Abstract：
The comorbidity of anxiety and depression frequently occurs in patients with neuropathic pain. The ventrolateral orbital cortex (VLO) plays a critical role in mediating neuropathic pain and anxiodepression in rodents. Previous studies suggested that 5-HT6 receptors in the VLO are involved in neuropathic pain. Strong evidence supports a close link between 5-HT6 receptors and affective disorders such as depression and anxiety disorders. However, it remains unclear whether the 5-HT6 receptors in the VLO are involved in neuropathic pain-induced anxiodepression. Using a rat neuropathic pain model of spared nerve injury (SNI), we demonstrated that rats exhibited significant anxiodepression-like behaviors and the expression of VLO 5-HT6 receptors obviously decreased four weeks after SNI surgery. Microinjection of the 5-HT6 receptor agonist EMD-386088 into the VLO or overexpression of VLO 5-HT6 receptors alleviated anxiodepression-like behaviors. These effects were blocked by pre-microinjection of a selective 5-HT6 receptor antagonist (SB-258585) or inhibitors of AC (SQ-22536), PKA (H89), and MEK1/2 (U0126) respectively. Meanwhile, the expression of p-ERK, p-CREB, and BDNF in the VLO decreased four weeks after SNI surgery. Furthermore, administration of EMD-386088 upregulated the expression of BDNF, p-ERK, and p-CREB in the VLO of SNI rats, which were reversed by pre-injection of SB-258585. These findings suggest that activating 5-HT6 receptors in the VLO has anti-anxiodepressive effects in rats with neuropathic pain via activating AC-cAMP-PKA-MERK-CREB-BDNF signaling pathway. Accordingly, 5-HT6 receptor in the VLO could be a potential target for the treatment of the comorbidity of neuropathic pain and anxiodepression.
摘要：
神经性疼痛患者常发生焦虑和抑郁共病。腹外侧眶皮质（VLO）在介导啮齿动物的神经性疼痛和焦虑抑郁中起关键作用。先前的研究表明，VLO中的5-HT6受体与神经性疼痛有关。强有力的证据支持5-HT6受体和情感障碍如抑郁症和焦虑症之间的密切联系。然而,目前尚不清楚VLO中的5-HT6受体是否与神经性疼痛引起的焦虑抑郁有关.使用备用神经损伤（SNI）的大鼠神经性疼痛模型，我们证明，SNI手术后四周，大鼠表现出明显的焦虑抑郁样行为，VLO5-HT6受体的表达明显下降。将5-HT6受体激动剂EMD-386088显微注射到VLO中或VLO5-HT6受体的过表达减轻了焦虑抑郁样行为。这些作用被预显微注射选择性5-HT6受体拮抗剂（SB-258585）或AC抑制剂（SQ-22536）阻断，PKA(H89),和MEK1/2(U0126)。同时,p-ERK的表达，p-CREB,SNI术后四周VLO中的BDNF降低。此外，施用EMD-386088上调BDNF的表达，p-ERK,和SNI大鼠VLO中的p-CREB，通过预先注入SB-258585逆转。这些发现表明，通过激活AC-cAMP-PKA-MERK-CREB-BDNF信号通路，激活VLO中的5-HT6受体对患有神经性疼痛的大鼠具有抗抑郁作用。因此，VLO中的5-HT6受体可能是治疗神经性疼痛和焦虑抑郁共病的潜在靶标。
