Possible role of the N-terminus of substance P in kainic acid-induced toxicity in rats

Subcutaneously administered kainic acid (KA) in the rat results in brain damage accompanied by a behavioral response characterized by wet dog shakes (WDS), seizures and brain damage, an effect that is potentiated by opioids. Based on the potentiative effect of the N-terminus of substance 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 undecapeptide SP, 15 min before administration of 12 mg/kg of KA potentiated the incidence of WDS. In contrast, after administration of 1 nmol of [d-Pro², 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 different from those in either the KA- or saline-injected rats. However, pretreatment with d-SP(1-7) completely blocked the potentiative effect of SP(1-7) on the KA-induced WDS. While the severity of KA-induced lesions was not significantly altered by pretreatment with 1 nmol of SP(1-7), the effect of KA was not significantly different from that in control rats when administered with 1 nmol of d-SP(1-7). These results suggest a possible involvement of endogenous SP N-terminal activity in the effects following subcutaneous (s.c.) administration of KA. While additional studies are needed to elucidate the mechanism by which the N-terminus of SP is involved in the effects of KA, the similarity in effects produced by SP(1-7) and d-SP(1-7) with those previously reported after morphine and naloxone, respectively, suggests the possible involvement of a common mechanism.