Modulation of kainic acid-induced activity in the mouse spinal cord by the amino terminus of substance P: Sensitivity to opioid antagonists

A. A. Larson, X. Sun

Research output: Contribution to journalArticlepeer-review

13 Scopus citations

Abstract

Behavioral sensitization to kainic acid (KA) in the mouse spinal cord appears to be mediated by the amino (N) terminus of substance P (SP), as potentiation of KA is sensitive to capsaicin, mimicked by SP1-7 but not SP5- 11, and blocked by SP1-7 antagonists but not by neurokinin antagonists. As naloxone inhibits some effects of SP1-7, this study examines the role of opioid receptors in the mediation of KA-induced sensitization by the N terminus of SP. All drugs were injected i.t. Behavioral sensitization to repeated injections of KA was inhibited by a large (1 μg) dose of naloxone. Pretreatment with either naloxonazine or β-funaltrexamine, μ-selective opioid antagonists, naltrindole, a δ selective opioid antagonist, or nor- binaltorphimine, a κ-selective antagonist, failed to alter the development of sensitization to KA, indicating that this phenomenon is not due to μ, δ or κ opioid receptors. The ability of 22.5 pmol of SP1-7 to enhance subsequent KA responses was blocked when coadministered with 0.1 μg of naloxone. When administered with KA, naloxone not only failed to reverse the potentiative effect of SP1-7, but further enhanced responses to KA for 2 hr after SP1-7. In contrast to pretreatment with SP1-7, coadministration of KA with SP1-7 inhibited the intensity of behaviors. The inhibitory effect of SP1-7 on responses to a single injection of KA was prevented by pretreatment with naltrindole, whereas pretreatment with β-funaltrexamine blocked the inhibitory effect of SP1-7 on responses to KA in a KA-sensitized animal. These data suggest that inhibitory effects of SP1-7 on KA are mediated by μ and δ opioid receptors, whereas potentiation of KA by SP1-7 is mediated by a novel, nonopioid SP N-terminal binding site which may play a role in pain. Excitatory effects of SP1-7 are prevented but not readily reversed by naloxone, suggesting a role in opioid withdrawal.

Original languageEnglish (US)
Pages (from-to)159-165
Number of pages7
JournalJournal of Pharmacology and Experimental Therapeutics
Volume265
Issue number1
StatePublished - 1993

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