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The a ntinociceptive activity of some c entrally-administered H 2 antagonists has led to the development of improgan-like analgesics, which produce powerful suppression of pain responses when injected into the brain. Although selected H 2 and H 3 antagonists have antinociceptive activity, structure-activity studies and other results have shown that blockade of neither receptor accounts for the pain-relieving properties of these drugs. Although improgan does not act through known histamine or opioid receptors, and over 60 receptors and ion channels have been excluded as targets for improgan action, the mechanism of action of improgan remains unknown. In vivo studies have shown that improgan activates non-opioid, descending, pain-relieving circuits in both the periaqueductal gray and raphe magnus. These circuits use brain stem CB 1 receptors and spinal alpha2 adrenergic receptors, but improgan does not act directly at these receptor sites. New findings show that a variety of aromatic heterocyclic derivatives in this series can produce potent antinociception. However, all such compounds in this series may not be acting by identical mechanisms. Development of more potent, brain-penetrating derivatives may lead to the discovery of effective non-opioid analgesics.

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 CB 1 antagonist N -(piperidin-1-yl)-5-(4-chloro phenyl)-1-(2,4-dichlorophenyl)-4-methyl-1 H -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 CB 1 receptors, ruling out a direct action at these sites. To test the hypothesis that CB 1 receptors indirectly participate in improgan signaling, the effects of improgan were assessed in mice with a null mutation of the CB 1 gene with and without SR141716A pretreatment. Surprisingly, improgan induced complete antinociception in both CB 1 (−/−) and wild-type control [CB 1 (+/+)] mice. Furthermore, SR141716A inhibited improgan antinociception in CB 1 (+/+) mice, but not in CB 1 (−/−) mice. Taken together, the results show that SR141716A reduces improgan antinociception, but neither cannabinoids nor CB 1 receptors seem to play an obligatory role in improgan signaling. Present and previous studies suggest that Δ 9 -tetrahydrocannabinol may act at both CB 1 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.