POSSIBLE ROLE OF THE N-TERMINUS OF SUBSTANCE-P IN KAINIC ACID-INDUCEDTOXICITY IN RATS

Subcutaneously administered kainic acid (KA) in the rat results in bra in damage accompanied by a behavioral response characterized by wet do g shakes (WDS), seizures and brain damage, an effect that is potentiat ed by opioids. Based on the potentiative effect of the N-terminus of s ubstance P (SP) on the ability of KA to induce behavioral responses in mice, we tested the hypothesis that the N-terminus of SP also plays a role in KA-induced neurotoxicity in rats. Pretreatment i.p. with 1 or 10 nmol of SP(1-7), a major N-terminal metabolite of the undecapeptid e SP, 15 min before administration of 12 mg/kg of KA potentiated the i ncidence of WDS. In contrast, after administration of 1 nmol of [D-Pro 2, D-Phe7]SP(1-7) (D-SP(1-7)), the D-isomer of SP(1-7) and a substance P N-terminal antagonist, the intensity of KA-induced WDS was no diffe rent from those in either the KA- or saline-injected rats. However, pr etreatment with D-SP(1-7) completely blocked the potentiative effect o f SP(1-7) on the KA-induced WDS. While the severity of KA-induced lesi ons was not significantly altered by pretreatment with 1 nmol of SP(1- 7), the effect of KA was not significantly different from that in cont rol rats when administered with 1 nmol of D-SP(1-7). These results sug gest a possible involvement of endogenous SP N-terminal activity in th e effects following subcutaneous (s.c.) administration of KA. While ad ditional studies are needed to elucidate the mechanism by which the N- terminus of SP is involved in the effects of KA, the similarity in eff ects produced by SP(1-7) and D-SP(1-7) with those previously reported after morphine and naloxone, respectively, suggests the possible invol vement of a common mechanism.