Abstract

Using a rat tail-flick analgesic assay that uses a cold water-ethylene glycol mixture (-10 degrees C) as the noxious stimulus, we have been able to demonstrate a dose-related, naloxone-reversible analgesic effect for dynorphin A (1-17), the proposed endogenous ligand for the kappa receptor. Male Sprague-Dawley rats were implanted surgically with cannulas in the right lateral ventricle at least 1 week before testing. Five microliters of either drug or saline, followed by a 3-microliter saline flush, were administered. Nociceptive threshold was measured as the latency for the rat to flick or remove its tail from the bath solution after immersion. Dynorphin produced a dose-related analgesia at doses of 1 to 50 micrograms i.c.v., reaching 100% maximum possible analgesia (compared to predrug base line) at the highest dose. We found similar dose-related analgesia when we tested the selective mu agonist [Try-D-Ala-Gly-NMe-Phe-Gly-ol] (0.01-1 microgram), the selective kappa receptor ligand U-50,488H (100-500 micrograms), the selective delta agonist [D-Pen2,5]-enkephalin (50-200 micrograms) and beta-endorphin (0.1-10 micrograms). Naloxone (1.0 mg/kg) was able to block the antinociceptive effect of all but the highest doses of dynorphin, which required 10.0 mg/kg of naloxone. When we compared the same dosages of dynorphin using hot water (55 degrees C) as the noxious stimulus, no antinociception was observed. Although we do not known the mechanisms responsible for the differences between the hot and cold water tests, it may be that the cold water tail-flick test, which is able to assess the antinociceptive activity of both opioid agonists and mixed agonist-antagonists, is a more sensitive measure of the type of analgesia mediated by kappa receptors.