Spinal Orexin-2 Receptors are Involved in Modulation of the Lateral Hypothalamic Stimulation-Induced Analgesia

  • Laleh Rezaee
  • Sakineh Salehi
  • Amir-Mohammad Alizadeh
  • Soheila Fazli-TabaeiEmail author
  • Abbas HaghparastEmail author
Original Paper


Role of the orexinergic system in pain modulation is well studied and involvement of the spinal orexin-1 receptors is well documented. In this study, we examined role of the spinal orexin-2 receptors in modulation of inflammatory pain in rat. Fifty-one adult male Wistar rats were implanted unilaterally with a guide cannula into the LH and intrathecal tubing in the lumbar space between L4 and L5. Chemical stimulation of LH by carbachol (250 nM/0.5 µL saline) induced remarkable analgesia during the two phases of formalin test and Intrathecal administration of different doses of TCS OX2 29 (10, 30 and 100 µM/ 0.5 µL DMSO) prior to LH stimulation, dose-dependently antagonized the antinociceptive effect of the LH-stimulation during the two phases of formalin test. The effect size of the TCS OX2 29 was η2 = 0.47 and η2 = 0. 87 for the early and late phases of the test, respectively. Also, intrathecal administration of TCS OX2 29 alone (without stimulation of the LH) had no significant effect on formalin induced pain-related behaviors. Our results showed that spinal orexin-2 receptors are involved in modulation of the LH-stimulation induced analgesia in a persistent inflammatory pain model. These findings may suggest spinal orexin-2 receptors in particular and the orexin system in general as a useful therapeutic target for treatment of chronic pains.


Pain Orexin-2 receptor Lateral hypothalamus Spinal cord Intrathecal administration Formalin test 



This study was supported by a research grant (No. 11290) from Tehran Medical Sciences Branch, Islamic Azad University, Tehran, Iran. This project was supported by the Vice-Chancellor for Research & Technology of Shahid Beheshti University of Medical Sciences (Grant No. 15854-61518/97/10/24). Also, the authors would like to thank the Neuroscience Research Center, School of Medicine, Shahid Beheshti University of Medical Sciences for valuable cooperation.


  1. 1.
    Razavi BM, Hosseinzadeh H (2017) A review of the role of orexin system in pain modulation. Biomed Pharmacother 90:187–193CrossRefGoogle Scholar
  2. 2.
    Sakurai T et al (1998) Orexins and orexin receptors: a family of hypothalamic neuropeptides and G protein-coupled receptors that regulate feeding behavior. Cell 92(4):573–585CrossRefGoogle Scholar
  3. 3.
    Cutler DJ et al (1999) Differential distribution of orexin-A and orexin-B immunoreactivity in the rat brain and spinal cord. Peptides 20(12):1455–1470CrossRefGoogle Scholar
  4. 4.
    Grudt TJ, van den Pol AN, Perl ER (2002) Hypocretin-2 (orexin-B) modulation of superficial dorsal horn activity in rat. J Physiol 538(Pt 2):517–525CrossRefGoogle Scholar
  5. 5.
    Haghparast A et al (2017) Functional roles of orexin/hypocretin receptors in reward circuit. Prog Brain Res 235:139–154CrossRefGoogle Scholar
  6. 6.
    Karimi S et al (2019) Orexin 1 receptors in the anterior cingulate and orbitofrontal cortex regulate cost and benefit decision-making. Prog Neuropsychopharmacol Biol Psychiatry 89:227–235CrossRefGoogle Scholar
  7. 7.
    Sadeghzadeh F et al (2016) Differential effects of intra-accumbal orexin-1 and -2 receptor antagonists on the expression and extinction of morphine-induced conditioned place preference in rats. Pharmacol Biochem Behav 142:8–14CrossRefGoogle Scholar
  8. 8.
    Zarrabian S et al (2018) The potential role of the orexin reward system in future treatments for opioid drug abuse. Brain Res. Google Scholar
  9. 9.
    Bingham S et al (2001) Orexin-A, an hypothalamic peptide with analgesic properties. Pain 92(1–2):81–90CrossRefGoogle Scholar
  10. 10.
    van den Pol AN (1999) Hypothalamic hypocretin (orexin): robust innervation of the spinal cord. J Neurosci 19(8):3171–3182CrossRefGoogle Scholar
  11. 11.
    Park KB, Weon H (2017) Orexin receptors mediate long-term depression of excitatory synaptic transmission in the spinal cord dorsal horn. Neurosci Lett 660:12–16CrossRefGoogle Scholar
  12. 12.
    Azhdari-Zarmehri H, Semnanian S, Fathollahi Y (2014) Orexin-A microinjection into the rostral ventromedial medulla causes antinociception on formalin test. Pharmacol Biochem Behav 122:286–290CrossRefGoogle Scholar
  13. 13.
    Azhdari Zarmehri H et al (2011) Intra-periaqueductal gray matter microinjection of orexin-A decreases formalin-induced nociceptive behaviors in adult male rats. J Pain 12(2):280–287CrossRefGoogle Scholar
  14. 14.
    Azhdari-Zarmehri H et al (2013) Involvement of orexin-2 receptors in the ventral tegmental area and nucleus accumbens in the antinociception induced by the lateral hypothalamus stimulation in rats. Peptides 47:94–98CrossRefGoogle Scholar
  15. 15.
    Haghparast A et al (2018) Blockade of the orexin receptors in the CA1 region of hippocampus decreased the lateral hypothalamic-induced antinociceptive responses in the model of orofacial formalin test in the rats. Peptides 99:217–222CrossRefGoogle Scholar
  16. 16.
    Cluderay JE, Harrison DC, Hervieu GJ (2002) Protein distribution of the orexin-2 receptor in the rat central nervous system. Regul Pept 104(1–3):131–144CrossRefGoogle Scholar
  17. 17.
    Hervieu GJ et al (2001) Gene expression and protein distribution of the orexin-1 receptor in the rat brain and spinal cord. Neuroscience 103(3):777–797CrossRefGoogle Scholar
  18. 18.
    Feng XM et al (2012) Involvement of spinal orexin A in the electroacupuncture analgesia in a rat model of post-laparotomy pain. BMC Complement Altern Med 12:225CrossRefGoogle Scholar
  19. 19.
    Jeong Y, Holden JE (2009) The role of spinal orexin-1 receptors in posterior hypothalamic modulation of neuropathic pain. Neuroscience 159(4):1414–1421CrossRefGoogle Scholar
  20. 20.
    Kajiyama S et al (2005) Spinal orexin-1 receptors mediate anti-hyperalgesic effects of intrathecally-administered orexins in diabetic neuropathic pain model rats. Brain Res 1044(1):76–86CrossRefGoogle Scholar
  21. 21.
    Yamamoto T et al (2003) Activation of spinal orexin-1 receptor produces anti-allodynic effect in the rat carrageenan test. Eur J Pharmacol 481(2–3):175–180CrossRefGoogle Scholar
  22. 22.
    Rezaee L et al (2018) Effects of intrathecal administration of orexin-1 receptor antagonist on antinociceptive responses induced by chemical stimulation of lateral hypothalamus in an animal model of tonic nociception. Neuropeptides 69:19–25CrossRefGoogle Scholar
  23. 23.
    Paxinos G, Watson C (2014) Paxino’s and Watson’s the rat brain in stereotaxic coordinates, 7th edn. Elsevier/AP, Academic Press is an imprint of Elsevier, Amsterdam. 1 volume (unpaged)Google Scholar
  24. 24.
    Wardach J et al (2016) Lateral hypothalamic stimulation reduces hyperalgesia through spinally descending orexin-A neurons in neuropathic pain. West J Nurs Res 38(3):292–307CrossRefGoogle Scholar
  25. 25.
    Dubuisson D, Dennis SG (1977) The formalin test: a quantitative study of the analgesic effects of morphine, meperidine, and brain stem stimulation in rats and cats. Pain 4(2):161–174CrossRefGoogle Scholar
  26. 26.
    Abbott FV, Franklin KB, Westbrook RF (1995) The formalin test: scoring properties of the first and second phases of the pain response in rats. Pain 60(1):91–102CrossRefGoogle Scholar
  27. 27.
    Shono K, Yamamoto T (2008) Orexin-2 receptors inhibit primary afferent fiber-evoked responses of ventral roots in the neonatal rat isolated spinal cord. Brain Res 1218:97–102CrossRefGoogle Scholar
  28. 28.
    Kimura M et al (2014) Effects of lidocaine and orexin on [Ca2+]i in dosal root ganglion neuron of rat segmental spinal nerve ligation model. Jpn Pharmacol Ther 42(10):723–734Google Scholar
  29. 29.
    Wang C, Fujita T, Kumamoto E (2018) Orexin B modulates spontaneous excitatory and inhibitory transmission in lamina ii neurons of adult rat spinal cord. Neuroscience 383:114–128CrossRefGoogle Scholar
  30. 30.
    Chou TC et al (2001) Orexin (hypocretin) neurons contain dynorphin. J Neurosci 21(19):RC168CrossRefGoogle Scholar
  31. 31.
    Furutani N et al (2013) Neurotensin co-expressed in orexin-producing neurons in the lateral hypothalamus plays an important role in regulation of sleep/wakefulness states. PLoS ONE 8(4):e62391CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of Physiology, Faculty of MedicineTehran Medical Sciences, Islamic Azad UniversityTehranIran
  2. 2.Neuroscience Research Center, School of MedicineShahid Beheshti University of Medical SciencesTehranIran

Personalised recommendations