repeated injections of orexin-a developed behavioral tolerance to its analgesic effects in rats

objective(s):reduction of pharmacological effectiveness or tolerance appears following repeated administration of many analgesic drugs. we investigated tolerance to anti-nociceptive effects of orexin-a, an endogenous potent analgesic peptide using the hot-plate test.materials and methods:orexin-a was microinjected icv (intracerebroventricular) with an interval of 12 hr for 7 continuous days and its anti-nociceptive responses were measured on days 1, 4 and 7 using the hot-plate test following the first day of administration. orexin-a was used at a dose of 100 pmol to induce analgesic effects. results:icv administration of orexin-a produced an effective anti-nociception on the first day of experiment as measured by hot-plate 5, 15, and 30 min after the injection, in comparison with both baselines (hot-plate test one day before the beginning of orexin-a administration and control, saline-administrated group). however, repeated administration of orexin-a on the following days revealed a significant reduction in this analgesic effect during day 4 to day 7. however, to rule out any associative tolerance resulting from learning related to experimental procedures and/or environmental cues, a single injection of orexin-a was administrated to animals of control group (which were receiving saline during 7 days of experiments) and the analgesic effect was observed. conclusion:these results, for the first time, indicated the appearance of tolerance to anti-nociceptive effects of orexin-a, following repeated administrations of this agent.