Mechanism of magnesium as an analgesic adjuvant
Although magnesium has no direct analgesic effect, it inhibits calcium ions entering cells by blocking NMDA receptors, which causes an antinociceptive effect. Furthermore, this antinociceptive effect is related to its prevention of central sensitization caused by peripheral tissue injury (Woolf and Thompson, 1991). Central sensitization is the result of the enhancement of neuronal properties in nociceptive pathways of the central nervous system, and is triggered by repetitive nociceptive afferent inputs, which manifests as a prolonged reduction in the pain threshold. Central sensitization produces pain hypersensitivity, such as wind-up or long-term potentiation of pain, that is, it causes pain even when peripheral stimuli are not intense and continues to cause pain after the initiating stimuli have disappeared (Latremoliere and Woolf, 2009; Woolf, 1983; Woolf and Salter, 2000).
Increased intracellular calcium levels seem to play a major role in the initiation of central sensitization (Pockett, 1995; Woolf and Chong, 1993), and the build-up of intracellular calcium is associated with various receptors on postsynaptic neurons of the spinal dorsal horn, such as, NMDA, α-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA), kainate, and glutamate receptors (Latremoliere and Woolf, 2009). Of these receptors, NMDA receptor activation has been demonstrated to be essential for initiating and maintaining central sensitization.
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The NMDA receptor is a membrane ion channel expressed in the central nervous system. It is a tetramer composed of four different subunits, that is, two NR1 and two NR2 (Dingledine et al., 1999). NMDA receptors regulate the cellular inflows of Na+ and Ca2+, and the outflow of K+. This voltage-dependent ion channel is blocked non-competitively in the resting state by the magnesium ion and by ketamine (phencyclidine site blockade), MK-801, memantine, and others (Felsby et al., 1996; Paoletti and Neyton, 2007) (Fig. 1). On the other hand, the NMDA receptor channel is opened by membrane depolarization induced by the sustained release of glutamate and neuropeptides, which include substance P and calcitonin gene-related peptide (CGRP) (Baranauskas and Nistri, 1998; Mayer et al., 1984).
Extracellular magnesium blocks the NMDA receptor in a voltage-dependent manner (Mayer et al., 1984), and thus, can prevent the establishment of central sensitization and abolish existing hypersensitivity. Other noncompetitive or competitive NMDA receptor antagonists, such as MK801 and D-CPP, also prevent and reverse the hyperexcitability of neurons produced by nociceptive afferent inputs (Ma and Woolf, 1995; Woolf and Thompson, 1991).
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