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 response to noxious colorectal distension (CRD) was examined. NKR antagonists or vehicle were given intrathecally (i.th.) to rats made hyperalgesic by intracolonic instillation of zymosan or after intracolonic instillation of saline (control). Given alone, the NK1R (up to 3 microg of SR140,333) and NK2R (up to 60 microg of SR48,968) antagonists tested failed to significantly affect responses to the noxious visceral stimulus. However, coadministration of 3 microg of SR140,333 and 60 microg of SR48,968 (both i.th.) significantly reduced responses to noxious CRD (p < 0.05 versus vehicle). The NK3R antagonist (60 microg of SR142,801) significantly reduced responses to noxious CRD when given alone to either hyperalgesic (zymosan-treated) or normal (saline-treated) rats (p < 0.05 versus vehicle for both groups). Responses of rats receiving the NK3R antagonist in combination with either the NK1R or the NK2R antagonist were not different from rats receiving the NK3R antagonist alone. These 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.