【作者】 党永辉；

【导师】 陈腾；

【作者基本信息】 西安交通大学 ， 法医学， 2010， 博士

【摘要】 腹外侧眶皮层(ventrolateral orbital cortex,VLO)是眶皮层(或眶额皮层,orbital cortex或orbitofrontal cortex)的主要组成,占前额叶皮层(prefrontal cotex,PFC)的大部分区域。解剖学研究提示VLO可能参与中枢神经系统复杂的功能整合。因为VLO主要接受来自丘脑中央下核(thalamic nucleus submedius,Sm)的投射,并发出纤维投射到导水管周围灰质(periaqueductal gray,PAG),因此,VLO作为Sm-VLO-PAG通路中一个的高级中枢,不仅参与痛觉感受,也参与伤害感受性调制;又因为VLO与其它情绪调节相关脑区如下丘脑(hypothalamus)、杏仁核(amygdala)等之间的联系,因此也可能参与情绪调控。本课题研究了:(1)多巴胺及D1、D2样多巴胺受体在VLO参与的抗大鼠神经病理性疼痛中的作用以及可能的机制;(2)多巴胺及D1、D2样多巴胺受体在VLO参与的抗大鼠持续性炎性疼痛中的作用;(3)组蛋白脱乙酰基酶(histone deacetylases,HDACs)抑制剂VPA微量注射于VLO诱发的抗抑郁样行为。结果如下:1.VLO内微量注射非选择性多巴胺受体激动剂apomorphine(1.0,2.5,5.0μg)剂量依赖性的减轻大鼠坐骨神经分支损伤模型(spared nerve injury,SNI)引起的触诱发痛;D2样多巴胺受体拮抗剂raclopride(1.5μg)阻滞这一效果,D1样多巴胺受体拮抗剂SCH23390(5.0μg)则增强上述效果;而D2样多巴胺受体激动剂quinpirole(0.5,1.0,2.0μg)产生的效应与apomorphine相同;较大剂量(10,20μg)SCH23390也显著缓解上述触诱发痛。进一步研究发现:VLO内微量注射GABAA受体拮抗剂bicuculline和picrotoxi(n均为200,300 ng)同样缓解上述触诱发痛,而小剂量bicuculline和picrotoxin(100 ng)加强quinpirole(0.5μg)的效果;GABAA受体激动剂muscimol(250 ng)或THIP(1.0μg)阻滞quinpirole(2.0μg)的效果。这些结果说明多巴胺能神经系统参与调节VLO的抗痛觉超敏作用:激活D2样多巴胺受体,或者抑制D1样多巴胺受体均具有抗痛觉超敏作用;GABA能脱抑制作用可能参与D2样多巴胺受体在神经病理痛中的作用。2.VLO内微量注射非选择性多巴胺受体激动剂apomorphine(1.0,2.5,5.0μg)剂量依赖性的抑制大鼠福尔马林实验晚时相伤害感受行为;D2样多巴胺受体拮抗剂raclopride(3.0μg)阻滞上述效应,而D2样多巴胺受体激动剂quinpirole(1.0,2.0,5.0μg)完全模拟了apomorphine的效应;D1样多巴胺受体拮抗剂SCH23390(2.5, 5.0, 10μg)则剂量依赖的抑制福尔马林诱发的伤害感受行为。这些结果说明D1、D2样多巴胺受体在VLO参与的抗大鼠持续性炎性疼痛中的作用不同:D2样多巴胺受体参与多巴胺引起的抗伤害感受效应,而D1样多巴胺受体对伤害感受行为具有紧张性易化作用,因此阻滞D1样多巴胺受体产生抗伤害感受作用。3.大鼠双侧VLO内微量注射组蛋白脱乙酰基酶(histone deacetylases,HDACs)抑制剂丙戊酸钠(sodium valproate,VPA,300μg),显著减少大鼠在强迫游泳实验(forced swimming test,FST)中的不动(immobility)时间,但并不会对大鼠的自主活动(locomotor activity)行为产生明显的影响,其效应与慢性腹腔注射SSRIs类抗抑郁剂氟西汀(fluoxetine,10mg/kg,连续14d)相似。上述结果表明VLO在情绪调控中起一定作用。更多还原

【Abstract】 The ventrolateral orbital cortex (VLO) in rat and cat is a major component of the orbital cortex, occupying a large region of the prefrontal cortex. Anatomical studies suggest that the VLO may be involved in regulation of various complex functions. Since the VLO receives a direct projection from thalamic nucleus submedius (Sm) and projects to periaqueductal gray (PAG), and the Sm has been demonstrated to be involved not only in nociception, but also in nociceptive modulation, it is reasonable to suspect that the VLO is involved as a higher center in nociceptive modulation of the Sm-VLO-PAG pathway. Furthermore, The complex connections between the orbitofrontal cortex and the amygdala, as well as other areas involved in emotion, suggest important implications for the role of the VLO in mood modulation. The present study examined : (1) The role of dopamine receptors in VLO-evoked anti-nociception in a rat model of neuropathic pain; (2) The roles of dopamine receptors in VLO-evoked antinociception in formalin test rats; (3) Effects of acute microinjection of histone deacetylases, sodium valproate (VPA), into the VLO in the rat forced swimming test. The results are as follows:1. Microinjection of apomorphine (1.0, 2.5, 5.0μg), a non-selective dopamine receptor agonist, into the VLO attenuated spared nerve injury (SNI)-induced mechanical allodynia in a dose-dependent manner. This effect was completely blocked by the D2- like dopamine receptor antagonist raclopride (1.5μg), but was enhanced by the D1-like dopamine receptor antagonist SCH23390 (5.0μg). The attenuating effect of apomorphine on mechanical allodynia was mimicked by application of the D2-like dopamine receptor agonist quinpirole (0.5, 1.0, and 2.0μg). In addition, microinjection of larger doses (10 and 20μg) of SCH23390 into the VLO significantly attenuated allodynia. Furthermore, microinjections of GABAA receptor antagonists, bicuculline and picrotoxin (200 and 300 ng for both drugs), into the VLO attenuated mechanical allodynia. A small dose of bicuculline or picrotoxin (100 ng) resulted in increased quinpirole (0.5μg)-induced anti-allodynia. In contrast, GABAA receptor agonists, muscimol hydrochloride (250 ng) or THIP (1.0μg), blocked quinpirole (2.0μg)-induced attenuation. These results suggest that the dopaminergic system is involved in mediating VLO-induced anti-hypersensitivity, activation of D2-like dopamine receptors, and inhibition of D1-like receptors resulting in anti-hypersensitivity. In addition, the mechanisms of GABAergic disinhibition might be involved in D2-like receptor mediating effects in neuropathic pain.2. Microinjection of a non-selective dopamine receptor agonist apomorphine (1.0, 2.5, 5.0μg) into the VLO depressed the later phase nociceptive behavior induced by formalin injected into the rat hindpaw, this effect was attenuated by D2-like dopamine receptor antagonist (3.0μg). The antinociception of apomorphine could be mimicked by microinjection of the D2-like dopamine receptor agonist quinpirole (1.0, 2.0 and 5.0μg) into the same VLO site. Furthermore, microinjection of the D1-like dopamine receptor antagonist SCH-23390 (2.5, 5.0, 10μg) into the VLO dose-dependently depressed the formalin-induced nociceptive behavior. These results suggest that the roles of D1-like and D2-like dopamine receptors in mediating the VLO-induced antinociception are different in the persistent inflammatory pain model, in which the D2-like receptors mediate the dopamine-induced antianociception, while the D1-like dopamine receptors have a tonic facilitatory action on the nociceptive behavior, thus block of the D1-like dopamine receptors produces antinociception.3. Acute microinjection of sodium valproate (VPA, 300μg) into the bilateral VLO decreased the immobility time of rats in the forced swimming test (FST), but did not influence the horizontal locomotion, which are similar to that typically seen in chronic intraperitoneal injection of standard antidepressant, fluoxetine (10mg/kg for 7 days). These results suggested that VPA may exert an antidepressant-like effect in rat FST through VLO-mediated functions in mood.更多还原