Vol. 299, Issue 1, 105-113, October 2001

Combinations of Neurokinin Receptor Antagonists Reduce Visceral Hyperalgesia

Elizabeth H. Kamp, Daniel R. Beck and G. F. Gebhart

Department of Pharmacology, College of Medicine, The University of Iowa, Iowa City, Iowa

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 µg of SR140,333) and NK2R (up to 60 µg of SR48,968) antagonists tested failed to significantly affect responses to the noxious visceral stimulus. However, coadministration of 3 µg of SR140,333 and 60 µg of SR48,968 (both i.th.) significantly reduced responses to noxious CRD (p < 0.05 versus vehicle). The NK3R antagonist (60 µg 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.