The ventrolateral orbital cortex (VLO) is identified as an integral component of the endogenous analgesic system comprising a spinal cord - thalamic nucleus submedius - VLO - periaqueductal gray (PAG) - spinal cord loop. The present study investigates the effects of 5-HT_5A receptor activation in the VLO on allodynia induced by spared nerve injury and formalin-evoked flinching behavior and spinal c-Fos expression in male SD rats, and further examines whether GABAergic modulation is involved in the effects evoked by VLO 5-HT_5A receptor activation. We found an upregulation of 5-HT_5A receptor expression in the VLO during neuropathic and inflammatory pain states. Microinjection of the non-selective 5-HT_5A receptor agonist 5-CT into the VLO dose dependently alleviated allodynia, and flinching behavior and spinal c-Fos expression, which were blocked by the selective 5-HT_5A receptor antagonist SB-699551. Moreover, application of the GABA_A receptor antagonist bicuculline in the VLO augmented the analgesic effects induced by 5-CT in neuropathic and inflammatory pain states, whereas the GABA_A receptor agonist muscimol attenuated these analgesic effects. Additionally, the 5-HT_5A receptors were found to be colocalized with GABAergic neurons in the VLO. These results provide new evidence for the involvement of central 5-HT_5A receptors in the VLO in modulation of neuropathic and inflammatory pain and support the hypothesis that activation of 5-HT_5A receptors may inhibit the inhibitory effect of GABAergic interneurons on output neurons projecting to the PAG (GABAergic disinhibitory mechanisms), consequently activating the brainstem descending inhibitory system that depresses nociceptive transmission at the spinal cord level.

腹外侧眶皮层 (VLO) 被认为是内源性镇痛系统的组成部分，包括脊髓 - 丘脑中下核 - VLO - 导水管周围灰质(PAG) - 脊髓环。本研究探讨了VLO 中5-HT _{5A受体激活}对雄性 SD 大鼠免遭神经损伤引起的异常性疼痛和福尔马林诱发的退缩行为以及脊髓 c-Fos 表达的影响，并进一步检查 GABAergic 调节是否参与了_{VLO 5-HT 5A受体激活}引起的效应。我们发现在神经性疼痛和炎性疼痛状态下 VLO 中5-HT _5A受体表达上调。将非选择性 5-HT _5A受体激动剂 5-CT 显微注射到 VLO 中，可剂量依赖性地减轻异常性疼痛、退缩行为和脊髓 c-Fos 表达，而选择性 5-HT _5A受体拮抗剂 SB-699551 可阻断这些症状。此外，在VLO中应用GABA _A受体拮抗剂_{荷包牡丹碱增强了5-CT在神经性和炎症性疼痛状态下诱导的镇痛作用，而GABA A}受体激动剂蝇蕈醇减弱了这些镇痛作用。此外，还发现 5-HT _5A受体与 VLO 中的 GABA 能神经元共定位。这些结果为VLO中枢 5-HT _{5A受体参与调节神经性疼痛和炎性疼痛提供了新的证据，并支持以下假设：5-HT 5A}受体的激活可能抑制 GABA 能中间神经元对投射到神经源的输出神经元的抑制作用。 PAG（GABA能去抑制机制），从而激活脑干下行抑制系统，抑制脊髓水平的伤害性传导。