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A pathway from the lateral hypothalamus to CA1 modulates early (0–3 min) and late phases (15–33 min) of formalin-induced orofacial nociception.Blockade of CA1 orexin receptors (OXRs) reduced LH-induced antinociception during the early and late phases of nociceptive responses.Antinociceptive effects of both OXR antagonists were more effective during the late phase.The role of hippocampus and lateral hypothalamus (LH) in modulation of formalin-induced nociception has been established. The present study aims to examine the role of orexin receptors in the Cornu Ammonis 1 (CA1) region of hippocampus in modulation of the LH-induced antinociception in the orofacial formalin test. Male Wistar rats were unilaterally implanted with two cannulae into the LH and CA1. Intra-LH microinjection of carbachol was done 5 min after intra-CA1 administration of SB-334867 (OX1R antagonist) or TCS OX2 29 (OX2R antagonist). After 5 min, 50 μl of 1% formalin was subcutaneously injected into the upper lip for inducing the nociceptive behaviors. Solely intra-LH administration of carbachol reduced early and late phases of formalin-induced orofacial nociception in a dose-dependent manner. The antinociception evoked by intra-LH injection of carbachol (0.5 μl of 250 nM carbachol) was antagonized by intra-CA1 administration of 0.5 μl of 3, 10 and 30 nM solutions of SB-334867 or TCS OX2 29 during the early and late phases of orofacial formalin test. This effect was more remarkable during the late phase in comparison to the early phase. In addition, anti-analgesic effect of SB-334867 was more than TCS OX2 29 during the early and late phases. The results suggest the interpretation that a neural pathway from the LH to the CA1 probably contributes to the modulation of formalin-induced orofacial nociception through recruitment of both CA1 orexin receptors. Clinical studies are recommended to study the probable effectiveness of orexinergic system in modulation of the orofacial nociceptive responses.