Combinations of neurokinin receptor antagonists reduce visceral hyperalgesia

The effect of selective neurokinin receptor (NKR) antagonists for the NK1R (SR140,333), NK2R (SR48,968), and NK3R (SR142,801) on the visceromotor resp onse to noxious colorectal distension (CRD) was examined. NKR antagonists o r vehicle were given intrathecally (i.th.) to rats made hyperalgesic by int racolonic instillation of zymosan or after intracolonic instillation of sal ine (control). Given alone, the NK1R (up to 3 mug of SR140,333) and NK2R (u p to 60 mug of SR48,968) antagonists tested failed to significantly affect responses to the noxious visceral stimulus. However, coadministration of 3 mug of SR140,333 and 60 Ag of SR48,968 (both i.th.) significantly reduced r esponses to noxious CRD (p < 0.05 versus vehicle). The NK3R antagonist (60 <mu>g of SR142,801) significantly reduced responses to noxious CRD when giv en alone to either hyperalgesic (zymosan-treated) or normal (saline-treated ) rats (p < 0.05 versus vehicle for both groups). Responses of rats receivi ng the NK3R antagonist in combination with either the NK1R or the NK2R anta gonist were not different from rats receiving the NK3R antagonist alone. Th ese results suggest that activation of spinal NK1R and NK2R, presumably by their endogenous ligands (substance P and neurokinin A), maintain visceral hyperalgesia and support the notion that activation of NK3R (presumably by neurokinin B) is pronociceptive.