Effects of tachykinins on phosphoinositide metabolism in the hypothalamus: is the NK1 receptor involved?
Substance P (SP) has been shown to stimulate the hydrolysis of inositol phospholipids in peripheral tissues and in the brain. In mammalian peripheral tissues, three tachykinin receptor subclasses, neurokinin 1 (NK1), neurokinin 2 (NK2) and neurokinin 3 (NK3), have been identified. The purpose of our study was to pharmacologically characterize the SP receptors in the hypothalamus using phosphoinositide breakdown as a functional response. SP, previously described as a NK1 agonist, and Neurokinin A (NKA), previously described as a NK2 agonist, stimulated phosphoinositide breakdown in the hypothalamus in a dose-dependent fashion, with SP being more potent than NKA. The NK2-selective antagonist L-659,877, at a dose of 10(-6) M, abolished the effect of SP (10(-8) M) without affecting basal phosphoinositide breakdown. However, this NK2-selective antagonist did not inhibit the NKA-induced stimulation in phosphoinositide metabolism. The NK1-selective antagonist L-668,169 stimulated phosphoinositide metabolism at a concentration of 10(-6) M, but not at 10(-8) M. This NK1-receptor antagonist did not significantly inhibit the effect of SP on phosphoinositide metabolism. Spantide II, another NK1-selective antagonist, also stimulated phosphoinositide metabolism at a dose of 10(-6) M. Like L-668,169, spantide II failed to inhibit the SP-induced stimulation of phosphoinositide metabolism, and even potentiated the response to SP.(ABSTRACT TRUNCATED AT 250 WORDS)
Lebrun
C J
CJ
Department of Pharmacology, University of Heidelberg, Germany.
Wende
P
P
Steckelings
U
U
Itoi
K
K
Unger
T
T
D000818:Animals; D002217:Carbachol / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D007031:Hypothalamus / Q000187:drug effects / Q000378:metabolism*; D066298:In Vitro Techniques; D007294:Inositol / Q000378:metabolism; D008297:Male; D015288:Neurokinin A / Q000494:pharmacology*; D010446:Peptide Fragments / Q000494:pharmacology; D010456:Peptides, Cyclic / Q000494:pharmacology; D010716:Phosphatidylinositols / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D018040:Receptors, Neurokinin-1 / Q000187:drug effects / Q000502:physiology*; D013373:Substance P / Q000031:analogs & derivatives / Q000494:pharmacology*; D015320:Tachykinins / Q000037:antagonists & inhibitors
D010446:Peptide Fragments; D010456:Peptides, Cyclic; D010716:Phosphatidylinositols; D018040:Receptors, Neurokinin-1; D015320:Tachykinins; C054724:senktide; C073361:cyclo(Gln-Trp-Phe-Gly-Leu-Met); C076509:L 668169; D013373:Substance P; D007294:Inositol; D015288:Neurokinin A; D002217:Carbachol