Abstract
Improgan, a nonopioid antinociceptive agent, activates descending, pain-relieving mechanisms in the brain stem, but the receptor for this compound has not been identified. Because cannabinoids also activate nonopioid analgesia by a brain stem action, experiments were performed to assess the significance of cannabinoid mechanisms in improgan antinociception. The cannabinoid CB1 antagonistN-(piperidin-1-yl)-5-(4-chloro phenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide (SR141716A) induced dose-dependent inhibition of improgan antinociception on the tail-flick test after i.c.v. administration in rats. The same treatments yielded comparable inhibition of cannabinoid {R-(+)-(2,3-dihydro-5-methyl-3-[(4-mor pholinyl)methyl]pyrol[1,2,3-de]-1,4-benzoxazin-6-yl)(1-naphthalenyl)methanone monomethanesulfonate, WIN 55,212-2} analgesia. Inhibition of improgan and WIN 55,212-2 antinociception by SR141716A was also observed in Swiss-Webster mice. Radioligand binding studies showed no appreciable affinity of improgan on rat brain, mouse brain, and human recombinant CB1 receptors, ruling out a direct action at these sites. To test the hypothesis that CB1 receptors indirectly participate in improgan signaling, the effects of improgan were assessed in mice with a null mutation of the CB1 gene with and without SR141716A pretreatment. Surprisingly, improgan induced complete antinociception in both CB1 (−/−) and wild-type control [CB1 (+/+)] mice. Furthermore, SR141716A inhibited improgan antinociception in CB1 (+/+) mice, but not in CB1 (−/−) mice. Taken together, the results show that SR141716A reduces improgan antinociception, but neither cannabinoids nor CB1 receptors seem to play an obligatory role in improgan signaling. Present and previous studies suggest that Δ9-tetrahydrocannabinol may act at both CB1 and other receptors to relieve pain, but no evidence was found indicating that improgan uses either of these mechanisms. SR141716A will facilitate the study of improgan-like analgesics.
Footnotes
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This work was supported by National Institute on Drug Abuse Grants DA-03816 (to L.B.H.) and DA-06888 (to S.K.D.).
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DOI: 10.1124/jpet.102.036251
- Abbreviations:
- CB
- cannabinoid
- SR141716A
- N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide
- WIN55,212-2
- R-(+)-(2,3-dihydro-5-methyl-3-[(4-morpholinyl)methyl] pyrol [1,2,3-de]-1,4-benzoxazin-6-yl)(1-naphthalenyl)methanone monomethanesulfonate
- THC
- Δ9-tetrahydrocannabinol
- DMSO
- dimethyl sulfoxide
- ANOVA
- analysis of variance
- Received March 22, 2002.
- Accepted June 11, 2002.
- The American Society for Pharmacology and Experimental Therapeutics
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