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Research ArticleNEUROPHARMACOLOGY

Combinations of Neurokinin Receptor Antagonists Reduce Visceral Hyperalgesia

Elizabeth H. Kamp, Daniel R. Beck and G. F. Gebhart
Journal of Pharmacology and Experimental Therapeutics October 2001, 299 (1) 105-113;
Elizabeth H. Kamp
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Daniel R. Beck
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G. F. Gebhart
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Abstract

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.

Footnotes

  • This study was supported by National Institutes of Health Grants NS19912 and DA02879 to G.F.G.. E.H.K. was supported by T32 GM07069.

  • Abbreviations:
    SP
    substance P
    NKA
    neurokinin A
    NKB
    neurokinin B
    NK1R
    neurokinin 1 receptor(s)
    NK2R
    neurokinin 2 receptor(s)
    NK3R
    neurokinin 3 receptor(s)
    NKR
    neurokinin receptor(s)
    CRD
    colorectal distension
    EMG
    electromyographic
    i.th.
    intrathecal(ly)
    AUC
    area under the curve
    ANOVA
    analysis of variance
    DMSO
    dimethyl sulfoxide
    MPO
    myeloperoxidase
    IBS
    irritable bowel syndrome
    • Received December 12, 2000.
    • Accepted June 22, 2001.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 299 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 299, Issue 1
1 Oct 2001
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Research ArticleNEUROPHARMACOLOGY

Combinations of Neurokinin Receptor Antagonists Reduce Visceral Hyperalgesia

Elizabeth H. Kamp, Daniel R. Beck and G. F. Gebhart
Journal of Pharmacology and Experimental Therapeutics October 1, 2001, 299 (1) 105-113;

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Research ArticleNEUROPHARMACOLOGY

Combinations of Neurokinin Receptor Antagonists Reduce Visceral Hyperalgesia

Elizabeth H. Kamp, Daniel R. Beck and G. F. Gebhart
Journal of Pharmacology and Experimental Therapeutics October 1, 2001, 299 (1) 105-113;
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