Intrathecal injection of mice with substance P or its C-terminal fragments evokes a well documented behavioral syndrome characterized by caudally-directed biting and scratching. We have previously shown that repeated injections of substance P result in naloxone-sensitive desensitization to this substance P-induced behavior, possibly through interactions of N-terminal fragments of substance P with mu opiate binding sites. The present investigation tests the hypothesis that substance P metabolites play a role in the development of desensitization to substance P by using the biting and scratching behavioral paradigm. While substance P-induced behaviors are produced by as little as 1 pmol of substance P, repeated injections of 7.5 pmol at 60-s intervals was found to be the minimum dose capable of causing desensitization. The C-terminal peptides, substance P3-11 and substance P5-11, elicited substance P-like behaviors, but repeated injection of these compounds did not result in desensitization to this behavior. In contrast to C-terminal fragments, intrathecal injection of N-terminal fragments, (substance P1-4, substance P1-7 and substance P1-9), did not elicit any overt substance P-like behaviors when administered alone, but when co-administered with substance P, decreased the magnitude of substance P-induced behaviors in a dose-related fashion. Various peptidase inhibitors significantly inhibited the catabolism of co-administered substance P. Co-administration of substance P with peptidase inhibitors enhanced and prolonged the substance P-induced behavioral episode, but also prevented the development of substance P-induced desensitization. Together these results support the hypothesis that the accumulation of endogenously generated N-terminal metabolites of substance P mediate desensitization to substance P-induced behaviors in the spinal cord. Substance P metabolism may therefore decrease ongoing substance P activity both by the hydrolysis of the C-terminal portion of substance P as well as by the production of N-terminal metabolites that are capable of inhibiting the effects of substance P.

译文

鞘内注射p物质或其C末端碎片的小鼠会引起一种有据可查的行为综合症,其特征是尾侧指向的咬伤和抓挠。我们先前已经表明,重复注射p物质会导致纳洛酮对该p物质诱导的行为敏感的脱敏,这可能是通过p物质的N末端片段与mu阿片结合位点的相互作用。本研究通过使用咬和刮擦行为范式来检验p物质代谢物在对p物质脱敏过程中起作用的假设。虽然只有1 pmol的p物质产生p物质诱导的行为,但发现以60s间隔重复注射7.5 pmol是能够引起脱敏的最小剂量。C端肽,物质P3-11和物质P5-11引起了物质P样行为,但是反复注射这些化合物并未导致对该行为的脱敏。与C末端片段相反,鞘内注射N末端片段 (物质P1-4,物质P1-7和物质P1-9) 在单独给药时不会引起任何明显的p物质样行为,但与p物质共同给药时,以剂量相关的方式降低p物质诱导的行为的程度。各种肽酶抑制剂可显着抑制共同施用的p物质的分解代谢。P物质与肽酶抑制剂的共同给药可增强和延长p物质诱导的行为发作,但也阻止了p物质诱导的脱敏反应的发展。这些结果共同支持以下假设: p物质的内源性N末端代谢物的积累介导了对p物质诱导的脊髓行为的脱敏。因此,p物质的代谢可能会通过水解p物质的C末端部分以及产生能够抑制p物质作用的N末端代谢物来降低正在进行的p物质活性。

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