基于化学遗传的腹外侧眶额叶激活对药物过度使用性头痛小鼠的镇痛作用研究

Study on the Analgesic Effects of Chemogenetic Activation of the Ventrolateral Orbitofrontal Cortex in Medication-Overuse Headache Mice

摘要:

目的 探究腹外侧眶额叶皮质(vlOFC)在利扎曲坦(RIZ)诱导的药物过度使用性头痛(MOH)小鼠模型中的镇痛作用。 方法 重复RIZ灌胃建立MOH模型,评估其基础痛阈,包括足底机械痛阈(PWT)和眶周机械痛阈(HWT)。应用免疫荧光技术检测c-Fos表达,分析OFC及相关脑区神经元激活水平；通过化学遗传技术调控神经元活性,评估其对MOH小鼠痛阈的影响。结果 RIZ组小鼠PWT和HWT显著低于生理盐水组(SAL)。免疫荧光结果显示,MOH小鼠vlOFC的c-Fos表达显著增加(t=3.821,P=0.012),而腹内侧丘脑(Vm)、前扣带皮层(ACC)、导水管周围灰质(PAG)c-Fos表达和生理盐水组无统计学差异(Vm: t<0.001, P>0.999; ACC: t=0.974, P=0.475; PAG: t=1.321, P=0.235)。进一步统计发现OFC被激活的区域集中在腹外侧(t=2.723,P=0.042),而内侧无统计学差异(t=0.251, P=0.812)。使用化学遗传学技术激活vlOFC脑区神经元,发现可以显著提高RIZ组小鼠PWT和HWT,抑制vlOFC效果不显著。结论 MOH小鼠vlOFC神经元活动增加,激活该脑区可缓解MOH引起的皮肤痛敏。

Abstract:

Objective To investigate the analgesic role of the ventrolateral orbitofrontal cortex (vlOFC) in a mouse model of medication-overuse headache (MOH) induced by rizatriptan (RIZ). Methods An MOH model was established by repeated intragastric administration of RIZ. Baseline withdrawal thresholds, including paw withdrawal threshold (PWT) and head withdrawal threshold (HWT), were evaluated. Immunofluorescence was employed to detect c-Fos expression and analyze neuronal activation levels in the OFC and related brain regions. Chemogenetic techniques were utilized to modulate neuronal activity and assess their effects on pain thresholds in MOH mice. Results The PWT and HWT of the RIZ group were significantly lower than those of the saline (SAL) group. Immunofluorescence revealed a marked increase in c-Fos expression in the vlOFC of MOH mice (t=3.821, P=0.012), while no statistical differences were observed in the ventromedial thalamus (VM), anterior cingulate cortex (ACC), or periaqueductal gray (PAG) compared to the SAL group (VM: t<0.001, P>0.999; ACC: t=0.974, P=0.475; PAG: t=1.321, P=0.235). Further analysis localized the activation to the ventrolateral subregion of the OFC (t=2.723, P=0.042), with no significant difference in the medial subregion (t=0.251, P=0.812). Chemogenetic activation of vlOFC neurons significantly elevated PWT and HWT in RIZ-treated mice, whereas inhibition of vlOFC showed no notable effect. Conclusion Enhanced neuronal activity in the vlOFC of MOH mice was observed, and activation of this region alleviated cutaneous hyperalgesia induced by MOH.