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Vol. 292, Issue 2, 538-544, February 2000

Effects of Spinal Cholecystokinin Receptor Antagonists on Morphine Antinociception in a Model of Visceral Pain in the Rat1

Ann E. Friedrich and Gerald F. Gebhart

Department of Pharmacology, University of Iowa College of Medicine, Bowen Science Building, Iowa City, Iowa.

The objective of the present study was to determine the effects of spinal cholecystokinin (CCK) receptor antagonists on morphine antinociception in a model of visceral nociception, colorectal distension, in rats with chronic colonic inflammation and vehicle-treated controls. Three to five days after intracolonic instillation of 2,4,6-trinitrobenzenesulfonic acid (TNBS), an enhanced visceromotor response to all pressures of colorectal distension (10-80 mm Hg) was evident. The ED50 of intrathecal morphine (0.93 µg) in vehicle-treated rats produced significantly greater antinociception in TNBS-treated rats. Intrathecal proglumide, a nonselective CCK receptor antagonist, dose dependently enhanced the antinociceptive effect of morphine in vehicle-treated rats, but not in TNBS-treated rats. Similarly, L-365,260, a specific CCKB receptor antagonist, dose dependently increased morphine's antinociceptive effects in vehicle-treated rats but had no effect in rats with TNBS-induced colonic inflammation. L-364,718, a specific CCKA receptor antagonist, had no effect on morphine antinociception in either vehicle-treated or TNBS-treated rats. These data indicate that CCK, acting at the CCKB receptor, is involved in modulating morphine antinociception following a noxious visceral stimulus. However, CCK receptor antagonists no longer enhance morphine antinociception after instillation of intracolonic TNBS, suggesting that visceral inflammation may lead to a reduction in spinal CCK release.

1 Supported by Grants NS 199121 and F31 DA 05852 (to A.E.F.).

0022-3565/00/2922-0538$03.00/0
THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Copyright © 2000 by The American Society for Pharmacology and Experimental Therapeutics


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