Analgesic activity of substance P in rats: Apparent mediation by met-enkephalin release

Abstract

The intracerebroventricular administration of Substance P (SP) produced a marked and short-lasting increase in the threshold for vocalization and vocalization afterdischarge in the rat after electrical stimulation of the tail. This effect was blocked by naloxone and potentiated by bacitracin, a peptidase inhibitor. The analgesic effect of SP was also blocked by the concomitant intraventricular injection of the specific antibody against the opioid peptide metenkephalin but not by the antibody against β-endorphin. Anti-met-enkephalin did not block other pharmacological actions of SP. The results suggest that SP produces an analgesic effect in rats by releasing met-enkephalin at supra-spinal levels involved in pain control. The undecapeptide Substance P (SP) produces analgesia in rodents after systemic or intracerebral administration (1–5). The analgesia has been generally observed after the administration of relatively low doses of the peptide and appears to be naloxone reversible. Since SP does not bind to opiate receptors of rat brain (6, 7) and lacks any direct action on the opiate receptors of the mouse vas deferens (2), it has been hypothesized that SP produces analgesia via the release of endogeneous opioid peptides (2, 3). Another suggested possibility is the metabolism of SP to a compound that binds to opiate receptors (8). The present study was planned to explore the above mentioned possibilities. If SP induces analgesia by releasing opioid peptides such as enkephalins or β-endorphin, the effect should be prevented by concomitant administration of specific antibodies to these opioid peptides. Alternatively, if SP requires metabolism to an active compound as a prerequisite to induce analgesia, peptidase inhibition should prevent or delay the analgesic activity of the undecapeptide.