title: Repeated injections of orexin-A developed behavioral tolerance to its analgesic effects in rats.
abstract: OBJECTIVE
  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.
  
  
  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.
  
  
  CONCLUSIONS
  These results, for the first time, indicated the appearance of tolerance to anti-nociceptive effects of orexin-A, following repeated administrations of this agent.
authors.affiliation: Cellular and Molecular Research Center, Sabzevar University of Medical Sciences, Sabzevar, Iran.
authors.forename: Elmira
authors.initials: E
authors.lastname: Ghasemi
authors.affiliation: Department of Physiology, Zanjan University of Medical Sciences, Zanjan, Iran.
authors.forename: Nima
authors.initials: N
authors.lastname: Heidari-Oranjaghi
authors.affiliation: Neuroscience Research Center, Torbat Heydariyeh University of Medical Sciences, Torbat Heydariyeh, Iran.
authors.forename: Hassan
authors.initials: H
authors.lastname: Azhdari-Zarmehri
authors.affiliation: Department of Physiology, Faculty of Medicine, Arak University of Medical Sciences, Arak, Iran.
authors.forename: Mehdi
authors.initials: M
authors.lastname: Sadegh
keywords: Anti-nociception; Hot plate; Orexin-A; Tolerance