Abstract：
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-HT5A 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-HT5A receptor activation. We found an upregulation of 5-HT5A receptor expression in the VLO during neuropathic and inflammatory pain states. Microinjection of the non-selective 5-HT5A 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-HT5A receptor antagonist SB-699551. Moreover, application of the GABAA receptor antagonist bicuculline in the VLO augmented the analgesic effects induced by 5-CT in neuropathic and inflammatory pain states, whereas the GABAA receptor agonist muscimol attenuated these analgesic effects. Additionally, the 5-HT5A receptors were found to be colocalized with GABAergic neurons in the VLO. These results provide new evidence for the involvement of central 5-HT5A receptors in the VLO in modulation of neuropathic and inflammatory pain and support the hypothesis that activation of 5-HT5A 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.
摘要：
腹外侧眶皮质（VLO）被确定为内源性镇痛系统的组成部分，该系统包括脊髓-丘脑中核-VLO-导水管周围灰色（PAG）-脊髓环。本研究研究了VLO中5-HT5A受体激活对雄性SD大鼠备用神经损伤和福尔马林诱发的退缩行为以及脊髓c-Fos表达引起的异常性疼痛的影响。并进一步检查GABA能调节是否参与VLO5-HT5A受体激活引起的效应。我们发现在神经性和炎性疼痛状态下VLO中5-HT5A受体表达上调。将非选择性5-HT5A受体激动剂5-CT显微注射到VLO剂量依赖性地减轻了异常性疼痛，退缩行为和脊髓c-Fos表达，被选择性5-HT5A受体拮抗剂SB-699551阻断。此外，在VLO中GABAA受体拮抗剂bicuculline的应用增强了5-CT在神经性和炎性疼痛状态中诱导的镇痛作用，而GABAA受体激动剂麝香酚减弱了这些镇痛作用。此外,发现5-HT5A受体与VLO中的GABA能神经元共定位。这些结果为VLO中中枢5-HT5A受体参与调节神经性和炎性疼痛提供了新的证据，并支持以下假设：5-HT5A受体的激活可能会抑制GABA能中间神经元对投射到PAG的输出神经元的抑制作用（GABA能解抑制机制），从而激活脑干下降抑制系统，抑制脊髓水平的伤害性传递。
