Repeated injections of orexin-A developed behavioral tolerance to its analgesic effects in rats

Document Type: Original Article

Authors

1 Cellular and Molecular Research Center, Sabzevar University of Medical Sciences, Sabzevar, Iran

2 Department of Physiology, Zanjan University of Medical Sciences, Zanjan, Iran

3 Neuroscience Research Center, Torbat Heydariyeh University of Medical Sciences, Torbat Heydariyeh, Iran

4 Department of Physiology, Faculty of Medicine, Arak University of Medical Sciences, Arak, Iran

Abstract

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.

Keywords


1. Mayer DJ, Mao J, Holt J, Price DD. Cellular mechanisms of neuropathic pain, morphine tolerance, and their interactions. Proc Natl Acad Sci U S A 1999; 96:7731-7736.

2. Van Vliet BJ, Van Rijswijk AL, Wardeh G, Mulder AH, Schoffelmeer AN. Adaptive changes in the number of Gs- and Gi-proteins underlie adenylyl cyclase sensitization in morphine-treated rat striatal neurons. Eur J Pharmacol 1993; 245:23-29.

3. Gintzler AR, Chakrabarti S. Post-opioid receptor adaptations to chronic morphine; altered functionality and associations of signaling molecules. Life Sci 2006; 79:717-722.

4. Williams JT, Christie MJ, Manzoni O. Cellular and synaptic adaptations mediating opioid dependence. Physiol Rev 2001; 81:299-343.

5. Wong CS, Cherng CH, Luk HN, Ho ST, Tung CS. Effects of NMDA receptor antagonists on inhibition of morphine tolerance in rats: binding at mu-opioid receptors. Eur J Pharmacol 1996; 297:27-33.

6. de Lecea L, Kilduff TS, Peyron C, Gao X, Foye PE, Danielson PE, et al. The hypocretins: hypothalamus-specific peptides with neuroexcitatory activity. Proc Natl Acad Sci U S A 1998; 95:322-327.

7. Sakurai T. The neural circuit of orexin (hypocretin): maintaining sleep and wakefulness. Nat Rev Neurosci 2007; 8:171-181.

8. Sofiabad M, Heidari N, Ghasemi E, Esmaeili MH, Haghdoost-Yazdi H, Erami E, et al. Assesment of orexin receptor 1 in stress attenuated nociceptive behaviours in formalin test. Physiol Pharmacol 2011; 15:395-402.

9. Peyron C, Faraco J, Rogers W, Ripley B, Overeem S, Charnay Y, et al. A mutation in a case of early onset narcolepsy and a generalized absence of hypocretin peptides in human narcoleptic brains. Nat Med 2000 ; 6:991-997.

10. Trivedi P, Yu H, MacNeil DJ, Van der Ploeg LH, Guan XM. Distribution of orexin receptor mRNA in the rat brain. FEBS Lett 1998; 438:71-75.

11. azhdari Zarmehri H, Semnanian S, Fathollahi Y. Comparing the analgesic effects of periaqueductal gray matter injection of orexin A and morphine on formalin- induced nociceptive behaviors. Physiol Pharmacol 2008; 12:188-193.

12. Azhdari Zarmehri H, Semnanian S, Fathollahi Y, Erami E, Khakpay R, Azizi H, et al. Intra-periaqueductal gray matter microinjection of orexin-A decreases formalin-induced nociceptive behaviors in adult male rats. J Pain 2011; 12:280-287.

13. Bingham S, Davey PT, Babbs AJ, Irving EA, Sammons MJ, Wyles M, et al. Orexin-A, an hypothalamic peptide with analgesic properties. Pain 2001; 92:81-90.

14. Ho YC, Lee HJ, Tung LW, Liao YY, Fu SY, Teng SF, et al. Activation of orexin 1 receptors in the periaqueductal gray of male rats leads to antinociception via retrograde endocannabinoid (2-arachidonoylglycerol)-induced disinhibition. J Neurosci 2011; 31:14600-14610.

15. Sadeghi S, Reisi Z, Azhdari-Zarmehri H, Haghparast A. Involvement of orexin-1 receptors in the ventral tegmental area and the nucleus accumbens in antinociception induced by lateral hypothalamus stimulation in rats. Pharmacol Biochem Behav 2013; 105:193-198.

16. Yamamoto T, Nozaki-Taguchi N, Chiba T. Analgesic effect of intrathecally administered orexin-A in the rat formalin test and in the rat hot plate test. Br J Pharmacol 2002; 137:170-176.

17. Yamamoto T, Saito O, Shono K, Aoe T, Chiba T. Anti-mechanical allodynic effect of intrathecal and intracerebroventricular injection of orexin-A in the rat neuropathic pain model. Neurosci Lett 2003 28; 347:183-186.

18. Azhdari-Zarmehri H, Esmaeili MH, Sofiabadi M, Haghdoost-Yazdi H. Orexin receptor type-1 antagonist SB-334867 decreases morphine-induced antinociceptive effect in formalin test. Pharmacol Biochem Behav 2013; 112:64-70.

19. Heidari-Oranjaghi N, Azhdari-Zarmehri H, Erami E, Haghparast A. Antagonism of orexin-1 receptors attenuates swim- and restraint stress-induced antinociceptive behaviors in formalin test. Pharmacol Biochem Behav 2012; 103:299-307.

20.Hervieu GJ, Cluderay JE, Harrison DC, Roberts JC, Leslie RA. Gene expression and protein distribution of the orexin-1 receptor in the rat brain and spinal cord. Neuroscience 2001; 103:777-797.

21. Mobarakeh JI, Takahashi K, Sakurada S, Nishino S, Watanabe H, Kato M, et al. Enhanced antinociception by intracerebroventricularly and intrathecally-administered orexin A and B (hypocretin-1 and -2) in mice. Peptides 2005; 26:767-777.

22. Trujillo KA. The neurobiology of opiate tolerance, dependence and sensitization: mechanisms of NMDA receptor-dependent synaptic plasticity. Neurotox Res 2002; 4:373-391.

23. Pernia-Andrade AJ, Tortorici V, Vanegas H. Induction of opioid tolerance by lysine-acetylsalicylate in rats. Pain 2004; 111:191-200.

24. Cheng JK, Chou RC, Hwang LL, Chiou LC. Antiallodynic effects of intrathecal orexins in a rat model of postoperative pain. J Pharmacol Exp Ther 2003; 307:1065-1071.

25. Mobarakeh JI, Takahashi K, Sakurada S, Nishino S, Watanabe H, Kato M, et al. Enhanced antinociception by intracerebroventricularly administered orexin A in histamine H1 or H2 receptor gene knockout mice. Pain 2005; 118:254-262.

26. Chiou LC, Lee HJ, Ho YC, Chen SP, Liao YY, Ma CH, et al. Orexins/hypocretins: pain regulation and cellular actions. Curr Pharm Des 2010; 16:3089-3100.

27. Novak CM, Levine JA. Daily intraparaventricular orexin-A treatment induces weight loss in rats. Obesity  2009; 17:1493-1498.

28. Yamanaka A, Sakurai T, Katsumoto T, Yanagisawa M, Goto K. Chronic intracerebroventricular administration of orexin-A to rats increases food
intake in daytime, but has no effect on body weight. Brain Res 1999; 849:248-252.

29. Kotz CM. Integration of feeding and spontaneous physical activity: role for orexin. Physiol Behav 2006 ; 88:294-301.

30. Liu JG, Anand KJ. Protein kinases modulate the cellular adaptations associated with opioid tolerance and dependence. Brain Res Brain Res Rev 2001; 381-319.

31. Zhu Y, Miwa Y, Yamanaka A, Yada T, Shibahara M, Abe Y, et al. Orexin receptor type-1 couples exclusively to pertussis toxin-insensitive G-proteins, while orexin receptor type-2 couples to both pertussis toxin-sensitive and -insensitive G-proteins. J Pharmacol Sci 2003; 92:259-266.

32. Gorojankina T, Grebert D, Salesse R, Tanfin Z, Caillol M. Study of orexins signal transduction pathways in rat olfactory mucosa and in olfactory sensory neurons-derived cell line Odora: multiple orexin signalling pathways. Regul Pept 2007; 141:73-85.

33. Ozcan M, Ayar A, Serhatlioglu I, Alcin E, Sahin Z, Kelestimur H. Orexins activates protein kinase C-mediated Ca(2+) signaling in isolated rat primary sensory neurons. Physiol Res 2010; 59:255-262.