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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 η 2  = 0.47 and η 2  = 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 control in opioid-dependent individuals is a clinical complication. The present study investigated the effects of different doses of amitriptyline in the three stages of the formalin test in morphine-dependent rats (MDRs). Morphine dependency was induced using the oral method, and then, amitriptyline-induced antinociceptive effects were measured at 4 doses (2.5, 5, 10, and 20 mg/kg) and compared with the control group in a formalin-based model of pain. There was no observed antinociceptive effect in the MDRs and morphine-naïve rats (MNRs) in phase I. In the interphase, amitriptyline induced pain suppression at doses of 5 and 20 mg/kg. In phase II, at doses of 5, 10, and 20 mg/kg, the hypoalgesic effect on pain-related behaviors was seen in the MNRs. In MDRs, amitriptyline at doses of 2.5 and 5 mg/kg caused the hyperalgesic effect, whereas at 10 and 20 mg/kg doses, it induced a hypoalgesic effect. A significant attenuation was observed in the latency to fall from the accelerating rotarod at doses of 10 and 20 mg/kg in the MDRs, and at a dose of 20 mg/kg in the MNRs. Data showed that amitriptyline dose-dependently induced paradoxical hypo- and hyper-algesic effects in MDRs., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Orexins are produced in the restricted regions of the lateral hypothalamus (LH). However, orexinergic receptors and projections are localized in wide regions like nucleus accumbens, ventral tegmental area, periaqueductal gray area and spinal cord which are involved in the pain modulation. This study was carried out to investigate the effects of intrathecal administration of orexin-1 receptor antagonist (SB-334867) in the spinal antinociception induced by intra-LH administration of carbachol (cholinergic receptor agonist) in both early and late phases of pain related behaviors in formalin test. In this study, pain-related behaviors (pain scores) were evaluated using the formalin test during 5-min block intervals for a 60-min period in seventy male Wistar rats were given SB-334867 (3, 10, 30 and 100 μM/10 μl) or vehicle (DMSO 12%; 10 μl) intrathecally following intra-LH administration of carbachol (250 nM/rat). Our data showed that intra-LH injection of carbachol attenuated the formalin-induced biphasic pain responses, and intrathecal administration of SB-334867 dose-dependently decreased LH stimulation-induced antinociceptive responses during both phases. Moreover, administration of different doses of SB-334867 during the early phase were more effective than those during the late phase. The antinociceptive role of orexinergic system in the formalin test through a neural pathway from the LH to the spinal cord provides evidence that orexins can be useful in therapeutic targets for pain relief., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Tina Matini,1 Amir Haghparast,1 Laleh Rezaee,2 Sakineh Salehi,2,3 Azita Tehranchi,4 Abbas Haghparast2 1School of Dentistry, International Branch of Shahid Beheshti University of Medical Sciences, Tehran, Iran; 2Neuroscience Research Center, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran; 3Department of Medicine, Ardabil Medical Sciences Branch, Islamic Azad University, Ardabil, Iran; 4Dental Research Center, Research Institute of Dental Sciences, Dental School, Shahid Beheshti University of Medical Sciences, Tehran, IranCorrespondence: Abbas HaghparastNeuroscience Research Center, School of Medicine, Shahid Beheshti University of Medical Sciences, P O Box 19615-1178, Tehran, IranTel/ Fax +98-21-2243-1624Email Haghparast@yahoo.comAzita TehranchiDental Deformities Research Center, Dental Research Institute, School of Dentistry, Shahid Beheshti University of Medical Sciences, Tehran, IranEmail Azitatehranchi@yahoo.comIntroduction: The ventral tegmental area (VTA), as one of the classical components of the brain reward circuitry, shares large neural networks with the pain processing system. We previously showed the role of VTA dopamine receptors in modulation of lateral hypothalamus (LH)-induced antinociception in acute pain conditions. However, considering the fact that the neural systems involved in the mediation of tonic pain are not the same as those that mediate phasic pain. In the present study, we aimed to examine the role of intra-VTA dopamine receptors in LH-induced antinociceptive responses during tonic orofacial pain conditions.Methods: Male Wistar rats weighing 230– 250 g were implanted with two separate cannulae into the LH and VTA on the same side. Different solutions of carbachol (62.5, 125 and 250 nM), as a non-selective cholinergic receptor agonist that activates the LH projecting neurons, were microinjected into the LH. In the other groups, D1-like dopamine receptor antagonist, SCH-23390 (0.25, 1 and 4 μg/03 μL saline) or D2-like dopamine receptor antagonist, Sulpiride (0.25, 1 and 4 μg/0.3 μL DMSO 12%) were microinjected into VTA, 5 min prior intra-LH carbachol (250 nM), then subjected to orofacial formalin test. Intra-LH carbachol microinjection dose-dependently attenuated biphasic orofacial pain.Results: Intra-VTA administration of SCH-23390 or Sulpiride dose-dependently decreased intra-LH carbachol-induced antinociception during both phases of orofacial formalin test with further effects in the late phase.Discussion: The findings suggest that chemical stimulation of the LH by carbachol possibly activates the orexin projecting neurons and subsequently, the VTA dopaminergic neurons involved in the orofacial pain modulation. Detecting such neural circuitry offers an alternative approach in the development of more efficient therapies for such debilitating pain conditions.Keywords: pain, D1-like dopamine receptor, D2-like dopamine receptor, ventral tegmental area, lateral hypothalamus, orofacial formalin test