Orexin-A modulated pain through the Brain Stem

Hassan Azhdari Zarmehri 1, 2, Saeed Semnanian 2, Yaghoub Fathollahi 2, Elaheh Erami 3 1- Department of Physiology, School of Medical sciences, Qazvin University of Medical Science, Qazvin, Iran 2- Department of Physiology, School of Medical sciences, Tarbiat Modares University, Tehran, Iran 3- Islamic Azad University of Abhar, Abhar, Iran Neuropeptide orexin-A is restricted to thousands of neurons in lateral hypothalamus. The recent discovery demonstrating orexin projection in the RVM region and the presence of orexin receptors in this region prompted us to investigate the possible role of Orexin-A in the brain stem. Orexin-A was microinjected into brainstem areas involving in the expression of nociceptive behaviors including rostral ventromedial medulla (RVM), paragigantocellularis lateralis (LPGi) and reticularis gigantocellularis (Gi) nuclei. Orexin-A microinjection into LPGi and RVM vigorously blunted formalin induced nociceptive behaviors; in LPGi was dose dependent during formalin test. In lightly anesthetized rats, based on changes in neuronal spiking due to tail flicking, three types of RVM neurons have been defined: firing of on-cells (On-cell burst) was increased whereas firing of off-cells (off-cell pause) was deceased and in some cells called neutral cells, firing rate did not change just prior to a tail flicking. ICV injection of orexinA inhibited or decreased the spontaneous firing rate of On-cells. RVM neurons thought to facilitate nociception, and initiated the firing of off-cells. RVM neurons believed to have an inhibitory effect on nociception. Moreover orexin-A also reduced the TF-related responses of on-cells and TF-related pause duration of off-cells. Whole cell patch clamp recordings under current-clamp mode revealed that Orexin-A either inhibited or exited type 1 neurons, while exited type 2 and type 3 neurons were unaffected by Orexin-A application. It is suggested that orexinergic system which is originated from hypothalamus and projected to LPGi and RVM might a potential role in the processing of pain information associated with descending pain modulation and nalgesia produced by orexin-A and opioids engages similar brainstem circuitry. Keywords: Orexin-A, Paragigantocellularis lateralis, Rostral ventromedial medulla, Formalin test; patch clamp

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