The tachykinin NK1 receptor antagonist GR205171 abolishes the retching activity of neurons comprising the central pattern generator for vomiting in dogs.
Tachykinin NK1 receptor antagonists are known to act centrally and to have broad-spectrum antiemetic effects, but their precise site of action has not yet been defined. To identify this site, the effects of the NK1 receptor antagonist GR205171 on the activities of neurons comprising the central pattern generator (CPG) for vomiting were observed in decerebrate paralyzed dogs. A non-respiratory neuron in each of nine dogs was considered to be a CPG neuron based on its response to abdominal vagal stimulation, its location in the CPG area in the reticular formation dorsomedial to the retrofacial nucleus, its firing patterns in prodromal and retching phases and its response to apomorphine. In response to vagal stimulation at 3-10 Hz, the firing of these neurons transiently increased at the onset of stimulation (fast component), gradually increased again (slow component), and finally developed into rhythmic bursts synchronous with retching bursts of the phrenic and abdominal muscle nerves. GR205171 (25-50 microg/kg, i.v.) abolished the slow component and retching bursts in the neurons, and the retching activities of both nerves, but did not change the fast component. The responses of these neurons to repetitive pulse-train vagal stimulation exhibited a vigorous 'wind-up' and finally developed into retching bursts. Both the 'wind-up' phenomenon and retching bursts disappeared after the application of GR205171. These results suggest that the site of the antiemetic action of NK1 receptor antagonists is located in the CPG or in the pathway connecting the solitary nucleus to the CPG.
Fukuda
H
H
Department of Physiology, Kawasaki Medical School, Kurashiki, Japan.
Koga
T
T
Furukawa
N
N
Nakamura
E
E
Shiroshita
Y
Y
D000818:Animals; D000932:Antiemetics / Q000494:pharmacology*; D001058:Apomorphine / Q000494:pharmacology; D003655:Decerebrate State / Q000503:physiopathology; D004285:Dogs; D004558:Electric Stimulation; D004639:Emetics / Q000494:pharmacology; D005260:Female; D008297:Male; D064729:Neurokinin-1 Receptor Antagonists; D009474:Neurons / Q000187:drug effects* / Q000502:physiology*; D010880:Piperidines / Q000494:pharmacology*; D012154:Reticular Formation / Q000166:cytology / Q000187:drug effects / Q000503:physiopathology*; D013777:Tetrazoles / Q000494:pharmacology*; D014630:Vagus Nerve / Q000503:physiopathology; D014839:Vomiting / Q000503:physiopathology*
D000932:Antiemetics; D004639:Emetics; D064729:Neurokinin-1 Receptor Antagonists; D010880:Piperidines; D013777:Tetrazoles; C103207:vofopitant; D001058:Apomorphine