Modulation of morphine antinociception by the brain-penetrating H2 antagonist zolantidine : detailed characterization in five nociceptive test systems

Because histamine (HA) in the CNS may be a mediator of antinociception, a detailed investigation of the effects of the brain-penetrating H2 antagonist zolantidine (ZOL) was performed on five nociceptive tests in the presence and absence of morphine (MOR) in rats. ZOL inhibited MOR antinociception on the tail flick test, although a diurnal difference (inhibition in the dark cycle >> light cycle) was found. Similar results were found with the hot plate test, although details of the test procedure were significant. In contrast, ZOL induced opposing effects on MOR antinociception on two nonthermal tests (jump test and tail pinch test); ZOL alone induced moderate antinociception on the former test and mild antinociception on the latter test. Thus, ZOL exerts differential effects on baseline nociception and on MOR antinociception that vary depending on the nociceptive test employed, the light-dark cycle of the subjects, and the degree of stress associated with the nociceptive testing. These complex effects reveal the heterogeneous nature of opiate-induced modulation of nociception, and show that ZOL is a powerful tool for studying the relationships between opiates, HA, and nociceptive mechanisms.