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, 123 (3), 701-6

Ablation of Least Shrew Central Neurokinin NK1 Receptors Reduces GR73632-induced Vomiting

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Ablation of Least Shrew Central Neurokinin NK1 Receptors Reduces GR73632-induced Vomiting

Andrew P Ray et al. Behav Neurosci.

Abstract

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.

Figures

Figure 1
Figure 1
Immunolabeling of NK1R-IR following intracerebroventricular injection of saline or SSP-SAP. A) Photomicrograph of the DVC from a shrew given i.c.v. saline. Numerous NK1R-IR labeled cells and dense neuropil were present in the DVC. B) The DVC of a shrew injected with SSP-SAP i.c.v. No immunoreactivity for NK1R-IR was present. C) A segment of the small intestine from the same animal (SSP-SAP injected i.c.v.). Cells are well-stained, morphologically uniform, and demonstrate extensive NK1R-immunopositive fibers, as seen in saline-injected controls. Abbreviations: AP – area postrema; DMNX – dorsal motor nucleus of the vagus; MP – myenteric plexus; NTS – nucleus of the solitary tract. Scale bar for all sections = 50 µm.
Figure 2
Figure 2
Vomiting and scratching following administration of GR73632 to i.c.v. saline (filled circles) or SSP-SAP (open circles) pre-injected shrews. The open triangles represent a dose of 5 mg/kg GR73632 tested against the combined (i.p./i.c.v.) SSP-SAP injections. In all cases, * represents a statistically significant increase in vomiting or scratching relative to the 0 mg/kg (vehicle) control group (p < 0.05), and # represents a statistically significant decrease in vomiting or scratching relative to the corresponding dose of GR73632 in saline pre-injected controls. (A) The percentage of animals vomiting in response to the various doses of GR73632. (B) The frequency of vomiting (mean ± SEM) in response to GR73632. (C) The frequency of scratches (mean ± SEM) in response to GR73632. The ^ indicates a trend towards a significant decrease in scratching (p < 0.1) relative to the saline pre-injected control group.

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