Interactions of substance P antagonists with serotonin in the mouse spinal cord.
Administered intrathecally (IT) to mice, the putative substance P antagonist [D-Pro2,D-Trp7,9-substance P (DPDT) blocked substance P- and serotonin-induced reciprocal hindlimb scratching with ID50 values of 4.6 (2.9-6.9) and 3.0 (1.9-4.8) micrograms, respectively. The duration of this antagonistic effect was 90-120 min. In contrast, DPDT did not block bombesin-, somatostatin-, glycine- or glutamate-induced scratching. These data indicate that DPDT is an effective antagonist of serotonin-induced behaviors in the mouse spinal cord. Phenoxybenzamine (IT) also blocked substance P- and serotonin-induced scratching. Its onset of action was more rapid for serotonin than for DPDT implying differences in agonist-induced receptor activation. Methysergide (IT) blocked serotonin-induced scratching [ID50 = 0.7 (0.3-1.5) micrograms], but not substance P-induced scratching. Similar to DPDT, [D-Arg1,D-Trp7,9,Leu11]-substance P, [des-Arg1,D-Pro2, D-Trp7,9]-substance P(2-11) and [D-Pro4,D-Trp7,9]-substance P(4-11) blocked substance P and serotonin-induced scratching. In contrast, [D-Pro2,D-Phe7,D-Trp9]-substance P and [D-Pro4,D-Trp7,9,10]-substance P(4-11) blocked only substance P-induced scratching. Thus, some, but not all putative substance P antagonists may also be behavioral antagonists of serotonin in the mouse spinal cord.
Vaught
J L
JL
Department of Biological Research, McNeil Pharmaceutical, Spring House, PA 19477.
Scott
R
R
D000818:Animals; D004347:Drug Interactions; D008297:Male; D008784:Methysergide / Q000494:pharmacology; D051379:Mice; D010643:Phenoxybenzamine / Q000494:pharmacology; D012701:Serotonin / Q000494:pharmacology*; D013116:Spinal Cord / Q000187:drug effects / Q000502:physiology*; D013239:Stereotyped Behavior / Q000187:drug effects*; D013329:Structure-Activity Relationship; D013373:Substance P / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors* / Q000494:pharmacology
D010643:Phenoxybenzamine; D012701:Serotonin; D013373:Substance P; C032132:substance P, prolyl(2)-tryptophan(7,9)-; D008784:Methysergide