Combined systemic administration of the glycine/NMDA receptor antagonist, (+)-HA966 and morphine attenuates pain-related behaviour in a rat model of trigeminal neuropathic pain.

Abstract

Chronic constriction injury to the infraorbital nerve (CCI-ION) by loose ligatures may represent a useful model for some trigeminal neuropathic pain disorders. Activation of the N-methyl-D-aspartate (NMDA) receptor is involved in the induction and maintenance of neuropathic pain and may contribute to the poor opioid sensitivity of this syndrome. We evaluated the effect of combined systemic administration of the functional antagonist at the glycine site of the N-methyl-D-aspartate (NMDA) receptor complex, (+)-(1-Hydroxy-3-aminopyrrolodine-2-one) ((+)-HA966) with morphine on mechanical allodynia-like behaviour in CCI-ION rats. Two weeks after surgery rats with a CCI-ION displayed mechanical hyperresponsiveness to von Frey filament stimulation of the vibrissal pad with a median at 0.217 g (95% confidence limits, 0. 217-0.224) versus > or = 12.5 g pre-operative. Administration of either (+)-HA966 (2.5 mg/kg s.c.) alone or morphine (1 mg/kg i.v.) alone was devoid of effects on the mechanical hyperresponsiveness. By contrast, combined administration of (+)-HA966 and morphine (0.25, 0. 5 and 1 mg/kg i.v.) dose-dependently increased the mechanical response thresholds (peak-effects 0.745 g (0.745-0.745), 4.64 (3.3-8. 7) and 12.5 g (8.4-12.5), respectively). This effect was prevented and reversed by naloxone (0.1 mg/kg i.v.). The drug combination produced no motor deficits in animals using the rotarod test. The present results indicate that combination therapy with NMDA/glycine receptor antagonists and morphine may be a useful approach for the clinical management of trigeminal neuropathic pain disorders.