Endothelin-1, -2 and -3 directly and big-endothelin-1 indirectly elicit an abdominal constriction response in mice.
When injected intraperitoneally into mice, endothelins ET-1, ET-2, ET-3 and big-endothelin-1[1-38] (big-ET-1[1-38]) produced a dose-related, robust and easily quantified abdominal constriction response within 20 min. The ED50 values for this response were 0.026, 0.005, 0.131, and 0.043 mg/kg, respectively. Hence, this test could provide a convenient in vivo endpoint for endothelin activity. The results also imply that ET-1, ET-2, ET 3 or big-ET-1[1-38] may be nociceptive under certain conditions. Morphine (4 mg/kg, s.c.) administered 30 min prior completely blocked the response produced by ET-1. Thus, in conjunction with other indicators, the test may also serve as an in vivo screen for agents useful in the treatment of abdominal or visceral pain. The effect of big-ET-1[1-38], but not ET-1, was blocked by pretreatment with the enzyme inhibitor phosphoramidon (10 mg/kg, s.c., 30 min prior), implying that the big-ET-1[1-38] must first be enzymatically cleaved, presumably to ET-1, in order to elicit the abdominal constriction response. This test might also serve as a discriminative antinociceptive screen, because the response to ET-1 was not blocked by acetaminophen (400 mg/kg, p.o.), ibuprofen (75 mg/kg, p.o.) or indomethacin (1.0 mg/kg, p.o.).
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Drug Discovery Research, R.W. Johnson Pharmaceutical Research Institute, Spring House, PA 19477-0776.
Jacoby
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D000005:Abdomen / Q000502:physiology*; D000009:Abdominal Muscles / Q000187:drug effects*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D003251:Constriction, Pathologic / Q000139:chemically induced; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D016232:Endothelins / Q000008:administration & dosage / Q000494:pharmacology*; D007274:Injections, Intraperitoneal; D007279:Injections, Subcutaneous; D008297:Male; D051379:Mice; D009020:Morphine / Q000008:administration & dosage / Q000494:pharmacology; D010146:Pain / Q000188:drug therapy; D010865:Pilot Projects; D013997:Time Factors
D016232:Endothelins; D009020:Morphine