Intrathecal substance P (1-7) prevents morphine-evoked spontaneous pain behavior via spinal NMDA-NO cascade.

摘要

Previous research has shown that injection of high-dose of morphine into the spinal lumbar intrathecal (i.t.) space of rats elicits an excitatory behavioral syndrome indicative of severe vocalization and agitation. Substance P N-terminal fragments are known to inhibit nociceptive responses when injected i.t. into animals. In this study, we investigated the effect of i.t. substance P (1-7) on both the nociceptive response and the extracellular concentrations of glutamate and nitric oxide (NO) metabolites (nitriteitrate) evoked by high-dose i.t. morphine (500nmol). The induced behavioral responses were attenuated dose-dependently by i.t. pretreatment with the substance P N-terminal fragment substance P (1-7) (100-400pmol). The inhibitory effect of substance P (1-7) was reversed significantly by pretreatment with [d-Pro(2), d-Phe(7)]substance P (1-7) (20 and 40nmol), a d-isomer and antagonist of substance P (1-7). In vivo microdialysis analysis showed a significant elevation of extracellular glutamate and NO metabolites in the spinal cord after i.t. injection of high-dose morphine (500nmol). Pretreatment with substance P (1-7) (400pmol) produced a significant reduction on the elevated concentrations of glutamate and NO metabolites evoked by i.t. morphine. The reduced levels of glutamate and NO metabolites were significantly reversed by the substance P (1-7) antagonist (40nmol). The present results suggest that i.t. substance P (1-7) may attenuate the excitatory behavior (vocalization and agitation) of high-dose i.t. morphine by inhibiting the presynaptic release of glutamate, and reducing NO production in the dorsal spinal cord.