Background Exposure to stressful experiences is often accompanied by suppressing pain perception, referred to as stress‐induced analgesia. The neuropeptides orexins are essential in regulating the mechanism that responds to stressful and painful stimuli. Meanwhile, the ventral tegmental area (VTA), as a part of descending pain inhibitory system, responds to noxious stimuli. This study aimed to investigate the role of intra‐VTA administration of orexin receptor antagonists on stress‐induced antinociceptive responses in the animal model of acute pain. Method Ninety‐three adult Wistar rats weighing 230–250 g were unilaterally implanted by a cannulae above the VTA. Animals were pretreated with different doses (1, 3, 10 and 30 nM/0.3 μl) of SB334867 as the orexin‐1 receptor antagonist and TCS OX2 29 as the orexin‐2 receptor antagonist into the VTA, just 5 min before 6 min exposure to forced swim stress (FSS). Nociceptive threshold was measured using the tail‐flick test as a model of acute pain. Results The results showed that exposure to FSS could significantly increase analgesic responses. Moreover, intra‐VTA administration of SB334768 and TCS OX2 29 blocked the antinociceptive effect of FSS in the tail‐flick test. Conclusion The findings suggest that OX1 and OX2 receptors in the VTA might modulate the antinociceptive behaviours induced by FSS in part. Significance Acute exposure to physical stress suppresses pain‐related behaviors in the animal model of acute pain. Blockade of the OX1 and OX2 receptors in the VTA attenuates antinociceptive responses induced by FSS. The contribution of the OX2 receptors in the VTA is more predominant than OX1 receptors in stress‐induced analgesia.

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Orexins are excitatory neuropeptides, mainly produced by neurons located in the lateral hypothalamus, which project to many brain areas. The orexinergic system plays a fundamental role in arousal, sleep/wakefulness, feeding, energy homeostasis, motivation, reward, stress and pain modulation. As a prominent part of the limbic system, the hippocampus has been involved in formalin-induced nociception modulation. Moreover, hippocampus regions express both orexin-1 (OX1) and orexin-2 (OX2) receptors. The present study investigated the role of OX2 receptors (OX2R) within the cornu ammonis 1 (CA1) region of the hippocampus in the mediation of lateral hypothalamusinduced antinociception. Fifty-three male Wistar rats were unilaterally implanted with two separate cannulae into the lateral hypothalamus and CA1. Animals were pretreated with intra-CA1 TCS OX2 29 as an OX2R antagonist before intra-lateral hypothalamus administration of carbachol (250 nM) as a muscarinic agonist for chemical stimulation of orexinergic neurons. Formalin test was used as an animal model of persistent pain, following intra-lateral hypothalamus carbachol microinjection. Results showed that the chemical stimulation of the lateral hypothalamus significantly attenuated formalin-evoked nociceptive behaviors during both phases of the formalin test, and administration of TCS OX2 29 into the CA1 blocked these antinociceptive responses in both phases, especially in the late phase. These findings suggest that OX2 receptors in the CA1 partially mediate the lateral hypothalamusinduced antinociceptive responses in persistent inflammatory pain.