Further studies on the effects of selective neurokinin agonists upon the activation of micturition reflex in rats. Evidence for a dual NK-1 receptor mediated excitatory and inhibitory activity.
The ability of SP and some selective agonists for NK-1, NK-2 and NK-3 receptor subtypes to interfere with the micturition reflex after intra-arterial (i.a.) or intracerebroventricular (i.c.v.) administration was investigated in the urethane anaesthetized rat. When administered i.a. SP, the selective NK-1 agonist GR 73632 and the selective NK-2 agonists GR 64349 were equipotent to activate micturition reflex, both the tonic or rhythmic bladder contractions. GR 73632 but not GR 64349-induced activation of micturition reflex was antagonized in a dose-dependent manner by the selective NK-1 antagonist GR 82334. After i.c.v. administration SP, GR 73632 and the selective NK-1 agonist [Sar9,Met(0(2))11]-SP but not GR 64349 inhibited saline-induced activation of rhythmic bladder contractions; the order of potency was GR 73632 > [Sar9,Met(0(2))11]SP >> SP. Also the inhibitory effect of GR 73632 was dose-dependently affected by GR 82334. In the two models the selective NK-3 agonist senktide both after i.a. or i.c.v. administration induced neither excitatory or inhibitory activity. These findings suggest that neurokinins activate at the peripheral level the micturition reflex by an interaction at NK-1 and NK-2 receptor subtypes. In addition, NK-1 receptors appear to modulate, at the central level, the inhibition of the micturition reflex.
Palea
S
S
Pharmacology Department, Glaxo Research Laboratories, Verona, Italy.
Dalforno
G
G
Gaviraghi
G
G
Hagan
R M
RM
Trist
D G
DG
Pietra
C
C
D000818:Animals; D004305:Dose-Response Relationship, Drug; D007269:Injections, Intra-Arterial; D007276:Injections, Intraventricular; D008297:Male; D015288:Neurokinin A / Q000031:analogs & derivatives* / Q000494:pharmacology; D010446:Peptide Fragments / Q000494:pharmacology*; D010803:Physalaemin / Q000031:analogs & derivatives* / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D018041:Receptors, Neurokinin-2; D017981:Receptors, Neurotransmitter / Q000145:classification / Q000187:drug effects / Q000502:physiology*; D012018:Reflex / Q000187:drug effects*; D013373:Substance P / Q000031:analogs & derivatives* / Q000494:pharmacology*; D001743:Urinary Bladder / Q000294:innervation; D014554:Urination / Q000187:drug effects* / Q000502:physiology
D010446:Peptide Fragments; D018041:Receptors, Neurokinin-2; D017981:Receptors, Neurotransmitter; C054724:senktide; C062618:substance P, Sar(9)-Met(O2)(11)-; C079014:GR 82334; C068032:GR 73632; C068031:neurokinin A (3-10), lysyl(3)-glycyl(8)-R-lactam-leucine(9)-; D010803:Physalaemin; D013373:Substance P; D015288:Neurokinin A