Characterization of endothelin-induced nociception in mice: evidence for a mechanistically distinct analgesic model.
The behavioral response elicited in mice by an i.p. injection of endothelin-1 (ET-1) (0.1 mg/kg) was differentiated from that elicited by standard agents such as acetylcholine (ACh) (5.5 mg/kg) or phenyl-p-quinone (PpQ) (1.25 mg/kg). First, there was lack of two-way "cross-tolerance' between test paradigms. That is, at equieffective doses, a 60-min prior i.p. injection of ET-1 blocked the behavioral response to a subsequent i.p. injection of ET-1 or PpQ, but not of ACh, whereas a 60-min prior injection of ACh or of PpQ had no effect on a subsequent i.p. injection of ACh, PpQ or ET-1. Second, differential antagonism of ET-1-, ACh- or PpQ-induced responses was observed in an examination of 36 test compounds. For example, cyclo-oxygenase inhibitors such as indomethacin and ibuprofen did not block the ET-1-induced response at > 10 times the doses that blocked ACh- or PpQ-induced responses, whereas other compounds (such as certain benzodiazepines) inhibited ET-1-induced, but not ACh- or PpQ-induced, responses. These findings suggest that ET-1 produces a novel nociceptive stimulus, mechanistically distinct from ACh and PpQ. Hence, the ET-1-induced behavioral response in mice serves as a rapid and convenient measure of in vivo endothelin activity. In addition, this test might be a model for clinical pains not adequately treated by present analgesic agents or adequately tested by preclinical antinociceptive screens using ACh or PpQ. As such, it is a potentially valuable model for the identification of novel analgesic and other agents.
Raffa
R B
RB
R. W. Johnson Pharmaceutical Research Institute, Spring House, Pennsylvania, USA.
Schupsky
J J
JJ
Lee
D K
DK
Jacoby
H I
HI
D000109:Acetylcholine / Q000494:pharmacology; D000698:Analgesia; D000818:Animals; D004305:Dose-Response Relationship, Drug; D016232:Endothelins / Q000494:pharmacology*; D007213:Indomethacin / Q000494:pharmacology; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D008959:Models, Neurological; D009020:Morphine / Q000494:pharmacology; D010147:Pain Measurement
D016232:Endothelins; D009020:Morphine; D000109:Acetylcholine; D007213:Indomethacin