The antinociceptive effect of combined systemic administration of morphine and the glycine/NMDA receptor antagonist, (+)‐HA966 in a rat model of peripheral neuropathy

Abstract

1 We evaluated the ability of the functional antagonist at the glycine site of the N-methyl-D-aspartate (NMDA) receptor complex, (+)-(1-Hydroxy-3-aminopyrrolodine-2-one) ((+)-HA966), to modulate the antinociceptive action of systemic morphine in a rat model of neuropathic pain produced by chronic constriction injury to the sciatic nerve. Mechanical (vocalization threshold to hindpaw pressure) and thermal (struggle latency to hindpaw immersion into a water bath) stimuli were used. 2 In the mechanical test, morphine (0.05, 0.1 and 0.3 mg kg 71 , i.v.) alone produced dose-dependent e ects in both neuropathic and uninjured rats. Likewise, morphine (0.1, 0.3 and 1 mg kg 71 , i.v.) dosedependently increased struggle latencies of the nerve-injured hindpaw in the hot noxious (468C) test but was ine ective in the non-noxious warm (448C) and cold (108C) test. 3 Pretreatment with (+)-HA966 (2.5 mg kg 71 , s.c.) dose-dependently enhanced the e ect of morphine in the mechanical test with the relative potency being nerve-injured hindpaw4contralateral hindpaw4uninjured rat. 4 Likewise, (+)-HA966 dose-dependently enhanced the e ect of morphine against a hot (468C) stimulus and produced, in combination with morphine, a dose-dependent e ect against a warm (448C) stimulus. In the cold (108C) test, (+)-HA966 reversed the ine ectiveness of the highest dose of morphine. 5 Naloxone blocked the e ect of the combination of (+)-HA966 with morphine in all tests. The drug combination produced no motor de®cits in animals using the rotarod test. 6 These ®ndings suggest that combined administration of antagonists, acting at the glycine site of the NMDA receptor complex and morphine may be a promising approach in the treatment of neuropathic and acute pain.

Effects of sufentanil and NMDA antagonists on a C‐fibre reflex in the rat

“…The partial agonist at the modulatory strychnine‐insensitive glycine site of the NMDA receptor complex, (+)‐HA966, has been shown to cross the blood‐brain barrier and to be associated with fewer motor side‐effects than other NMDA receptor antagonists ( Kemp & Leeson, 1993 ). (+)‐HA966 potentiated morphine antinociception in a behavioural model of peripheral neuropathy ( Christensen et al ., 1998 ) and the reduction of carragenin‐induced c‐Fos expression in the spinal cord ( Honore et al ., 1996 ).…”

Dual ultrastructural localization of ?-opiate receptors and substance p in the dorsal horn

“…These data support the idea that NMDA receptors and the MOR are present in single dorsal horn neurons, as they are in other brain regions (Gracy et al, 1997;Wang et al, 1999), and these individual neurons are activated by SP and/or glutamate (De Biasi and Rustioni, 1988;Dougherty and Willis, 1991;Dougherty et al, 1993). This receptor colocalization is likely to underlie the efficacy of combined drug therapies aimed at MOR, NMDA, and/or tachykinin receptors, which appear to be more effective than individual drugs used alone in the treatment of pain (Christensen et al, 1998).…”

N-Methyl-D-Aspartate Receptor (NMDA) Antagonists as Potential Pain Therapeutics

“…A similar compound, [156] Thermal hyperalgesia, CCI i.th. r (+) [189] Mechanical allodynia, opiod attenuation s.c r (+) (+) [190] Mechanical allodynia, nerve injury-opiate attenuation s.c. r (+) (+) h [191] Thernmal allodynia, nerve injury -opiate attenuation s.c. r (+) (+) h [191] R(+)-HA-966 IC50 = 12. Thermal hyperalgesia, CCI i.th.…”