Effects of the tachykinin NK1 receptor antagonist, RP 67580, on central cardiovascular and behavioural effects of substance P, neurokinin A and neurokinin B.

1. We have investigated the effects of the non-peptide NK1 tachykinin receptor antagonist, RP 67580, and its inactive enantiomer, RP 68651, on the cardiovascular and behavioural responses to substance P (SP), neurokinin A (NKA) and neurokinin B (NKB) injected intracerebroventricularly (i.c.v.) in conscious rats. 2. The SP and NKA (25 pmol)-induced increases in blood pressure (BP) and heart rate (HR) were of the same magnitude. The cardiovascular responses to both peptides were associated with excessive grooming behaviour and wet dog shakes (WDS). Relative to SP, NKA was weaker in inducing hindquarter grooming (HG), but more effective in eliciting WDS. The cardiovascular response to NKB (50 pmol) comprised an increase in BP and HR, while the behavioural response was weak. 3. RP 67580 (100 pmol), injected 10 or 30 min prior to SP, effectively inhibited the cardiovascular and behavioural responses to the peptide whereas lower doses were ineffective. Pretreatment with 500 pmol of RP 67580, 10 or 30 min prior to SP, reduced the BP response. Of the behavioural manifestations, only face washing was attenuated when the antagonist was injected 10 min before SP. At 2500 pmol, the antagonist exaggerated the BP response to the peptide without affecting the behavioural response. RP 68651 (100 or 2500 pmol) did not modify the central responses to SP. 4. Neither RP 67580 nor RP 68651 (100 pmol), affected the cardiovascular and behavioural responses to NKA or NKB. 5. Our results indicate that RP 67580 is a selective and high affinity antagonist at central NK1 tachykinin receptors in the rat.