Major metabolites of substance P degraded by spinal synaptic membranes antagonize the behavioral response to substance P in rats

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Abstract
Substance P (SP) was degraded by synaptic membranes of rat spinal cord. Cleavage products were separated by reversed phase high performance liquid chromatography and identified by amino acid composition analyses. Major products of SP were phenylalanine, SP(1-4), SP(1-6), SP(1-7), SP(10-11), and SP(8-9). Both the degradation of SP and the accumulation of the major cleavage products were strongly inhibited by a metal chelator, o-phenanthroline, and also by specific inhibitors of endopeptidase-24.11, thiorphan, and phosphoramidon. Thus, endopeptidase-24.11 plays a major role in SP degradation in the rat spinal cord. N-Terminal fragments, SP(1-7) and SP(1-4), detected after incubation with spinal synaptic membranes were examined in vivo for antagonism against the scratching, biting, and licking response induced by intrathecal (IT) injection of SP (3.0 nmol) in rats. When IT coadministered with SP, SP(1-7) and SP(1-4) produced a significant inhibition of behavioral response to SP with ED50 of 135.0 pmol and 6.2 nmol, respectively. These results suggest that the degradation of SP in the spinal cord is not only responsible for inactivation of parent peptide, but may also lead to the formation of N-terminal SP-fragments which are shown to display a novel physiological function.