Magnesium attenuates chronic hypersensitivity and spinal cord NMDA receptor phosphorylation in a rat model of diabetic neuropathic pain

Abstract

Neuropathic pain is a common diabetic complication affecting 8-16% of diabetic patients. It is characterized by aberrant symptoms of spontaneous and stimulus-evoked pain including hyperalgesia and allodynia. Magnesium (Mg) deficiency has been proposed as a factor in the pathogenesis of diabetes-related complications, including neuropathy. In the central nervous system, Mg is also a voltage-dependant blocker of the N -methyl-d-aspartate receptor channels involved in abnormal processing of sensory information. We hypothesized that Mg deficiency might contribute to the development of neuropathic pain and the worsening of clinical and biological signs of diabetes and consequently, that Mg administration could prevent or improve its complications. We examined the effects of oral Mg supplementation (296 mg l −1 in drinking water for 3 weeks) on the development of neuropathic pain and on biological and clinical parameters of diabetes in streptozocin (STZ)-induced diabetic rats. STZ administration induced typical symptoms of type 1 diabetes. The diabetic rats also displayed mechanical hypersensitivity and tactile and thermal allodynia. The level of phosphorylated NMDA receptor NR1 subunit (pNR1) was higher in the spinal dorsal horn of diabetic hyperalgesic/allodynic rats. Magnesium supplementation failed to reduce hyperglycaemia, polyphagia and hypermagnesiuria, or to restore intracellular Mg levels and body growth, but increased insulinaemia and reduced polydipsia. Moreover, it abolished thermal and tactile allodynia, delayed the development of mechanical hypersensitivity, and prevented the increase in spinal cord dorsal horn pNR1. Thus, neuropathic pain symptoms can be attenuated by targeting the Mg-mediated blockade of NMDA receptors, offering new therapeutic opportunities for the management of chronic neuropathic pain.

Analgesic effect and safety of single-dose intra-articular magnesium after arthroscopic surgery: a systematic review and meta-analysis

“…Mg could be effective in pain relief by exerting the antinociceptive effect46, inhibiting TNF-α47, and modulating hypesthesia and hyperalgesia4849, by blocking the NMDA receptor. The pain relief effect of Mg has been illustrated by several studies in many cases, such as postoperative sore throat50, tourniquet pain51, major non-laparoscopic gastrointestinal surgery52, diabetic neuropathic pain53, cardiac surgery54, and cancer-related neuropathic pain55. The present study also demonstrated that the single-dose IA Mg was effective in pain relief after arthroscopic surgery.…”

The antinociceptive effects of magnesium sulfate and MK-801 in visceral inflammatory pain model: The role of NO/cGMP/K+ATP pathway

“…Several lines of evidence indicate that magnesium enhances the analgesic effects of opioids, general, and local anesthetics in different animal models of pain (Assi, 2001;Liu et al, 2001;Nechifor, 2011). As a sole drug, magnesium demonstrated analgesic efficacy against neuropathic pain (Begon et al, 2000;Rondón et al, 2010). There are controversial results in the previous studies investigating the effect of magnesium in a model of somatic inflammatory pain induced by injection of formalin into the rat paw (Begon et al, 2002;Takano et al, 2000).…”

Endomorphin-2 Inhibition of Substance P Signaling within Lamina I of the Spinal Cord Is Impaired in Diabetic Neuropathic Pain Rats

“…Neurokinin release from central terminals is controlled by numerous presynaptic modulatory receptors, including inhibition by GABA B (Marvizón et al, 1999; Riley et al, 2001; Zhang et al, 2010), α 2 -adrenergic (Takano et al, 1993) and opioid (Kondo et al, 2005; Beaudry et al, 2011; Chen et al, 2014) receptors, and facilitation by capsaicin (Marvizón et al, 2003), serotonin (Inoue et al, 1997) and NMDA (Liu et al, 1997; Trafton and Basbaum, 2000) receptors. In the condition of DNP, the overexpression of NMDA receptors (Tomiyama et al, 2005; Rondon et al, 2010) and decreased function of GABA B (Wang et al, 2007) at the primary afferent terminals mobilizes excessive SP release (Marvizón et al, 1999) and counteracts the effects of EM2. In the present study, we provided evidence that the decreased level of presynaptic MORs might account for the reduced efficacy of EM2 on SP release.…”