Substance P analogues containing D-histidine antagonize the behavioural effects of intrathecally co-administered substance P in mice.
The antagonistic effect of newly synthesized substance P (SP) analogues containing D-histidine was examined on behavioural responses induced in mice by SP, neurokinin (NK) A, physalaemin, eledoisin, somatostatin and bombesin. [D-Pro2,D-Trp7,9]SP (DPDT-SP) and [D-Arg1,D-Trp7,9,Leu11]SP (spantide) were used as references for comparison. When co-administered with SP intrathecally, all the SP analogues used decreased the SP-induced response which consists of scratching, biting and licking. DPDT-SP and spantide attenuated non-specifically the SP-like behavioural responses induced by physalaemin, eledoisin, NK A and somatostatin. In general, the introduction of D-histidine in position 9 of the SP molecule resulted in potent antagonistic activity of the SP derivative on the behavioural responses to SP. Of these SP analogues, [D-Arg1,D-Pro2,4,D-Phe7,D-His9]SP attenuated selectively the behavioural responses produced by NK-1 receptor agonists such as SP and physalaemin. Simultaneous injection of [D-Phe7,D-His9]SP-(6-11) selectively inhibited the SP-induced behavioural response without affecting the other peptide-induced behavioral response. The results suggest that the behavioural antagonism induced by [D-Arg1,D-Pro2,4,D-Phe7,D-His9]SP and [D-Phe7,D-His9]SP-(6-11) is probably due to the specific blockade of spinal NK-1 receptors.
Sakurada
T
T
Department of Pharmacology, Tohoku College of Pharmacy, Sendai, Japan.
Yamada
T
T
Sakurada
S
S
Kisara
K
K
Ohba
M
M
D000595:Amino Acid Sequence; D000818:Animals; D001362:Avoidance Learning / Q000187:drug effects; D001522:Behavior, Animal / Q000187:drug effects*; D006639:Histidine / Q000032:analysis* / Q000494:pharmacology; D007278:Injections, Spinal; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000494:pharmacology*; D010455:Peptides / Q000494:pharmacology; D011597:Psychomotor Performance / Q000187:drug effects; D011761:Pyrrolidonecarboxylic Acid / Q000031:analogs & derivatives; D013329:Structure-Activity Relationship; D013373:Substance P / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D015320:Tachykinins / Q000494:pharmacology
D010446:Peptide Fragments; D010455:Peptides; D015320:Tachykinins; D013373:Substance P; D006639:Histidine; C032292:substance P (6-11); C042867:spantide; D011761:Pyrrolidonecarboxylic Acid