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

• Published in: International journal of molecular sciences 2021-12, Vol.22 (24), p.13599
• Main Authors: Kulik, Kamila, Żyżyńska-Granica, Barbara, Kowalczyk, Agnieszka, Kurowski, Przemysław, Gajewska, Małgorzata, Bujalska-Zadrożny, Magdalena
• Format: Article
• Language: English
• Subjects: Analgesia; Analgesics; Analgesics, Opioid - therapeutic use; Animals; Chronic pain; Cyclin-dependent kinases; Diabetes; Drug dosages; Experiments; Glutamic acid receptors; Hyperalgesia; Kinases; Magnesium; Magnesium - therapeutic use; Male; Morphine; Morphine - therapeutic use; N-methyl-D-aspartate receptor; N-Methyl-D-aspartic acid receptors; Narcotics; Neuralgia - drug therapy; Neuralgia - metabolism; Opioid receptors; Pain; Pain perception; Periaqueductal gray area; Phosphorylation; Phosphorylation - drug effects; Physiology; Protein kinase A; Protein kinase C; Protein Kinase C - metabolism; Proteins; Rats; Rats, Wistar; receptor association; Receptors, N-Methyl-D-Aspartate - antagonists & inhibitors; Receptors, N-Methyl-D-Aspartate - metabolism; Receptors, Opioid, mu - metabolism; Streptozocin; Substantia grisea; µ-opioid receptor
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms222413599

The effectiveness of opioids in the treatment of neuropathic pain is limited. It was demonstrated that magnesium ions (Mg ), 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 Mg 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 Mg (40 mg/kg intraperitoneally). Mg administered alone significantly decreased the level of pNR1, pMOR, and activity of both tested kinases. The results suggest that blocking NMDAR signaling by Mg restores the MOR-NMDAR complex and thus enables morphine analgesia in neuropathic rats.