title: Differential contribution of orexin receptors within the ventral tegmental area to modulation of persistent inflammatory pain.
abstract: Orexinergic neurons in the lateral hypothalamus (LH) play an important role in pain modulation. In addition, ventral tegmental area (VTA) is known as a part of descending pain modulatory circuitry. Little is known about the interaction between the LH and neural substrates involving in modulation of formalin-induced nociception. Accordingly, we aimed to examine the pain modulatory role of VTA orexin receptors in the formalin test.
  
  
  
  Seventy-eight male Wistar rats were unilaterally implanted with two cannulae above the LH and VTA. Intra-VTA administration of SB-334867 (orexin-1 receptor antagonist) or TCS OX2 29 (orexin-2 receptor antagonist) was performed 5 min before intra-LH microinjection of carbachol (a cholinergic receptor agonist). The procedure was followed by subcutaneous injection of formalin after 5-min interval time.
  
  
  
  Carbachol attenuated formalin-induced biphasic pain responses and SB-334867 or TCS OX2 29 administration dose-dependently antagonized the LH-induced analgesia during both phases. Blockade of orexin-1 and -2 receptors had more profound effects on the reduction of antinociception during the late phase compared to the early phase. Also, contribution of orexin-1 receptors in mediation of LH-induced analgesia was greater than orexin-2 receptors during the late phase.
  
  
  
  Formalin test, a model of persistent inflammatory pain, mimics the conditions encountered in clinical situations. Pain modulatory role of orexinergic system in the formalin test through a neural pathway from the LH to the VTA provides the evidence that orexins can be useful therapeutic targets for chronic pain treatment. WHAT DOES THIS STUDY ADD?: There is a pathway from the lateral hypothalamus (LH) to the ventral tegmental area (VTA) which modulates biphasic formalin-induced pain. Blockade of VTA orexin receptors dose-dependently reduces LH-induced analgesia during both phases. Anti-analgesic effect of orexin receptor antagonists is more considerable during the late phase. Contribution of orexin-1 receptors to mediation of LH-induced analgesia is more than orexin-2 receptors during the late phase.
authors: Department of Basic Sciences, Faculty of Veterinary Medicine, University of Tehran, Iran.
authors: S
authors: S
authors: Ezzatpanah
authors: Department of Basic Sciences, Faculty of Veterinary Medicine, University of Tehran, Iran.
authors: V
authors: V
authors: Babapour
authors: Neuroscience Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
authors: A
authors: A
authors: Haghparast
mesh_terms: D000818:Animals; D001583:Benzoxazoles / Q000494:pharmacology; D002217:Carbachol; D007026:Hypothalamic Area, Lateral; D007546:Isoquinolines / Q000494:pharmacology; D008297:Male; D009287:Naphthyridines; D059225:Nociception / Q000187:drug effects; D000068796:Orexin Receptor Antagonists / Q000494:pharmacology; D064446:Orexin Receptors / Q000502:physiology*; D010146:Pain / Q000209:etiology* / Q000503:physiopathology; D010147:Pain Measurement; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D014508:Urea / Q000031:analogs & derivatives / Q000494:pharmacology; D017557:Ventral Tegmental Area
chemical_list: C420062:1-(2-methylbenzoxazol-6-yl)-3-(1,5)naphthyridin-4-yl urea; C572065:1-(3,4-dihydro-6,7-dimethoxy-2(1H)-isoquinolinyl)-3,3-dimethyl-2-((4-pyridinylmethyl)amino)-1-butanone; D001583:Benzoxazoles; D007546:Isoquinolines; D009287:Naphthyridines; D000068796:Orexin Receptor Antagonists; D064446:Orexin Receptors; D011725:Pyridines; D014508:Urea; D002217:Carbachol