Abstract
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 CCKBreceptor 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.
Footnotes
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Send reprint requests to: A. E. Friedrich, Department of Pharmacology, University of Iowa College of Medicine, Bowen Science Building, Iowa City, IA 52242-1109. E-mail: ann-friedrich{at}uiowa.edu
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↵1 Supported by Grants NS 199121 and F31 DA 05852 (to A.E.F.).
- Abbreviations:
- CCK
- cholecystokinin
- CRD
- colorectal distension
- i.th.
- intrathecal
- EMG
- electromyographic
- TNBS
- 2,4,6-trinitrobenzenesulfonic acid
- VMR
- visceromotor response
- DMSO
- dimethyl sulfoxide
- MPO
- myeloperoxidase
- AUC
- area under the curve
- Received July 23, 1999.
- Accepted October 14, 1999.
- The American Society for Pharmacology and Experimental Therapeutics
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