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 5min 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.