Role of tachykinin NK(1) and NK(2) receptors in colonic sensitivity and stress-induced defecation in gerbils.
The pharmacology of tachykinin NK receptors varies greatly among species. The aim of the present study was to assess the role of NK(1) and NK(2) receptors in mediating colorectal distension-evoked nociception and psychological stress-induced defecation in gerbils, a species with human-like NK receptor pharmacology. The effects of the selective NK(1) and NK(2) receptor antagonists, aprepitant and saredutant, on acute (1 h) restraint stress-evoked defecation and plasma adenocorticotropin (ACTH) levels in gerbils were assessed. The effects of antagonists alone or in combination on colorectal distension-evoked visceral pain in conscious gerbils were evaluated using the visceromotor response as a surrogate marker of pain. Restraint stress increased fecal pellet output 2-3-fold and plasma ACTH levels 9-fold. Aprepitant inhibited the defecatory and endocrine responses to stress by 50%, while saredutant completely normalized the same parameters. Visceral pain responses during colorectal distension were attenuated by both compounds, but aprepitant (19+/-6% inhibition, P<0.01) was slightly more effective than saredutant (10+/-9% inhibition, P<0.05). A combination of both compounds resulted in an additive effect (30+/-10% inhibition, P<0.01). The results demonstrate that NK(1) and NK(2) receptors are involved in stress-related colonic motor alterations and visceral pain responses in gerbils and that combined antagonism provides enhanced inhibition of visceral pain responses. This suggests that for therapeutic use in for instance functional gastrointestinal disorders, dual NK(1)/NK(2) receptor antagonists may provide better clinical outcome than selective compounds.
Kakol-Palm
Dorota
D
AstraZeneca R&D, Mölndal, Sweden.
Brusberg
Mikael
M
Sand
Elin
E
Larsson
Håkan
H
Martinez
Vicente
V
Johansson
Anders
A
von Mentzer
Bengt
B
Påhlman
Ingrid
I
Lindström
Erik
E
D000324:Adrenocorticotropic Hormone / Q000097:blood; D000818:Animals; D000077608:Aprepitant; D001549:Benzamides / Q000494:pharmacology; D003106:Colon / Q000187:drug effects / Q000503:physiopathology*; D003672:Defecation / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D005769:Gastrointestinal Motility / Q000187:drug effects; D005849:Gerbillinae; D008297:Male; D009025:Morpholines / Q000494:pharmacology; D064729:Neurokinin-1 Receptor Antagonists; D010146:Pain / Q000503:physiopathology; D010880:Piperidines / Q000494:pharmacology; D018040:Receptors, Neurokinin-1 / Q000502:physiology*; D018041:Receptors, Neurokinin-2 / Q000037:antagonists & inhibitors / Q000502:physiology*; D013315:Stress, Psychological / Q000503:physiopathology*
D001549:Benzamides; D009025:Morpholines; D064729:Neurokinin-1 Receptor Antagonists; D010880:Piperidines; D018040:Receptors, Neurokinin-1; D018041:Receptors, Neurokinin-2; D000077608:Aprepitant; C073839:SR 48968; D000324:Adrenocorticotropic Hormone