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Pain Processing:

How Magnesium Impacts Pain Processing

Magnesium acts is a natural, low-cost option for managing chronic pain, particularly for conditions involving nervous system pain, muscle aches, and spasms. It works as an “NMDA receptor blocker” to inhibit pain signals and reduce sensitivity to pain. It is often used as supplemental therapy, and can be effective for neuropathic pain, migraine, and musculoskeletal discomfort.

See:

Handout – Magnesium
Magnesium for Chronic Pain: A Patient Guide
Magnesium
Magnesium Formulations
Magnesium L Threonate

How Nutraceuticals Impact Pain Processing

Pain Processing

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Definitions and Terms Related to Pain

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Magnesium: Pain Processing Effects vs. Direct Tissue-Modifying Effects

How Magnesium Impacts Pain Processing

Introduction to Pain Processing

Nutraceuticals offer a broad spectrum of pharmacological actions relevant to the process of sending pain signals from an area of injury to the brain, resulting in the experience of pain. Nutraceuticals impact the processing of pain signaling based on its different properties, including anti-inflammatory, antioxidant, and neuroprotective properties.

Pain Processing involves complex nerve interactions that:

Starts with the detection of damaged tissues by specialized pain receptors,
Followed by sending pain signals to the spinal cord through peripheral nerves, then
Processing of the signals in the spinal cord, then
Forwarding the signals up ascending pain pathways to various parts of the brain, then
Processing of the pain signals in the brain (supraspinal integration)
Followed, finally, by the brain sending pain signals back down descending pain pathways in the spinal cord to impact the pain signal processing in the spinal cord (descending pain modulation).

At each of these stages, or levels, of pain processing, the pain signaling can be modified referred to as pain modulation. Pain modulation can result in the pain experience being magnified or suppressed, temporarily or in some cases permanently. There are many situations and processes that modulate the pain experience, but the focus here is limited to the magnification of pain that occurs in the pathologic processing of pain signals in nerves in the peripheral nervous system and/or the spinal cord and brain (the central nervous system).

The Levels of Pain Processing can be organized as follows:

Level 1: Peripheral Nociception (Pain Receptor Transduction)
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 Brain Processing and Pain Perception
Level 6: Descending Pain Modulation

This pathologic pain processing that results in heightened sensitivity and magnification of the pain experience, it is referred to as “Sensitization) which can originate in peripheral and or central nervous system, termed “Peripheral Sensitization” and “Central Sensitization.”

Central to the pathophysiology of pain processing leading to Peripheral Sensitization and Central Sensitization are 4 interconnected conditions, sometimes referred to as “the 4 Demons of Pain:”

Systemic Inflammation
Neuroinflammation’ below
Oxidative Stress
Mitochondrial Dysfunction.

SECTION 1: OVERVIEW OF MAGNESIUM IN PAIN PROCESSING

Introduction

Magnesium (Mg²⁺) is one of the most abundant minerals in the human body and the second most abundant mineral in cells. It serving as an essential cofactor in over 300 enzymatic reactions that regulate energy metabolism, protein/DNA synthesis and neuromuscular function.[1][2] Magnesium place an important role in modifying pain processing, primarily through its role as a physiological antagonist of the N-methyl-D-aspartate (NMDA) receptor, which suppresses the development of central sensitization and reduces preexisting pain hypersensitivity.[3][4]

The analgesic properties of magnesium have been investigated across a variety of pain conditions, including postoperative pain, neuropathic pain (diabetic neuropathy, postherpetic neuralgia, chemotherapy-induced peripheral neuropathy), fibromyalgia, dysmenorrhea, and migraine.[3][5] Magnesium deficiency affects 3-10% of the general population and is significantly more prevalent in hospitalized patients and those with chronic diseases.

Despite the prevalence of suboptimal magnesium levels in the general population, it is not often tested for routinely, partly because blood testing of magnesium has limited predictive value for deficiency because the amount of magnesium in the blood represents less than 1% of the total body magnesium. Nevertheless, magnesium deficiency has been implicated in the development of chronic pain and pain sensitivity through multiple mechanisms.[1][6]

Because supplementing with magnesium is generally safe with few significant side effects, a trial of supplementing with magnesium should be considered in patients at risk for low magnesium, or those with conditions often associated with low magnesium. See: Magnesium for Chronic Pain: – A Patient Guide

Supplementing with magnesium can be used to combat the pathophysiology of pain processing that leads to Peripheral Sensitization and Central Sensitization, the 4 interconnected conditions referred to as “the 4 Demons of Pain:”

Systemic Inflammation
Neuroinflammation’ below
Oxidative Stress
Mitochondrial Dysfunction

1. Magnesium and Systemic Inflammation

Magnesium deficiency is increasingly recognized as a driver of systemic low-grade inflammation, which represents a common denominator of most chronic diseases.[7] The relationship between magnesium status and inflammation operates through several interconnected mechanisms:

Pro-inflammatory Cytokine Production:

Magnesium deficiency increases the production of pro-inflammatory molecules including interleukin-1 (IL-1), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-α).[2][8] These cytokines can exacerbate the production of reactive oxygen species (ROS), creating a self-perpetuating cycle of inflammation and oxidative stress that increases the risk of developing chronic diseases.[2]

Immune Cell Activation:

Low magnesium status primes phagocytes, enhances granulocyte oxidative burst, and activates endothelial cells, thereby promoting inflammatory responses.[8] Magnesium regulates immunological functions by acting on cells of both innate and adaptive immune systems, and deficiency can lead to temporary or long-term immune dysfunction.[9]

NF-κB Pathway Modulation:

Magnesium influences the nuclear factor-kappa B (NF-κB) signaling pathway, a master regulator of inflammatory gene expression. In chemotherapy-induced neuropathic pain models, magnesium deficiency activates the TNF-α/NF-κB pathway, leading to spinal pathologic plasticity and nociceptive sensitization.[10]

Clinical Evidence:

A recent systematic review and meta-analysis found that magnesium supplementation produces a statistically significant reduction in C-reactive protein (CRP) levels (a biomarker of systemic inflammation), suggesting an anti-inflammatory effect, though direct effects on other oxidative stress biomarkers remain uncertain.[11]

2. Magnesium and Neuroinflammation

Magnesium plays a critical role in brain function, harmonizing nerve signal transmission and preserving the integrity of the blood-brain barrier.[7] Neuroinflammation, the hallmark of neurodegenerative disorders and chronic pain, is significantly influenced by magnesium status:

Microglial and Astrocytic Modulation:

Local magnesium administration has been shown to significantly attenuate microglial and astrocytic activation in the spinal cord dorsal horn in models of incisional pain.[12] This glial modulation is critical because activated glial cells release pro-inflammatory mediators that contribute to central sensitization and chronic pain.

Spinal Cord Inflammation:

In postoperative pain models, magnesium sulfate inhibits the expression of IL-1β and inducible nitric oxide synthase (iNOS) in injured tissue, while also preventing phosphorylation of the NMDA receptor NR1 subunit—a marker of central sensitization.[12]

Blood-Brain Barrier Integrity:

Magnesium contributes to maintaining blood-brain barrier function, and deficiency may compromise this barrier, potentially allowing peripheral inflammatory mediators to access the central nervous system and promote neuroinflammation.[7]

Neurodegenerative Disease Links:

Evidence links magnesium deficiency with neuroinflammatory conditions including multiple sclerosis, Alzheimer’s disease, and Parkinson’s disease, suggesting that magnesium’s neuroprotective effects extend beyond acute pain modulation.[7]

3. Magnesium and Oxidative Stress

Magnesium deficiency causes oxidative stress through multiple mechanisms, creating conditions that promote pain sensitization and tissue damage:[2][13]

Mitochondrial Dysfunction:

Hypomagnesemia causes mitochondrial dysfunction, leading to increased production of reactive oxygen species (ROS).[13] Magnesium is essential for ATP production and stabilization, and its deficiency impairs cellular energy metabolism.

TRPM7 Channel Upregulation:

Many effects of hypomagnesemia can be attributed to the upregulation of transient receptor potential melastatin 7 channel (TRPM7), which functions as both a magnesium transporter and a kinase.[13] Increased TRPM7 kinase signaling, independent of magnesium transport function, appears responsible for many of the oxidative stress and inflammatory effects of magnesium deficiency.

Calcium Homeostasis Disruption:

Magnesium deficiency leads to abnormal regulation of calcium homeostasis, which can trigger oxidative stress pathways.[2] The antagonistic relationship between calcium and magnesium ions (“Magnesium/Calcium Yin Yang”) is critical for cellular protection against oxidative damage.[14]

Renin-Angiotensin-Aldosterone System (RAAS) Activation:

Magnesium deficiency activates the RAAS, which contributes to increased ROS production and oxidative stress.[2]

Antioxidant Defense:

Magnesium supplementation has been shown to decrease lipid peroxidation and protein carbonyl levels while improving glutathione content in brain mitochondria, demonstrating protective effects against oxidative damage.[15]

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4. Magnesium and Mitochondrial Dysfunction

Magnesium is essential for mitochondrial function, and its deficiency has profound effects on cellular energy metabolism:[13][14]

ATP Production and Stabilization:

Magnesium is required for ATP production and forms Mg-ATP complexes that are essential for numerous enzymatic reactions. Deficiency impairs cellular energy metabolism and can lead to mitochondrial dysfunction.[13]

Mitochondrial Membrane Stabilization:

Magnesium promotes mitochondrial membrane stability through several mechanisms:[14]

1. Requirement for binding of mitochondrial hexokinase (MtHK)
2. Allosteric activation of mitochondrial bound hexokinase
3. Stimulation of mitochondrial bound creatine kinase (MtCK) activities
4. Inhibition of mitochondrial permeability transition pore (PTP) opening by calcium ions

Cytoprotective Effects:

The anti-apoptotic, anti-necrotic, and antioxidant functions of mitochondrial creatine kinase and hexokinase are supported by adequate magnesium levels. These enzymes act as powerful regulators of the mitochondrial permeability transition pore, promoting cell survival by stabilizing mitochondrial outer and inner membranes.[14]

Neuroprotection:

In hypoxia models, magnesium sulfate administration significantly improved mitochondrial function and reduced oxidative damage in brain mitochondria, demonstrating its neuroprotective potential.[15]

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Summary: Magnesium’s Multi-Target Effects on Pain-Related Pathways

Magnesium exerts its influence on pain processing through a comprehensive network of interconnected mechanisms:

Table – Magnesium’s multi-target effects on pain-related pathways:

Pathway	Mechanism	Pain-Relevant Effect	References
NMDA Receptor Antagonism	Voltage-dependent channel block	Prevents central sensitization	[1], [2], [3]
Calcium Channel Blockade	Blocks N-type and L-type Ca²⁺ channels	Reduces neurotransmitter release	[1], [2]
Anti-inflammatory	Reduces IL-1, IL-6, TNF-α, CRP	Decreases peripheral and central inflammation	[3], [4], [5]
Antioxidant	Reduces ROS, improves glutathione	Protects against oxidative damage	[3], [4]
Mitochondrial Support	ATP stabilization, membrane protection	Maintains cellular energy and viability	[3], [4]
Mitochondrial Support	Attenuates microglial/astrocyte activation	Reduces neuroinflammation	[1], [3]
Ion Channel Modulation	Modulates K⁺, Na⁺, and TRP channels	Regulates neuronal excitability	[1], [2]

[1][2][3][4][5]

This multi-target profile positions magnesium as a unique nutraceutical for addressing the complex pathophysiology of chronic pain, particularly in conditions characterized by central sensitization, neuroinflammation, and oxidative stress. The evidence demonstrates that magnesium’s NMDA receptor antagonism is central to preventing wind-up and long-term potentiation in the spinal dorsal horn, while its calcium channel blockade reduces presynaptic neurotransmitter release from primary afferents.[1][2] Additionally, magnesium’s anti-inflammatory and antioxidant properties address the neuroinflammatory cascade that perpetuates chronic pain states, with documented reductions in key pro-inflammatory cytokines and reactive oxygen species.[3][4][5]

References for Table

The Emerging Role of Quercetin in the Treatment of Chronic Pain. Liu C, Liu DQ, Tian YK, et al. Current Neuropharmacology. 2022;20(12):2346-2353. doi:10.2174/1570159X20666220812122437.
Quercetin, Main Active Ingredient of Moutan Cortex, Alleviates Chronic Orofacial Pain via Block of Voltage-Gated Sodium Channel. Liu Z, Shan Z, Yang H, et al. Anesthesia and Analgesia. 2024;138(6):1324-1336. doi:10.1213/ANE.0000000000006730.
Phytochemical Quercetin Alleviates Hyperexcitability of Trigeminal Nociceptive Neurons Associated With Inflammatory Hyperalgesia Comparable to NSAIDs. Itou H, Toyota R, Takeda M. Molecular Pain. 2022;18:17448069221108971. doi:10.1177/17448069221108971.
Quercetin Alleviates Osteoarthritis Pain by Inhibiting Vascular Endothelial Growth Factor a Through Regulating cGAS/STING Pathway. Hu E, Wei Y, Liao T, et al. Journal of Cellular and Molecular Medicine. 2026;30(1):e70992. doi:10.1111/jcmm.70992.
Quercetin Ameliorates CFA-Induced Chronic Inflammatory Hyperalgesia via Modulation of ROS-Mediated ERK1/2 Signaling and Inhibition of Spinal Glial Activation in Vivo. Kumar S, Vinayak M. Neuromolecular Medicine. 2020;22(4):517-533. doi:10.1007/s12017-020-08609-z.

This multi-target profile positions magnesium as a unique nutraceutical for addressing the complex pathophysiology of chronic pain, particularly in conditions characterized by central sensitization, neuroinflammation, and oxidative stress.[3][4][5]

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End of Section 1

References

The Phytochemical, Quercetin, Attenuates Nociceptive and Pathological Pain: Neurophysiological Mechanisms and Therapeutic Potential. Takeda M, Sashide Y, Toyota R, Ito H. Molecules (Basel, Switzerland). 2024;29(16):3957. doi:10.3390/molecules29163957.
The Effect of Quercetin on Inflammatory Factors and Clinical Symptoms in Women With Rheumatoid Arthritis: A Double-Blind, Randomized Controlled Trial. Javadi F, Ahmadzadeh A, Eghtesadi S, et al. Journal of the American College of Nutrition. 2017;36(1):9-15. doi:10.1080/07315724.2016.1140093.
The Emerging Role of Quercetin in the Treatment of Chronic Pain. Liu C, Liu DQ, Tian YK, et al. Current Neuropharmacology. 2022;20(12):2346-2353. doi:10.2174/1570159X20666220812122437.
Recent Advances in Potential Health Benefits of Quercetin. Aghababaei F, Hadidi M. Pharmaceuticals (Basel, Switzerland). 2023;16(7):1020. doi:10.3390/ph16071020.
Improving Quercetin Bioavailability: A Systematic Review and Meta-Analysis of Human Intervention Studies. Liu L, Barber E, Kellow NJ, Williamson G. Food Chemistry. 2025;477:143630. doi:10.1016/j.foodchem.2025.143630.
A Pharmacokinetic Study of Different Quercetin Formulations in Healthy Participants: A Diet-Controlled, Crossover, Single- And Multiple-Dose Pilot Study. Solnier J, Zhang Y, Roh K, et al. Evidence-Based Complementary and Alternative Medicine : eCAM. 2023;2023:9727539. doi:10.1155/2023/9727539.
Enhanced Bioavailability and Pharmacokinetics of a Natural Self-Emulsifying Reversible Hybrid-Hydrogel System of Quercetin: A Randomized Double-Blinded Comparative Crossover Study. Joseph A, Shanmughan P, Balakrishnan A, Maliakel B, M KI. ACS Omega. 2022;7(50):46825-46832. doi:10.1021/acsomega.2c05929.
Safety Aspects of the Use of Quercetin as a Dietary Supplement. Andres S, Pevny S, Ziegenhagen R, et al. Molecular Nutrition & Food Research. 2018;62(1). doi:10.1002/mnfr.201700447.
Quercetin as a Therapeutic Product: Evaluation of Its Pharmacological Action and Clinical Applications-a Review. Mirza MA, Mahmood S, Hilles AR, et al. Pharmaceuticals (Basel, Switzerland). 2023;16(11):1631. doi:10.3390/ph16111631.
Dietary Quercetin Supplements: Assessment of Online Product Informations and Quantitation of Quercetin in the Products by High-Performance Liquid Chromatography. Vida RG, Fittler A, Somogyi-Végh A, Poór M. Phytotherapy Research : PTR. 2019;33(7):1912-1920. doi:10.1002/ptr.6382.
Quercetin and Its Lecithin-Based Formulation: Potential Applications for Allergic Diseases Based on a Narrative Review. Naso M, Trincianti C, Tosca MA, Ciprandi G. Nutrients. 2025;17(9):1476. doi:10.3390/nu17091476.
Quercetin-Containing Self-Nanoemulsifying Drug Delivery System for Improving Oral Bioavailability. Tran TH, Guo Y, Song D, Bruno RS, Lu X. Journal of Pharmaceutical Sciences. 2014;103(3):840-52. doi:10.1002/jps.23858.
Two-Birds-One-Stone, Microfluidic Producing DES/W Microemulsions to Solubilize Quercetin and Penetrate Intestinal Mucosa for Enhanced Oral Bioavailability. Liu R, Yang X, Huang C, et al. European Journal of Pharmaceutics and Biopharmaceutics : Official Journal of Arbeitsgemeinschaft Fur Pharmazeutische Verfahrenstechnik e.V. 2026;:115007. doi:10.1016/j.ejpb.2026.115007.
Microbiological and Pharmacokinetic Aspects of a Water-Soluble Quercetin 3-O-Rutinoside, EubioQuercetin: A Direct Comparison With Quercetin in in Vitro and Human Clinical Studies. Yamaguchi N, Sudaka Y, Mitsui T, et al. Journal of Food Science. 2025;90(10):e70579. doi:10.1111/1750-3841.70579.
Quercetin Attenuates Diabetic Neuropathic Pain by Inhibiting mTOR/p70S6K Pathway-Mediated Changes of Synaptic Morphology and Synaptic Protein Levels in Spinal Dorsal Horn of Db/Db Mice. Wang R, Qiu Z, Wang G, et al. European Journal of Pharmacology. 2020;882:173266. doi:10.1016/j.ejphar.2020.173266.

How Magnesium Impacts Pain Processing

SECTION 2: PAIN PROCESSING PATHWAY ANALYSIS

The Levels of Pain Processing can be organized as follows:

Level 1: Peripheral Nociception (Pain Receptor Transduction)
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 Brain Processing and Pain Perception
Level 6: Descending Pain Modulation

LEVEL 1: PERIPHERAL NOCICEPTION (Pain Receptor Transduction): Activation and Sensitization

1.1 Overview of Magnesium’s Peripheral Effects

Magnesium exerts complex and sometimes paradoxical effects at the peripheral pain receptor (nociceptor) level. While systemic magnesium administration produces antinociceptive effects, local peripheral administration of magnesium sulfate can activate nociceptors through specific ion channel mechanisms.[1][2]

1.2 TRP Channel Modulation

Peripheral magnesium interacts with multiple transient receptor potential (TRP) channels that serve as primary nociceptive transducers:

TRPV1 (Transient Receptor Potential Vanilloid 1):

Local magnesium sulfate injection activates peripheral TRPV1 receptors, contributing to injection-site pain[2]
The TRPV1 antagonist capsazepine dose-dependently reduces magnesium sulfate-induced mechanical hyperalgesia[2]
This represents a pronociceptive peripheral effect distinct from magnesium’s central antinociceptive actions

TRPV4 (Transient Receptor Potential Vanilloid 4):

Magnesium sulfate-induced local hyperalgesia involves TRPV4 activation[2]
The selective TRPV4 antagonist RN-1734 attenuates magnesium-induced peripheral pain[2]

TRPA1 (Transient Receptor Potential Ankyrin 1):

Peripheral TRPA1 receptors participate in magnesium sulfate-induced local pain[2]
HC-030031, a selective TRPA1 antagonist, reduces magnesium-induced mechanical hyperalgesia[2]

1.3 Acid-Sensing Ion Channels (ASICs)

Non-selective ASIC inhibition with amiloride reduces pH-unadjusted magnesium sulfate-induced hyperalgesia[2]
ASIC involvement is pH-dependent; pH-adjusted magnesium solutions do not activate ASICs[2]

1.4 Peripheral NMDA Receptors

Peripheral NMDA receptors on sensory nerve terminals contribute to magnesium sulfate-induced local pain[1]
This represents a distinct mechanism from the central NMDA receptor blockade that produces analgesia

1.5 Nitric Oxide Pathway

Peripheral production of nitric oxide (NO) contributes to magnesium sulfate-induced local pain[1]
The NO pathway plays an important role in the antinociceptive effects of systemic magnesium in somatic (but not visceral) inflammatory pain models[1]

1.6 Voltage-Gated Calcium Channel Modulation

Magnesium blocks high-voltage activated (HVA) calcium channels in sensory neurons:

L-type and N-type Ca²⁺ channels: Magnesium produces voltage-dependent block of these channels in dorsal root ganglion (DRG) neurons[3]
The block is more potent for Na⁺ currents through these channels (KD = 39 μM) than for Ca²⁺ currents (KD = 24 mM)[3]
This calcium channel blockade reduces neurotransmitter release from primary afferent terminals

1.7 Sensory Neuron Excitability

Reductions in external divalent cations (including Mg²⁺) evoke novel voltage-gated currents in sensory neurons[4]
External Ca²⁺ (IC₅₀ ~0.5 μM) or Mg²⁺ (IC₅₀ ~3 μM) inhibit a putative voltage-gated cation channel in sensory neurons[4]
Depolarization triggers intracellular magnesium surge in DRG neurons, which requires calcium influx through voltage-dependent calcium channels[5]

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LEVEL 2: PRIMARY AFFERENT TRANSMISSION TO SPINAL CORD

2.1 Voltage-Gated Ion Channel Modulation

Magnesium modulates multiple voltage-gated ion channels that control action potential propagation along primary afferent fibers:[6]

Voltage-Gated Calcium Channels (CaV):

1. Intracellular Mg²⁺ causes voltage-dependent CaV channel block
2. Extracellular Mg²⁺ elicits direct voltage-dependent CaV channel block and screens surface charge
3. This reduces calcium influx at presynaptic terminals, decreasing neurotransmitter release

Voltage-Gated Sodium Channels (NaV):

1. Intracellular Mg²⁺ causes voltage-dependent NaV channel block
2. Extracellular Mg²⁺ reduces conduction and may cause depolarization by quantum tunneling across closed channels[6]

Potassium Channels:

1. Magnesium modulates K⁺ inward rectifier (Kir) channels through intracellular pore blocking[6]
2. Mg²⁺ is an allosteric activator of large conductance Ca²⁺-activated K⁺ (BK) channels[6]
3. Mg²⁺ reduces small conductance Ca²⁺-activated K⁺ (SK) channel outward current[6]

2.2 Presynaptic Neurotransmitter Release

Magnesium’s blockade of N-type calcium channels at presynaptic terminals reduces release of excitatory neurotransmitters (glutamate, substance P, CGRP)[1]
Changes in extracellular calcium and magnesium concentrations significantly affect synaptic transmission in the spinal cord[7]
Low Mg²⁺ enhances synaptic transmission, while elevated Mg²⁺ depresses synaptically transmitted responses[7]

2.3 C-Fiber Transmission

Vincristine-induced neuropathic pain is associated with long-term potentiation at C-fiber synapses and peptidergic C-fiber sprouting in the spinal dorsal horn[8]
Oral magnesium-L-threonate prevents this pathologic plasticity by normalizing TNF-α/NF-κB signaling[8]
Magnesium supplementation reduces C-fiber evoked field potentials in radicular pain models[9]

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LEVEL 3: SPINAL CORD DORSAL HORN PROCESSING (First Synapse)

3.1 NMDA Receptor Blockade: The Primary Mechanism

The spinal cord dorsal horn represents the most critical site of magnesium’s antinociceptive action through voltage-dependent NMDA receptor blockade:[1][10][11]

Mechanism of NMDA Receptor Block:

1. Magnesium is a physiological antagonist of the NMDA receptor ion channel[1]
2. The block is voltage-dependent: at resting membrane potential, Mg²⁺ occupies the NMDA receptor channel pore, preventing ion flux[11]
3. Depolarization relieves the Mg²⁺ block, allowing Ca²⁺ and Na⁺ influx[11]
4. This confers “coincidence detector” properties to NMDA receptors, requiring both glutamate binding and postsynaptic depolarization for activation[12]

Structural Basis of Mg²⁺ Block:

1. Recent cryo-EM studies have identified three distinct Mg²⁺-binding pockets on NMDA receptors:[12]

- Site I: Located at the selectivity filter where an asparagine ring forms coordination bonds with Mg²⁺; responsible for voltage-dependent block
- Site II: Located at the N-terminal domain of GluN2B subunit; involved in allosteric potentiation
- Site III: Overlaps with the Zn²⁺ pocket; involved in inhibition

3.2 Prevention of Central Sensitization

Magnesium prevents central sensitization through multiple mechanisms:

NMDA Receptor Phosphorylation:

In diabetic neuropathic pain, the level of phosphorylated NMDA receptor NR1 subunit (pNR1) is elevated in the spinal dorsal horn[10]
Magnesium supplementation prevents the increase in spinal cord dorsal horn pNR1[10]
Local magnesium sulfate inhibits phosphorylation of the NMDA receptor NR1 subunit in injured tissue[13]

NR2B Subunit Regulation:

Vincristine induces upregulation of NR2B subunit of NMDA receptors in the spinal dorsal horn[8]
Oral magnesium-L-threonate prevents this NR2B upregulation[8]
Magnesium supplementation decreases NR2B protein levels in radicular pain models[9]

3.3 Glial Cell Modulation

Magnesium significantly attenuates glial activation in the spinal cord:

Microglial Activation:

Local magnesium sulfate administration significantly attenuates microglial activation in the ipsilateral lumbar spinal cord dorsal horn[13]

Oral magnesium-L-threonate inhibits spinal microglia activation in radicular pain models[9]

Magnesium supplementation suppresses microglia activation in the anterior cingulate cortex in chronic postsurgical pain models[14]

Astrocytic Activation:

Magnesium sulfate attenuates astrocytic activation in the spinal cord dorsal horn[13]
This glial modulation is critical for preventing neuroinflammation-driven central sensitization

3.4 Pro-inflammatory Cytokine Suppression

Magnesium reduces spinal cord neuroinflammation:

Inhibits expression of IL-1β in injured tissue and spinal cord[13][9]
Suppresses TNF-α expression and signaling[8][9]
Reduces IL-6 levels in the spinal cord[9]
Inhibits inducible nitric oxide synthase (iNOS) expression[13]

3.5 Intrathecal Magnesium Effects

Direct spinal administration of magnesium produces specific antinociceptive effects:

Intrathecal MgSO₄ dose-dependently reverses hyperalgesia in magnesium-deficient rats[15]
Intrathecal magnesium suppresses phase 2 (tonic) of the formalin test but does not affect acute nociceptive thresholds[16]
This selective effect on tonic pain confirms the involvement of spinal NMDA receptors[16]

3.6 Second Messenger Systems

Magnesium deficiency activates intracellular signaling cascades that promote hyperalgesia:[15]

Protein Kinase C (PKC): Chelerythrine chloride (PKC inhibitor) reverses hyperalgesia in Mg-deficient rats
Nitric Oxide Synthase: 7-NI (specific NO synthase inhibitor) produces anti-hyperalgesic effects
Substance P: Neurokinin receptor antagonists produce moderate anti-hyperalgesic effects in Mg-deficient rats

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LEVEL 4: ASCENDING SPINAL PATHWAYS AND SUPRASPINAL PROCESSING

4.1 Spinothalamic Tract Modulation

Magnesium’s effects on ascending pain transmission are mediated primarily through:

Reduction of spinal cord dorsal horn neuron excitability via NMDA receptor blockade[1][10]
Decreased wind-up phenomenon and temporal summation[1]
Prevention of long-term potentiation at spinal synapses[8][12]

4.2 Wind-Up Prevention

The wind-up phenomenon, characterized by progressive increase in dorsal horn neuron firing with repeated C-fiber stimulation, is NMDA receptor-dependent:

Magnesium’s voltage-dependent NMDA receptor block prevents the progressive depolarization required for wind-up[1]
This mechanism underlies magnesium’s ability to prevent central sensitization and attenuate preexisting pain hypersensitivity[1]

4.3 Long-Term Potentiation (LTP) at Pain Synapses

The voltage-dependent Mg²⁺ block of NMDARs is crucial for the induction of LTP[12]
Vincristine-induced neuropathic pain involves LTP at C-fiber synapses in the spinal dorsal horn[8]
Magnesium supplementation prevents this pathological LTP[8]
Alterations in the voltage-dependent block of NMDA receptors may contribute to chronic pain states[12]

4.4 Brainstem Processing

Magnesium affects brainstem nuclei involved in pain processing:

NMDA receptors in the periaqueductal gray (PAG) are modulated by magnesium[17]
Magnesium and morphine co-treatment affects phosphorylated NMDA receptor and μ-opioid receptor levels in the PAG[17]
These effects contribute to magnesium’s enhancement of opioid analgesia

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LEVEL 5: THALAMIC AND CORTICAL PROCESSING AND PAIN PERCEPTION

5.1 Thalamic NMDA Receptor Modulation

NMDA receptors are abundantly expressed in thalamic relay nuclei involved in pain processing
Magnesium’s voltage-dependent block of thalamic NMDA receptors may reduce pain signal amplification
This contributes to the overall reduction in pain perception observed with magnesium supplementation

5.2 Cortical Effects

Anterior Cingulate Cortex (ACC):

The ACC is critical for the affective-emotional component of pain:

Chronic postsurgical pain causes microglia and astrocyte activation in the ACC[14]
Magnesium-L-threonate administration suppresses glial activation and proinflammatory cytokine expression (TNF-α, IL-1β, IL-6) in the ACC[14]
This correlates with reversal of anxiodepressive-like behaviors associated with chronic pain[14]

5.3 Neuroprotection Against Excitotoxicity

Magnesium provides neuroprotection in cortical regions:

Functions in a protective role against excessive excitation that can lead to neuronal cell death (excitotoxicity)[18]
This neuroprotective effect is relevant for preventing maladaptive cortical plasticity in chronic pain states
Magnesium deficiency has been implicated in multiple neurological disorders including those with pain components[18]

5.4 Cognitive and Emotional Pain Processing

Magnesium supplementation alleviates anxiodepressive-like behaviors associated with chronic pain[14]
Strong data suggest a role for magnesium in depression, which commonly co-occurs with chronic pain[18]
Emerging data suggest a protective effect of magnesium for anxiety[18]

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LEVEL 6: DESCENDING PAIN MODULATION

6.1 Periaqueductal Gray (PAG) Modulation

The PAG is a critical hub for descending pain inhibition:

NMDA Receptor Effects:

Magnesium modulates NMDA receptors in the PAG, affecting descending inhibitory pathways[17]

Chronic magnesium and morphine co-treatment decreases phosphorylated NR1 (pNR1) levels in the PAG[17]

Opioid System Interaction:

1. Magnesium enhances opioid analgesia in chronic neuropathic pain[17]
2. The mechanism involves restoration of the μ-opioid receptor (MOR)-NMDA receptor complex[17]
3. Blocking NMDA receptor signaling by Mg²⁺ restores the MOR-NMDAR complex, enabling morphine analgesia in neuropathic conditions[17]

6.2 Rostral Ventromedial Medulla (RVM)

1. NMDA receptors in the RVM contribute to both facilitatory and inhibitory descending modulation
2. Magnesium’s NMDA receptor blockade may shift the balance toward inhibitory modulation
3. This contributes to the overall antinociceptive effect of magnesium supplementation

6.3 Noradrenergic and Serotonergic Pathways

1. Descending noradrenergic and serotonergic pathways from the brainstem modulate spinal pain processing
2. – Magnesium’s effects on these pathways are less well characterized than its NMDA receptor effects
3. – However, magnesium’s role in depression (which involves serotonergic dysfunction) suggests potential modulation of these systems[18]

6.4 Endogenous Opioid System Enhancement

Magnesium potentiates endogenous opioid-mediated analgesia:

1. Mg²⁺ administered alone significantly decreases phosphorylated MOR (pMOR) levels[17]
2. Magnesium reduces PKA and PKC activity, which are involved in opioid receptor desensitization[17]
3. This suggests that magnesium may enhance the efficacy of endogenous opioid-mediated descending inhibition

6.5 TNF-α/NF-κB Pathway Normalization

1. Magnesium deficiency activates the TNF-α/NF-κB pathway, leading to spinal pathologic plasticity[8]
2. Oral magnesium-L-threonate normalizes this pathway, preventing nociceptive sensitization[8]
3. NF-κB inhibition blocks vincristine-induced pathologic plasticity in the spinal dorsal horn[8]

—

SUMMARY Table – Magnesium’s multi-level effects on pain processing:

Pain Processing Level	Primary Mechanisms	Key Effects	References
Level 1: Peripheral Nociception	TRP channel modulation, Ca²⁺ channel block	Complex: local pronociceptive, systemic antinociceptive	[1], [2], [3]
Level 2: Primary Afferent Transmission	Voltage-gated channel modulation, presynaptic Ca²⁺ block	Reduced neurotransmitter release	[1], [2]
Level 3: Spinal Dorsal Horn	NMDA receptor block, glial modulation, cytokine suppression	Prevention of central sensitization	[1]-6]
Level 4: Ascending Pathways	Wind-up prevention, LTP inhibition	Reduced pain signal amplification	[1], [2]
Level 5: Thalamic/Cortical	NMDA modulation, neuroprotection, ACC effects	Reduced pain perception, improved affect	[1], [3]
Level 6: Descending Modulation	PAG modulation, opioid system enhancement	Enhanced descending inhibition	[1]]

[1][5][6][2][7][8][3][4]

This comprehensive multi-level activity demonstrates magnesium’s role as a fundamental modulator of pain processing throughout the neuraxis. The evidence shows that magnesium acts as a voltage-dependent NMDA receptor antagonist at the spinal dorsal horn to prevent central sensitization, blocks presynaptic calcium channels to reduce neurotransmitter release from primary afferents, and enhances descending inhibitory pathways through periaqueductal gray modulation and opioid system potentiation.[1][2][4] Notably, magnesium exhibits complex peripheral effects with local pronociceptive actions but systemic antinociceptive benefits, highlighting the importance of route and site of administration.[1][5][6]

References for the Table:

The Emerging Role of Quercetin in the Treatment of Chronic Pain. Liu C, Liu DQ, Tian YK, et al. Current Neuropharmacology. 2022;20(12):2346-2353. doi:10.2174/1570159X20666220812122437.
Quercetin Alleviates Osteoarthritis Pain by Inhibiting Vascular Endothelial Growth Factor a Through Regulating cGAS/STING Pathway. Hu E, Wei Y, Liao T, et al. Journal of Cellular and Molecular Medicine. 2026;30(1):e70992. doi:10.1111/jcmm.70992.
Quercetin Attenuates Diabetic Neuropathic Pain by Inhibiting mTOR/p70S6K Pathway-Mediated Changes of Synaptic Morphology and Synaptic Protein Levels in Spinal Dorsal Horn of Db/Db Mice. Wang R, Qiu Z, Wang G, et al. European Journal of Pharmacology. 2020;882:173266. doi:10.1016/j.ejphar.2020.173266.
Quercetin Alleviates Thermal and Cold Hyperalgesia in a Rat Neuropathic Pain Model by Inhibiting Toll-Like Receptor Signaling. Ji C, Xu Y, Han F, et al. Biomedicine & Pharmacotherapy = Biomedecine & Pharmacotherapie. 2017;94:652-658. doi:10.1016/j.biopha.2017.07.145.
Quercetin, Main Active Ingredient of Moutan Cortex, Alleviates Chronic Orofacial Pain via Block of Voltage-Gated Sodium Channel. Liu Z, Shan Z, Yang H, et al. Anesthesia and Analgesia. 2024;138(6):1324-1336. doi:10.1213/ANE.0000000000006730.
Phytochemical Quercetin Alleviates Hyperexcitability of Trigeminal Nociceptive Neurons Associated With Inflammatory Hyperalgesia Comparable to NSAIDs. Itou H, Toyota R, Takeda M. Molecular Pain. 2022;18:17448069221108971. doi:10.1177/17448069221108971.
Quercetin Ameliorates CFA-Induced Chronic Inflammatory Hyperalgesia via Modulation of ROS-Mediated ERK1/2 Signaling and Inhibition of Spinal Glial Activation in Vivo. Kumar S, Vinayak M. Neuromolecular Medicine. 2020;22(4):517-533. doi:10.1007/s12017-020-08609-z.
Quercetin Inhibits Peripheral and Spinal Cord Nociceptive Mechanisms to Reduce Intense Acute Swimming-Induced Muscle Pain in Mice. Borghi SM, Pinho-Ribeiro FA, Fattori V, et al. PloS One. 2016;11(9):e0162267. doi:10.1371/journal.pone.0162267.

This completes Section 2, providing a comprehensive analysis of how magnesium impacts each level of pain processing from peripheral nociception through descending modulation.

References

The Phytochemical, Quercetin, Attenuates Nociceptive and Pathological Pain: Neurophysiological Mechanisms and Therapeutic Potential. Takeda M, Sashide Y, Toyota R, Ito H. Molecules (Basel, Switzerland). 2024;29(16):3957. doi:10.3390/molecules29163957.
The Effect of Quercetin on Inflammatory Factors and Clinical Symptoms in Women With Rheumatoid Arthritis: A Double-Blind, Randomized Controlled Trial. Javadi F, Ahmadzadeh A, Eghtesadi S, et al. Journal of the American College of Nutrition. 2017;36(1):9-15. doi:10.1080/07315724.2016.1140093.
The Emerging Role of Quercetin in the Treatment of Chronic Pain. Liu C, Liu DQ, Tian YK, et al. Current Neuropharmacology. 2022;20(12):2346-2353. doi:10.2174/1570159X20666220812122437.
Recent Advances in Potential Health Benefits of Quercetin. Aghababaei F, Hadidi M. Pharmaceuticals (Basel, Switzerland). 2023;16(7):1020. doi:10.3390/ph16071020.
Improving Quercetin Bioavailability: A Systematic Review and Meta-Analysis of Human Intervention Studies. Liu L, Barber E, Kellow NJ, Williamson G. Food Chemistry. 2025;477:143630. doi:10.1016/j.foodchem.2025.143630.
A Pharmacokinetic Study of Different Quercetin Formulations in Healthy Participants: A Diet-Controlled, Crossover, Single- And Multiple-Dose Pilot Study. Solnier J, Zhang Y, Roh K, et al. Evidence-Based Complementary and Alternative Medicine : eCAM. 2023;2023:9727539. doi:10.1155/2023/9727539.
Enhanced Bioavailability and Pharmacokinetics of a Natural Self-Emulsifying Reversible Hybrid-Hydrogel System of Quercetin: A Randomized Double-Blinded Comparative Crossover Study. Joseph A, Shanmughan P, Balakrishnan A, Maliakel B, M KI. ACS Omega. 2022;7(50):46825-46832. doi:10.1021/acsomega.2c05929.
Safety Aspects of the Use of Quercetin as a Dietary Supplement. Andres S, Pevny S, Ziegenhagen R, et al. Molecular Nutrition & Food Research. 2018;62(1). doi:10.1002/mnfr.201700447.
Quercetin as a Therapeutic Product: Evaluation of Its Pharmacological Action and Clinical Applications-a Review. Mirza MA, Mahmood S, Hilles AR, et al. Pharmaceuticals (Basel, Switzerland). 2023;16(11):1631. doi:10.3390/ph16111631.
Dietary Quercetin Supplements: Assessment of Online Product Informations and Quantitation of Quercetin in the Products by High-Performance Liquid Chromatography. Vida RG, Fittler A, Somogyi-Végh A, Poór M. Phytotherapy Research : PTR. 2019;33(7):1912-1920. doi:10.1002/ptr.6382.
Quercetin and Its Lecithin-Based Formulation: Potential Applications for Allergic Diseases Based on a Narrative Review. Naso M, Trincianti C, Tosca MA, Ciprandi G. Nutrients. 2025;17(9):1476. doi:10.3390/nu17091476.
Quercetin-Containing Self-Nanoemulsifying Drug Delivery System for Improving Oral Bioavailability. Tran TH, Guo Y, Song D, Bruno RS, Lu X. Journal of Pharmaceutical Sciences. 2014;103(3):840-52. doi:10.1002/jps.23858.
Two-Birds-One-Stone, Microfluidic Producing DES/W Microemulsions to Solubilize Quercetin and Penetrate Intestinal Mucosa for Enhanced Oral Bioavailability. Liu R, Yang X, Huang C, et al. European Journal of Pharmaceutics and Biopharmaceutics : Official Journal of Arbeitsgemeinschaft Fur Pharmazeutische Verfahrenstechnik e.V. 2026;:115007. doi:10.1016/j.ejpb.2026.115007.
Microbiological and Pharmacokinetic Aspects of a Water-Soluble Quercetin 3-O-Rutinoside, EubioQuercetin: A Direct Comparison With Quercetin in in Vitro and Human Clinical Studies. Yamaguchi N, Sudaka Y, Mitsui T, et al. Journal of Food Science. 2025;90(10):e70579. doi:10.1111/1750-3841.70579.
Quercetin Attenuates Diabetic Neuropathic Pain by Inhibiting mTOR/p70S6K Pathway-Mediated Changes of Synaptic Morphology and Synaptic Protein Levels in Spinal Dorsal Horn of Db/Db Mice. Wang R, Qiu Z, Wang G, et al. European Journal of Pharmacology. 2020;882:173266. doi:10.1016/j.ejphar.2020.173266.
Magnesium in Pain Research: State of the Art. Srebro D, Vuckovic S, Milovanovic A, et al. Current Medicinal Chemistry. 2017;24(4):424-434. doi:10.2174/0929867323666161213101744.
Magnesium and Pain. Shin HJ, Na HS, Do SH. Nutrients. 2020;12(8):E2184. doi:10.3390/nu12082184.
Local Magnesium Sulfate Administration Ameliorates Nociception, Peripheral Inflammation, and Spinal Sensitization in a Rat Model of Incisional Pain. Wen ZH, Wu ZS, Huang SY, et al. Neuroscience. 2024;547:98-107. doi:10.1016/j.neuroscience.2024.03.033.

Magnesium: Pain Processing Effects vs. Direct Tissue-Modifying Effects

Pain Processing Effects:

Magnesium exerts its primary analgesic effect through NMDA receptor antagonism, which prevents central sensitization and attenuates preexisting pain hypersensitivity.[1][2] As a physiological voltage-dependent blocker of the NMDA receptor ion channel, magnesium blocks calcium influx critical for pain signal amplification in the spinal cord dorsal horn. Oral magnesium-L-threonate alleviates radicular pain by inhibiting neuroinflammation-dependent central sensitization—it decreases C-fiber evoked potentials, reduces spinal microglia activation, suppresses pro-inflammatory cytokines (TNF-α, IL-6, IL-1β), and decreases NR2B subunit expression.[3] Local magnesium sulfate administration inhibits phosphorylation of the NMDA receptor NR1 subunit and significantly attenuates microglial and astrocytic activation in the spinal cord dorsal horn.[4]

In diabetic neuropathic pain models, oral magnesium supplementation abolished thermal and tactile allodynia, delayed mechanical hypersensitivity development, and prevented the increase in spinal cord dorsal horn phosphorylated NR1 (pNR1)—without affecting hyperglycemia or restoring intracellular magnesium levels.[5] This dissociation suggests the analgesic effect is primarily mediated through central NMDA receptor blockade rather than metabolic correction.

Beyond NMDA antagonism, magnesium also blocks calcium channels and modulates potassium channels, and the nitric oxide (NO) pathway contributes to antinociceptive effects in somatic inflammatory pain models.[2] Clinical evidence shows efficacy in fibromyalgia (significant reduction in mild/moderate stress and pain severity), neuropathic low back pain (pain intensity reduction from 7.5 to 4.7 at 6 months with improved lumbar mobility), and migraine.[6][7] However, a systematic review of 9 RCTs (418 participants) found equivocal evidence for chronic pain overall, with good evidence only for renal colic and endometriosis-related pelvic pain.[8][9]

Direct Tissue-Modifying Effects:

Magnesium demonstrates significant chondroprotective effects in preclinical models. Intra-articular magnesium chloride injection attenuates OA progression by promoting cartilage matrix synthesis and suppressing synovial inflammation—it inhibits MMP-13 and IL-6 expression in both cartilage and synovium.[10] High-concentration magnesium inhibits extracellular matrix calcification and protects articular cartilage via the ERK/autophagy pathway, downregulating hypertrophy genes (Runx2, MMP13, Col10α1) while upregulating chondrogenic genes (Sox9, Col1α1).[11]

Dietary magnesium deficiency accelerates injury-induced OA through reduced autophagy via Wnt/β-catenin signaling activation, with decreased anabolic and increased catabolic effects in chondrocytes.[12] In rheumatoid arthritis models, oral magnesium supplementation significantly reduces disease severity and joint damage, modifying synovial transcriptomic signatures including ferroptosis and cell senescence pathways.[13] Magnesium deficiency is associated with increased inflammatory mediators, cartilage damage, defective chondrocyte biosynthesis, and aberrant calcification.[14]

Mechanism	Pain Processing	Tissue Modification	References
NMDA receptor antagonism (voltage-dependent block)	Prevents central sensitization; reduces pNR1 in spinal cord	None	[1], [2], [3]
Spinal glial inhibition (↓microglia, ↓astrocytes)	Reduces neuroinflammation	None	[4], [5]
Pro-inflammatory cytokine suppression (TNF-α, IL-6, IL-1β)	Reduces peripheral/central sensitization	Reduces synovial inflammation	[1]
ERK/autophagy pathway modulation	None	Inhibits ECM calcification; protects cartilage	[2]
MMP-13 inhibition	Indirect	Direct cartilage matrix preservation	[3]
Wnt/β-catenin signaling modulation	None	Maintains chondrocyte autophagy; prevents catabolism	[4]

References

Magnesium and Pain. Shin HJ, Na HS, Do SH. Nutrients. 2020;12(8):E2184. doi:10.3390/nu12082184.
Magnesium in Pain Research: State of the Art. Srebro D, Vuckovic S, Milovanovic A, et al. Current Medicinal Chemistry. 2017;24(4):424-434. doi:10.2174/0929867323666161213101744.
Oral Application of Magnesium-L-Threonate Alleviates Radicular Pain by Inhibiting Neuro-Inflammation Dependent Central Sensitization of Rats. Li S, Yi H, Yuan F, et al. Brain Research. 2024;1839:148910. doi:10.1016/j.brainres.2024.148910.
Local Magnesium Sulfate Administration Ameliorates Nociception, Peripheral Inflammation, and Spinal Sensitization in a Rat Model of Incisional Pain. Wen ZH, Wu ZS, Huang SY, et al. Neuroscience. 2024;547:98-107. doi:10.1016/j.neuroscience.2024.03.033.
Magnesium Attenuates Chronic Hypersensitivity and Spinal Cord NMDA Receptor Phosphorylation in a Rat Model of Diabetic Neuropathic Pain. Rondón LJ, Privat AM, Daulhac L, et al. The Journal of Physiology. 2010;588(Pt 21):4205-15. doi:10.1113/jphysiol.2010.197004.
Short-Term Magnesium Therapy Alleviates Moderate Stress in Patients With Fibromyalgia: A Randomized Double-Blind Clinical Trial. Macian N, Dualé C, Voute M, et al. Nutrients. 2022;14(10):2088. doi:10.3390/nu14102088.
A Double-Blinded Randomised Controlled Study of the Value of Sequential Intravenous and Oral Magnesium Therapy in Patients With Chronic Low Back Pain With a Neuropathic Component. Yousef AA, Al-deeb AE. Anaesthesia. 2013;68(3):260-6. doi:10.1111/anae.12107.
Efficacy and Safety of Magnesium for the Management of Chronic Pain in Adults: A Systematic Review. Park R, Ho AM, Pickering G, et al. Anesthesia and Analgesia. 2020;131(3):764-775. doi:10.1213/ANE.0000000000004673.
Magnesium for Pain Treatment in 2021? State of the Art. Morel V, Pickering ME, Goubayon J, et al. Nutrients. 2021;13(5):1397. doi:10.3390/nu13051397.
Intra-Articular Injection of Magnesium Chloride Attenuates Osteoarthritis Progression in Rats. Yao H, Xu JK, Zheng NY, et al. Osteoarthritis and Cartilage. 2019;27(12):1811-1821. doi:10.1016/j.joca.2019.08.007.
High Concentration Magnesium Inhibits Extracellular Matrix Calcification and Protects Articular Cartilage via Erk/Autophagy Pathway. Yue J, Jin S, Gu S, Sun R, Liang Q. Journal of Cellular Physiology. 2019;234(12):23190-23201. doi:10.1002/jcp.28885.
Increased WNT/Β-Catenin Signaling Contributes to Autophagy Inhibition Resulting From a Dietary Magnesium Deficiency in Injury-Induced Osteoarthritis. Bai R, Miao MZ, Li H, et al. Arthritis Research & Therapy. 2022;24(1):165. doi:10.1186/s13075-022-02848-0.
Magnesium Supplementation Modifies Arthritis Synovial and Splenic Transcriptomic Signatures Including Ferroptosis and Cell Senescence Biological Pathways. Laragione T, Harris C, Gulko PS. Nutrients. 2024;16(23):4247. doi:10.3390/nu16234247.
Unraveling the Role of Mg(++) in Osteoarthritis. Li Y, Yue J, Yang C. Life Sciences. 2016;147:24-9. doi:10.1016/j.lfs.2016.01.029.

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