Inhibition of improgan antinociception by the cannabinoid (CB)(1) antagonist N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide (SR141716A): lack of obligatory role for endocannabinoids acting at CB(1) receptors.

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-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 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 Delta(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.

[Postoperative, intra-abdominal adhesions--a new standardized and objective animal model and testing of substances for the prevention of adhesions]. / Postoperative, intraabdominelle Adhäsionen--Ein neues standardisiertes und objektiviertes Tiermodell und Testung von Substanzen zur Adhäsionsprophylaxe.

80 male Sprague Dawley rats were divided in 8 groups of equal size. After median laparotomy defined abrasions of the serosa of abdominal wall, cecum and ileum were performed (400p, abrasive paper 280 grains/cm2, 8 cm2). The control group (I) received no medication. In the treatment groups 5 ml of the following agents were instilled before closure of the abdominal wall: normal saline (II), 16,250 IE Neomycin with 1250 IE Bacitracin (III), 30% dextrose (MW 70,000) (IV), 50,000 IE Streptokinase with 12,500 IE Streptodornase (V), or TCDO in concentrations of 10% (VI), 50% (VII), and 100% (VIII). All animals were relaparotomized on the 7th postoperative day, the adhesions were dissected and their extent was calculated by computer aid. Furthermore specimens were obtained for microscopic studies. Compared to the controls no reduction of adhesions could be achieved by dextrose. Significantly more adhesions were observed after treatment with Neomycin/Bacitracin. A reduction of about 23% was registered with normal saline and TCDO 10%. The greatest reduction of adhesions was seen after application of Streptokinase/Streptodornase as well as TCDO in concentrations of 50% and 100% (63%). The results were significant after evaluation with the t-test. Histologically there was a correlation between the extent of adhesions and the fibrin film. The new animal model has proven to result in reproducible data if used to evaluate substances for prevention of adhesions. Clinical studies with the best of these agents could serve as an approach to solve the problem of adhesion ileus.