Abstract
Caffeine, an adenosine A1, A2A, and A2B receptor antagonist, is frequently used as an adjuvant analgesic in combination with nonsteroidal anti-inflammatory drugs or opioids. In this study, we have examined the effects of novel specific adenosine receptor antagonists in an acute animal model of nociception. Several A2B-selective compounds showed antinociceptive effects in the hot-plate test. In contrast, A1- and A2A-selective compounds did not alter pain thresholds, and an A3 adenosine receptor antagonist produced thermal hyperalgesia. Evaluation of psychostimulant effects of these compounds in the open field showed only small effects of some antagonists at high doses. Coadministration of low, subeffective doses of A2B-selective antagonists with a low dose of morphine enhanced the efficacy of morphine. Our results indicate that analgesic effects of caffeine are mediated, at least in part, by A2B adenosine receptors.
Footnotes
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O.M.A.-S. was on leave from the Faculty of Pharmacy (Al-Azhar University) with a scholarship of the Egyptian government. A.M.H. was on leave from the Faculty of Pharmacy (Assiut University) with a scholarship of the Egyptian government. A.Z. was supported by Deutsche Forschungsgemeinschaft (FOR425), the State of North-Rhine-Westfalia (Innovationsprogramm Forschung), and the BONFOR Program. C.E.M. was supported by the Deutsche Forschungsgemeinschaft (FOR425).
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DOI: 10.1124/jpet.103.056036.
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ABBREVIATIONS: CNS, central nervous system; DPCPX, 8-cyclopentyl-1,3-dipropylxanthine; PSB-36, 1-butyl-8-(3-noradamantyl)-3-(3-hydroxypropyl)xanthine; DMPX, 3,7-dimethyl-1-propargylxanthine; MSX-3, phosphoric acid mono-(3-{8-[2-(3-methoxyphenyl)vinyl]-7-methyl-2,6-dioxo-1-prop-2-ynyl-1,2,6,7-tetrahydropurin-3-yl}propyl)ester; PSB-50, 8-(p-bromophenyl)-1-propargylxanthine; PSB-53, 4-(1-butylxanthin-8-yl)-benzoic acid; PSB-1115, 1-propyl-8-(p-sulfophenyl)xanthine; PSB-55, 8-{4-[2-(4-benzylpiperazin-1-yl)-2-oxo-ethoxy]phenyl}-1-butylxanthine; enprofylline, 3-propylxanthine; PSB-10, (R)-8-ethyl-4-methyl-2-(2,3,5-trichlorophenyl)-4,5,7,8-tetrahydro-1H-imidazo[2,1-i]purin-5-one; 8-SPT, 8-(p-sulfophenyl)theophylline; 8-SPC, 8-(p-sulfophenylcaffeine); THC, Δ9-tetrahydrocannabinol; MPE, maximal possible effect; ANOVA, analysis of variance; 7-(2-phenylethyl)-5-amino-2-(2-furyl)-pyrazolo-[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine.
- Received July 1, 2003.
- Accepted August 21, 2003.
- The American Society for Pharmacology and Experimental Therapeutics
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Antinociceptive Effects of Novel A2B Adenosine Receptor Antagonists
