Ablation of least shrew central neurokinin NK1 receptors reduces GR73632-induced vomiting.
The neurocircuitry mediating the emetic reflex is still incompletely understood, and a key question is the degree to which central and/or peripheral components contribute to the overall vomiting mechanism. Having previously found a significant peripheral component in neurokinin NK-receptor mediated emesis, the authors undertook this study to examine the putative central component. Adult least shrews were injected intracerebroventricularly (icv) with saline or the blood-brain barrier impermeable toxin, stable substance P-saporin (SSP-SAP), which ablates cells expressing NK receptors. After 3 days, shrews were challenged intraperitoneally with the emetogenic NK agonist GR73632 at different doses, and vomiting and scratching behaviors were quantified. Ablation of NK1-bearing cells was verified immunohistochemically. Although SSP-SAP injection reduced emesis at GR73632 doses of 2.5 and 5 mg/kg, no injections completely eliminated emesis. These data demonstrate that there is both a major central nervous system component and a minor peripheral nervous system component to tachykinin-mediated vomiting. Side effects of the current generation of antiemetics could potentially be reduced by improving bioavailability of the drugs in the more potent central nervous system compartment while reducing bioavailability in the less potent peripheral compartment.
Ray
Andrew P
AP
Department of Basic Medical Sciences, College of Osteopathic Medicine of the Pacific, Western University of Health Sciences, Pomona, CA 91766, USA.
Chebolu
Seetha
S
Ramirez
Juan
J
Darmani
Nissar A
NA
D000704:Analysis of Variance; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001933:Brain Stem / Q000187:drug effects / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D005260:Female; D007150:Immunohistochemistry; D007274:Injections, Intraperitoneal; D007276:Injections, Intraventricular; D007421:Intestine, Small / Q000378:metabolism; D009197:Myenteric Plexus / Q000378:metabolism; D010446:Peptide Fragments; D010784:Photomicrography; D018040:Receptors, Neurokinin-1 / Q000819:agonists / Q000378:metabolism*; D054789:Ribosome Inactivating Proteins, Type 1 / Q000633:toxicity; D000076985:Saporins; D012788:Shrews; D013373:Substance P / Q000031:analogs & derivatives / Q000633:toxicity; D014839:Vomiting / Q000139:chemically induced* / Q000378:metabolism*
D010446:Peptide Fragments; D018040:Receptors, Neurokinin-1; D054789:Ribosome Inactivating Proteins, Type 1; C468274:substance P-saporin; C068032:GR 73632; D013373:Substance P; D000076985:Saporins