Magnesium and Morphine in the Treatment of Chronic Neuropathic Pain–A Biomedical Mechanism of Action

Abstract

The effectiveness of opioids in the treatment of neuropathic pain is limited. It was demonstrated that magnesium ions (Mg2+), physiological antagonists of N-methyl-D-aspartate receptor (NMDAR), increase opioid analgesia in chronic pain. Our study aimed to determine the molecular mechanism of this action. Early data indicate the cross-regulation of µ opioid receptor (MOR) and NMDAR in pain control. Morphine acting on MOR stimulates protein kinase C (PKC), while induction of NMDAR recruits protein kinase A (PKA), leading to a disruption of the MOR-NMDAR complex and promoting functional changes in receptors. The mechanical Randall-Selitto test was used to assess the effect of chronic Mg2+ and morphine cotreatment on streptozotocin-induced hyperalgesia in Wistar rats. The level of phosphorylated NMDAR NR1 subunit (pNR1) and phosphorylated MOR (pMOR) in the periaqueductal gray matter was determined with the Western blot method. The activity of PKA and PKC was examined by standard enzyme immunoassays. The experiments showed a reduction in hyperalgesia after coadministration of morphine (5 mg/kg intraperitoneally) and Mg2+ (40 mg/kg intraperitoneally). Mg2+ administered alone significantly decreased the level of pNR1, pMOR, and activity of both tested kinases. The results suggest that blocking NMDAR signaling by Mg2+ restores the MOR-NMDAR complex and thus enables morphine analgesia in neuropathic rats.

NMDARs mediate peripheral and central sensitization contributing to chronic orofacial pain

“…The functional state of NMDARs in the central nervous system is mainly regulated by Mg 2+ . As a physiological antagonist of NMDARs, Mg 2+ can block the calcium influx of the channel and maintain the resting membrane potential (Kulik et al, 2021 ). The depolarization process removes the Mg 2+ -induced blockade of NMDARs in a voltage-dependent manner, resulting in hyperexcitability and consequently a sustained state of depolarization and increased synaptic strength (Johnson and Ascher, 1990 ).…”

“…Similarly, Mg 2+ deficient rats develop mechanical hyperalgesia, which is reversed by NMDAR antagonists (Begon et al, 2001 ). Preclinical studies have found that the combination of Mg 2+ and opioids can relieve neuropathic pain in diabetic rats by reducing the level of PKA in the PAG and increasing opioid receptor activity, indicating that Mg 2+ can be used as a supplement for the treatment of pain (Rondon et al, 2010 ; Kulik et al, 2021 ). In addition to Mg 2+ , in vitro studies on mouse hippocampal neurons have confirmed that Zn 2+ can selectively block NMDAR-mediated central neuron excitation (Westbrook and Mayer, 1987 ; Choi and Lipton, 1999 ; Morabito et al, 2022 ).…”

Recent Advances in the Study of Na+/K+-ATPase in Neurodegenerative Diseases

“…Under normal resting potential, Mg 2+ ions blocked the pore of NMDAR. However, when the membrane was depolarized, the Mg 2+ left NMDAR and allowed free entry of Ca 2+ , which eventually led to neuronal loss [ 114 ]. Furthermore, a strong correlation between NKA deficiency and oxidative stress was reported in HD.…”

Postoperative Magnesium Sulfate Repletion Decreases Narcotic Use in Abdominal-Based Free Flap Breast Reconstruction

“…Magnesium, acting as an N-methyl-D-aspartate (NMDA) receptor antagonist, has garnered attention as a potential adjuvant to opioids, theorized to possess analgesic properties due to its modulation of pain transmission pathways within the central nervous system 4,5…”