Comparison of antagonistic effects of sendide and CP-96,345 on a spinally mediated behavioural response in mice

Intrathecal administration of the tachykinin NK1 receptor agonists, substance P, physalaemin, septide and [Sar9, Met(O2)11]substance P, elicited a characteristic behavioural response consisting of scratching, biting and licking in mice. The behavioural response induced by substance P was significantly inhibited by simultaneous intrathecal injection of a tachykinin NK1 receptor antagonist, [Tyr6,D-Phe7,D-His9]substance P-(6-11) (sendide), and a non-peptide antagonist, [(2S,3S)-cis-2-(di-phenylmethyl)-N-[(2- methoxyphenyl)-methyl]-1-azabicyclo[2.2.2]octan-3-amine](CP-96,345). The duration of the antagonistic effect of sendide was similar to that of CP-96,345. The antagonistic effect of sendide on the response induced by tachykinin NK1 receptor agonists was approximately 1000 times more potent than that of CP-96,345. Neither antagonist inhibited neurokinin A-, D-septide-, neurokinin B- and eledoisin-induced scratching, biting and licking responses. Sendide was without effect on motor performance as measured by the rotarod test, while motor incoordination was elicited only 2 min after intrathecal injection of CP-96,345. These results indicate that sendide and CP-96,345 are selective antagonists of tachykinin NK1 receptors with a long duration of action.