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.
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Acknowledgements. This research was supported by U.S. Public Health Service Grants DA04090, DA04190 and DA00124 to A.A.L. We gratefully acknowledge the technical assistant of Paul R. Staab and the editorial advice of Drs. Julie S. Kreeger, Virginia Goettl and Darrell D. Mousseau.
- Excitatory amino acid
- Kainic acid
- Substance P
- Wet dog shake