N-methyl-D-aspartate receptor antagonist MK-801 suppresses glial pro-inflammatory cytokine expression in morphine-tolerant rats.

Chronic opioid therapy induces tolerance and hyperalgesia, which hinders the efficacy of opioid treatment. Previous studies have shown that inhibition of neuroinflammation and glutamatergic receptor activation prevents the development of morphine tolerance. The aim of the present study was to examine whether N-Methyl-D-aspartate receptors are involved in the regulation of chronic morphine-induced neuroinflammation in morphine-tolerant rats. Morphine tolerance was induced in male Wistar rats by intrathecal infusion of morphine (15 μg/h) for 5 days. Tail-flick latency was measured to estimate the antinociceptive effect of morphine. Morphine challenge (15 μg, intrathecally) on day 5 at 3h after discontinuation of morphine infusion produced a significant antinociceptive effect in saline-infused rats, but not in morphine-tolerant rats. Pretreatment with MK-801 (20 μg, intrathecally) 30 min before morphine challenge preserved its antinociceptive effect in morphine-tolerant rats. Morphine-tolerant rats expressed high levels of the pro-inflammatory cytokines interleukin-1β, interleukin-6, and tumor necrosis factor-α and the increase in interleukin-1β and interleukin-6, and tumor necrosis factor-α levels was prevented by MK-801 pre-treatment at both the protein and mRNA levels. The results show that a single dose of MK-801 reduces the increase in pro-inflammatory cytokines in the spinal cord, thus re-sensitizing neurons to the antinociceptive effect of morphine in morphine-tolerant rats. This study provides a piece of theoretical evidence that NMDA antagonist can be a therapeutic adjuvant in treating morphine tolerant patients for pain relief.