Brain a-type receptors are thought to mediate hallucinogenic effects of certain benzomorphan opiates in humans. The biochemical characterization of or receptors has been difficult because of the lack of potent and selective ligands. We report here the synthesis and characterization of a tritiated, symmetrically substituted guanidine derivative, 1,3-di(2- [

1 The selective NK, receptor antagonist, CP-99,994, produced dose-related (0.1-1.0 mg kg- ', s.c.) inhibition of vomiting and retching in ferrets challenged with central (loperamide and apomorphine), peripheral (CuS04) and mixed central and peripheral (ipecac, cisplatin) emetic stimuli. 2 Parallel studies with the enantiomer, CP-100,263 (1 mg kg-', s.c.), which is > 1 000 fold less potent as a NK1 antagonist, indicated that it was without significant effect against CuS04, loperamide, cisplatin and apomorphine-induced emesis. Against ipecac, it inhibited both retching and vomiting, expressing approximately 1/10th the potency of CP-99,994. 6 In dogs, CP-99,994 (40 gkg-' bolus and 300 jgkg-'h-', i.v.) produced statistically significant reductions in vomiting to CuS04 and apomorphine as well as retching to CuS04. 7 Together, these studies support the hypothesis that the NK, receptor antagonist properties of CP-99,994 are responsible for its broad spectrum anti-emetic effects. They also suggest that CP-99,994 acts within the brainstem, most probably within the nucleus tractus solitarius although the involvement of the area postrema could not be excluded.

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Respiratory syncytial virus (RSV) is a major respiratory pathogen in infants. The first goal of this study was to determine whether the infection following endotracheal inoculation of RSV in Fischer 344 rats results in increased inflammatory responses to substance P (SP) either released by capsaicin from sensory nerves or injected into the circulation. Five days after inoculation, the extravasation of Evans blue-labeled albumin after capsaicin or SP was significantly greater in RSV-infected airways than in pathogen-free controls. The peptide-degrading activity of the regulatory enzyme neutral endopeptidase was unaffected by RSV. However, SP(NK(1)) receptor mRNA levels increased fivefold in RSV-infected lungs, and the density of SP binding sites in the bronchial mucosa increased threefold. These data suggest that RSV makes the airways abnormally susceptible to the proinflammatory effects of SP by upregulating SP(NK(1)) receptor gene expression, thereby increasing the density of these receptors on target cells. This effect may contribute to the inflammatory reaction to the virus and could be a target for the therapy of RSV disease and its sequelae.