The glycine/NMDA receptor antagonist (+)-HA966 enhances the peripheral effect of morphine in neuropathic rats.

Systemic opioid dosing until adequate analgesia in neuropathic pain may involve intolerable and untreatable side effects. Peripheral opioid receptor mechanisms may participate in the antinociceptive effect of systemic morphine. We evaluated the effect of peripherally injected morphine alone, and the ability of the functional antagonist at the glycine site of the N-methyl-D-aspartate (NMDA) receptor complex (+)-HA966 to modulate the antinociceptive effect of peripheral morphine in a rat model of neuropathic pain. Mononeuropathy was induced by placing four ligatures around the common sciatic nerve. Experiments were performed 2 weeks after the nerve ligature, when the pain-related behavior reached a stable maximum. Rats received injections of either subcutaneous (+)-HA966 (2.5mg/kg) or saline administered 20 min before morphine (50-150 microg injected into the nerve-injured hindpaw). The antinociceptive effect was tested against mechanical (vocalization threshold to hindpaw pressure) or thermal (struggle latency to hindpaw immersion into a 46 degrees C hot water bath) stimuli. In both tests, morphine alone (100-150 microg) produced antinociception. Pretreatment with (+)-HA966 did not potentiate the analgesic effectiveness of the two highest doses of morphine, but it did produce analgesia when combined with a low dose of morphine (50 microg), which did not produce analgesia by itself. These effects were reversed by intraplantar naloxone methiodide (50 microg injected into the nerve-injured hindpaw) indicating a peripherally opioid-mediated mechanism of action. The present studies suggested that combined administration of glycine/NMDA receptor antagonists, and peripherally acting morphine may be an interesting approach in the treatment of neuropathic pain.