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 ۱۲ hr for ۷ continuous days and its anti-nociceptive responses were measured on days ۱, ۴ and ۷ using the hot-plate test following the first day of administration. Orexin-A was used at a dose of ۱۰۰ 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 ۵, ۱۵, and ۳۰ 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 ۴ to day ۷. 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 ۷ 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.

Keywords:

Anti-nociception , Hot plate , Orexin-A , Tolerance