Protein Through Protein Translation, Protein-Protein Interaction, and Post-Translational Modification. Wu S, Xia Y, Liu X, Sun J. The International Journal of Biochemistry & Cell Biology. 2010;42(2):329-36. doi:10.1016/j.biocel.2009.11.012.
- The Hormone-Bound Vitamin D Receptor Enhances the FBW7-dependent Turnover of NF-κB Subunits. Fekrmandi F, Wang TT, White JH. Scientific Reports. 2015;5:13002. doi:10.1038/srep13002.
- 1, 25(oh)d-Induced Interaction of Vitamin D Receptor With P50 Subunit of NF-κB Suppresses the Interaction Between KLF5 and P50, Contributing to Inhibition of LPS-induced Macrophage Proliferation. Ma D, Zhang RN, Wen Y, et al. Biochemical and Biophysical Research Communications. 2017;482(2):366-374. doi:10.1016/j.bbrc.2016.11.069.
- In Vivo Vitamin D Target Genes Interconnect Key Signaling Pathways of Innate Immunity. Jaroslawska J, Ghosh Dastidar R, Carlberg C. PloS One. 2024;19(7):e0306426. doi:10.1371/journal.pone.0306426.
- Vitamin D3 Attenuates Neuropathic Pain via Suppression of Mitochondria-Associated Ferroptosis by Inhibiting PKCα/NOX4 Signaling Pathway. Zhang W, Yu S, Jiao B, et al. CNS Neuroscience & Therapeutics. 2024;30(9):e70067. doi:10.1111/cns.70067.
- Cholecalciferol (Vitamin D) Reduces Rat Neuropathic Pain by Modulating Opioid Signaling. Poisbeau P, Aouad M, Gazzo G, et al. Molecular Neurobiology. 2019;56(10):7208-7221. doi:10.1007/s12035-019-1582-6.
- 1,25(OH)₂D₃ Inhibits Ferroptosis in Nucleus Pulposus Cells via VDR Signaling to Mitigate Lumbar Intervertebral Disc Degeneration. Li Q, Peng J, Ding F. Scientific Reports. 2025;15(1):7968. doi:10.1038/s41598-025-92405-x.
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- The Effect of Vitamin D Replacement on Spinal Inhibitory Pathways in Women With Chronic Widespread Pain. Kenis-Coskun O, Giray E, Gunduz OH, Akyuz G. The Journal of Steroid Biochemistry and Molecular Biology. 2020;196:105488. doi:10.1016/j.jsbmb.2019.105488.
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- Upregulation of Microglial Sirt6 and Inhibition of Microglial Activation by Vitamin D3 in Lipopolysaccharide-Stimulated Mice and BV-2 Cells. Li Y, Ma Y, Gao L, et al. Neuroscience. 2023;526:85-96. doi:10.1016/j.neuroscience.2023.06.008.
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- FTO-dependent M6A Demethylation Activates Mxd1 to Enhance Vitamin D-Induced Suppression of Neuroinflammation via PTEN/AKT/PGC-1α Signaling Pathways in Microglia. Hu Z, Liu R, Zhang B, et al. Inflammation. 2026;:10.1007/s10753-026-02450-5. doi:10.1007/s10753-026-02450-5.
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- Regulatory Mechanisms of Vitamin D on Production of Nitric Oxide and Pro-Inflammatory Cytokines in Microglial BV-2 Cells. Dulla YA, Kurauchi Y, Hisatsune A, et al. Neurochemical Research. 2016;41(11):2848-2858. doi:10.1007/s11064-016-2000-3.
- Increased Vitamin D Receptor Expression in Dorsal Root Ganglia Neurons of Diabetic Rats. Filipović N, Ferhatović L, Marelja I, Puljak L, Grković I. Neuroscience Letters. 2013;549:140-5. doi:10.1016/j.neulet.2013.05.023.
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- Intracellular Distribution of the Vitamin D Receptor in the Brain: Comparison With Classic Target Tissues and Redistribution With Development. Eyles DW, Liu PY, Josh P, Cui X. Neuroscience. 2014;268:1-9. doi:10.1016/j.neuroscience.2014.02.042.
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