irl-1620 and Pain

Development of analgesic tolerance and constipation remain a major clinical concern during long-term administration of morphine in pain management. Central endothelin mechanisms are involved in morphine analgesia and tolerance. The present study was conducted to investigate the effect of intracerebroventricular (i.c.v.) and peripheral administration of endothelin ET(A) receptor antagonist, BMS182874, and endothelin ET(B) receptor agonist, IRL1620, on morphine analgesia and changes in gastrointestinal transit in male Swiss Webster mice. Results indicate that morphine (6 mg/kg, s.c.) produced a significant increase in tail flick latency compared to control group. Pretreatment with BMS182874 (50 microg, i.c.v.) significantly enhanced morphine-induced analgesia, while IRL1620 (30 microg, i.c.v.) pretreatment did not affect tail-flick latency values. Changes in gastrointestinal transit were measured by percent of distance traveled by charcoal in the small intestine of gastrointestinal tract. Percent distance traveled in morphine (6 mg/kg, s.c.) treated mice (48.45+/-5.65%) was significantly lower (P<0.05) compared to control group (85.07+/-1.82%). Administration of BMS182874 centrally (50 mug, i.c.v.) or peripherally (10 mg/kg, i.p.) did not affect morphine-induced inhibition of gastrointestinal transit. Pretreatment with IRL1620 (30 microg, i.c.v., or 10 mg/kg, i.v.) also did not affect morphine-induced inhibition of gastrointestinal transit. This study demonstrates that endothelin ET(A) receptor antagonists delivered to the CNS enhance morphine analgesia without affecting gastrointestinal transit.

Topics: Analgesics, Opioid; Animals; Dansyl Compounds; Drug Synergism; Endothelin A Receptor Antagonists; Endothelin B Receptor Antagonists; Endothelins; Gastrointestinal Transit; Injections, Intravenous; Injections, Intraventricular; Male; Mice; Morphine; Pain; Pain Measurement; Pain Threshold; Peptide Fragments; Receptor, Endothelin A; Receptor, Endothelin B; Time Factors

We showed previously that subcutaneous injection of the injury-associated peptide mediator endothelin-1 (ET-1) into the rat plantar hindpaw produces pain behavior and selective excitation of nociceptors, both through activation of ET(A) receptors likely on nociceptive terminals. The potential role of ET(B) receptor activation in these actions of ET-1-has not been examined. Therefore, in these experiments, we studied the effect of blocking or activating ET(B) receptors on ET-1-induced hindpaw flinching and excitation of nociceptors in rats. An ET(B) receptor-selective antagonist, BQ-788 (3 mm), coinjected with ET-1 (200 microm) reduced the time-to-peak of flinching and significantly enhanced the average maximal flinch frequency (MFF). In contrast, coinjection of an ET(B) receptor selective agonist, IRL-1620 (100 or 200 microm), with ET-1 reduced the average MFF and the average total number of flinches. Interestingly, this unexpected inhibitory effect of IRL-1620 was prevented by the nonselective opioid receptor antagonist naloxone (2.75 mm). To confirm these inhibitory actions, we studied the effects of IRL-1620 on ET-1-induced spike responses in single, physiologically characterized nociceptive C-fibers. IRL-1620 suppressed spike responses to ET-1 in all (n = 12) C-units, with mean and maximum response frequencies of 0.08 +/- 0.02 and 1.5 +/- 0.4 impulses/sec versus 0.32 +/- 0.07 and 4.17 +/- 0.17 impulses/sec for ET-1 alone. In additional support of the behavioral results, coinjection of naloxone (2.75 mm) completely prevented this inhibitory action of IRL-1620. These results establish that ET(B) receptor activation inhibits ET-1-induced pain behavior and nociception in a naloxone-sensitive manner and point to a previously unrecognized dual modulation of acute nociceptive signaling by ET(A) and ET(B) receptors in cutaneous tissues.

Topics: Action Potentials; Animals; Behavior, Animal; Dose-Response Relationship, Drug; Drug Antagonism; Drug Synergism; Endothelin Receptor Antagonists; Endothelin-1; Endothelins; Hindlimb; Injections, Subcutaneous; Male; Naloxone; Nerve Fibers; Nociceptors; Oligopeptides; Pain; Pain Measurement; Peptide Fragments; Piperidines; Rats; Rats, Sprague-Dawley; Reaction Time; Receptor, Endothelin B; Receptors, Endothelin