Magnesium increases morphine analgesic effect in different experimental models of pain

Background: An excess of excitatory pathway activation via N-methyl-Di-aspartate (NMDA) receptors has been described in neuropathic pain that responds poorly to morphine. However, in this situation, several published data sets show that coadministration of NMDA receptor antagonists restores the efficacy of opioids. Considering that magnesium behaves like an NMDA receptor antagonist, we investigated the effect of the combination of magnesium and morphine in experimental models of chronic and tonic pain. Methods: Mechanical hyperalgesia was assessed with the paw-pressure test in mononeuropathic (chronic constrictive injury model) and diabetic rats. Behavioral reactions were scored in a model of inflammation induced by formalin. The animals were assigned to one of three groups according to the intraperitoneal pretreatment: magnesium (30 mg/kg x 3), magnesium (30 mg/kg), and saline. Before testing, morphine was injected intravenously in mononeuropathic (0.3 mg/kg) and diabetic rats (1 mg/kg) and by the subcutaneous route in rats with the formalin test (1.5 mg/kg). Results: Magnesium alone induced a significant antihyperalgesic effect in mononeuropathic and diabetic rats after a cumulative dose of 90 mg/kg. Furthermore, it significantly increased morphine analgesia, regardless of the loading dose used (30 or 90 mg/kg) hi the two models of neuropathic pain. In the formalin test, magnesium alone did not have a significant effect. However, in combination with morphine, it revealed the analgesic effect of this opiate. Conclusions: These data show that magnesium amplifies the analgesic effect of low-dose morphine in conditions of sustained pain. Considering the good tolerability of magnesium, these findings may have clinical applications in neuropathic and persistent pain.