孤啡肽受体对痛觉调控作用的研究进展

孤啡肽受体是继经典的mu阿片受体、kappa阿片受体和delta阿片受体之后发现的又一类新型阿片受体,不仅在结构上具有同上述阿片受体相类似的特征,而且可介导相同或相似的细胞内生物学反应.孤啡肽受体对痛觉反应具有独特的调控模式.一方面,在背根神经节以及脊髓水平,孤啡肽受体主要介导镇痛效应,并且在脊髓水平还与其他阿片受体有协同效应以增强镇痛效果.另一方面,在脊髓上水平,孤啡肽受体往往产生痛敏而拮抗了其他阿片受体的镇痛效应.此外孤啡肽受体对痛觉的调控在不同物种间也表现一定的差异性.这为进一步阐明内源性阿片系统的痛觉调控作用提供一定的理论依据.     

孤啡肽受体的配体研究进展

孤啡肽(nociceptin或orphanin FQ)发现于1995年底, 它是阿片受体样受体(ORL1或LC 132) 的内源性配体,在痛觉调节、心血管系统、离子通道、依赖和耐受、学习和记忆等方面具有广泛的生物学活性. 最近几年, 对孤啡肽受体与相关配体构效关系的研究成为一个新的热点.对在研究构效关系过程中所发现的孤啡肽受体相关配体（片段、拮抗剂、激动剂、部分激动剂和阻断剂）的研究情况进行了介绍.     

孤啡肽（OFQ）的分布,特性及其可能作用

孤啡肽是１９９５年底新发现的一种结构与内阿片肽类似的物质,它的发现引发了国际上相关研究的热潮。近年来的研究已经基本阐明了孤啡肽在中枢及外周的分布及其生化与药理特性,并初步发现该物质参与痛觉调制、影响运动与行为、调控递质释放,还可能参与情绪反应与学习记忆、神经内分泌与免疫过程以及胃的活动等,但其确切作用仍有待于进一步阐明。     

鞘内注射孤啡肽对大鼠足底注入蜜蜂毒诱致长时程自发痛、痛敏和炎症的不同效果

为进一步了解孤啡肽在脊髓水平是否具有抗伤害及抗炎作用,本实验在具有多种痛行为表现的蜜蜂毒模型上观察了鞘内注射孤啡肽对大鼠一侧后足底注入蜜蜂毒所诱致的同侧自发缩足反射、原发热和机械性痛敏以及注射部位炎症反应的影响,同时观察了新的高选择性孤啡肽受体拮抗剂CompB的作用.结果表明与生理盐水对照组比较,鞘内注射孤啡肽(3、10、30 nmol/10μl)对蜜蜂毒诱发的自发缩足反射次数的抑制作用随剂量提高而增大,抑制率分别为37±7,43±6and57±11%(三个剂量vs对照,P＜0.05);而对蜜蜂毒诱发的注射部位炎症反应(爪体积、爪背腹厚度和蛋白渗出的增加)无显著影响.CompB(30 nmo1)可完全翻转10 nmol孤啡肽对自发缩足反射的抑制作用.鞘内单次或重复注射孤啡肽(10 nmol/10μl)对蜜蜂毒诱致的原发性热和机械性痛敏的发生和维持均无作用.本实验结果提示,外源性孤啡肽在脊髓通过孤啡肽受体的介导产生一定的镇痛作用,但是它可能仅对持续性自发痛有抑制作用,而对热和机械性痛敏及炎症反应均无影响.     

孤啡肽在癫痫中作用的研究进展

孤啡肽(nociceptin/orphanin FQ)是1995年发现的阿片受体样受体(opioid receptor like 1 receptor,ORL1 receptor)的内源性配体。孤啡肽和孤啡肽受体系统构成一种新的神经肽系统,具有多种生物学功能。越来越多的研究表明,孤啡肽通过调节神经递质(包括兴奋性神经递质和抑制性神经递质)的释放或传递而对癫痫起作用。本文就孤啡肽和孤啡肽受体的分布及生物学功能进行综述,重点阐述孤啡肽在癫痫中的作用的研究进展。     

腹外侧眶皮层在痛觉调制和针刺镇痛中的作用

腹外侧眶皮层 (ventrolateral orbital cortex, VLO) 是眶皮层的主要成分,它与导水管周围灰质(PAG)、丘脑和其它皮层之间有广泛的纤维联系.VLO不仅是一个痛觉感受中枢,而且也是一个痛觉调制中枢,通过激活PAG脑干下行抑制系统在脊髓和三叉水平抑制伤害性信息的输入.研究还证实,阿片、 5-HT和GABA等神经递质及其受体参与VLO的抗伤害效应.此外,VLO在针刺镇痛中也发挥重要作用.本文就腹外侧眶皮层在痛觉调制和针刺镇痛中的作用进行综述.     

孤啡肽在大鼠脑内对抗吗啡镇痛

脑内全新的阿片受体样受体（１９９４）及其内源性配体孤啡肽（１９９５）的发现形成了中枢神经系统阿片／抗阿片相互关系的研究领域中一个新的推动力。基于它们与阿片家族的高同源性及在脑内痛觉整合相关区域的丰富表达,本实验观察了ＯＦＱ在大鼠脑内对吗啡镇痛作用的影响。结果表明：（１）ＯＦＱ可以对抗脑室注射生理盐水引起的镇痛,后者可能是一种由内源性阿片系统介导的应激镇痛。（２）脑室注射ＯＦＱ在很大的剂量范围（４０     

cAMP应答元件结合蛋白与痛觉调制

cAMP应答元件结合蛋白（cAMP response element binding protein,CREB）是刺激诱导的一种转录因子,通过磷酸化实现调节转录功能。疼痛和痛觉过敏是组织损伤或炎症时常伴有的生理病理过程,谷氨酸、P物质等神经递质或神经肽以及细胞内的信号转导途径参与此过程。近年来研究发现CREB通过自身磷酸化,在炎症、神经损伤等诱发的自发性疼痛、痛觉过敏及痛觉超敏中具有重要作用。本文从CREB的一般特性及其在脊髓水平的痛觉调制中的作用等方面予以综述。     

激活脊髓MrgC受体抑制大鼠痛觉过敏

本研究旨在探讨激活脊髓Mrg C(Mas-related gene C)受体对痛觉过敏的作用及细胞学机制。在大鼠足底皮下注射(Tyr6)-γ2-MSH-6–12(MSH)或完全弗氏佐剂(complete Freund’s adjuvant,CFA)形成痛觉过敏或炎性痛模型,通过缩足反射和免疫组织化学等方法观察鞘内给予Mrg C受体特异性激动剂MSH或牛肾上腺髓质8-22肽(bovine adrenal medulla 8-22,BAM8-22)对痛觉过敏的影响。结果显示,鞘内给予MSH不影响正常大鼠对热伤害性刺激引起的缩足潜伏期变化,但能抑制足底注射MSH引起的急性痛觉敏感反应,还能降低CFA引起的痛觉过敏,鞘内给予μ阿片受体(μ-opioid receptor,MOR)拮抗剂CTAP(D-Phe-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH2)能阻止鞘内给予MSH的延迟抗痛觉过敏作用。鞘内给予BAM8-22能显著降低CFA引起的脊髓背角L3~L5节段一氧化氮合酶(nitric oxide synthase,NOS)阳性神经元数量和降钙素基因相关肽(calcitonin gene-related peptide,CGRP)样免疫活性物质的表达。以上结果提示,鞘内激活Mrg C受体通过抑制NOS阳性神经元活性和下调CGRP阳性产物表达来降低痛觉过敏,并能通过间接机制调制MOR起到延时持续抗痛觉过敏作用。因此,Mrg C受体激动剂有望成为一类新型抗炎症痛觉过敏的药物。     

降钙素基因相关肽家族在疼痛和阿片耐受中的作用北大核心CSCD

降钙素基因相关肽(calcitonin gene-related peptide,CGRP)家族成员主要包括CGRPα、CGRPβ、肾上腺髓质素(adrenom edullin,AM)、降钙素(calcitonin,CT)和胰淀粉样蛋白(amylin,AMY)。CGRP家族成员及其受体广泛分布于哺乳动物中枢和外周神经系统。研究表明,CGRP、AM等CGRP家族成员在伤害性信息传递过程中具有重要作用。在脊髓水平,CGRP促进痛觉信息传递、脊髓阿片耐受、偏头痛、炎性痛和神经病理性痛;在脊髓以上水平,CGRP则抑制痛觉信息的传递。AM是近年来才证实的与疼痛感受有密切关系的神经多肽,在脊髓水平促进痛觉信息的传递,在阿片耐受形成和维持中亦有重要作用。AMY和CT与疼痛的关系尚不十分明确。     

Brain mechanisms of pain affect and pain modulation

Recent animal studies reveal ascending nociceptive and descending modulatory pathways that may contribute to the affective-motivational aspects of pain and play a critical role in the modulation of pain. In humans, a reliable pattern of cerebral activity occurs during the subjective experience of pain. Activity within the anterior cingulate cortex and possibly in other classical limbic structures, appears to be closely related to the subjective experience of pain unpleasantness and may reflect the regulation of endogenous mechanisms of pain modulation.     

Neurobiology of pain

The neurobiology of pain had a notable interest in research focused on the study of neuronal plasticity development, nociceptors, molecular identity, signaling mechanism, ionic channels involved in the generation, modulation and propagation of action potential in all type of excitable cells. All the findings open the possibility for developing new therapeutic treatment. Nociceptive/inflammatory pain and neuropathic pain represent two different kinds of persistent chronic pain. We have reviewed the different mechanism suggested for the maintenance of pain, like descending nociceptive mechanism and their changes after tissue damage, including suppression and facilitation of defence behavior during pain. The role of these changes in inducing NMDA and AMPA receptors gene expression, after prolonged inflammation is emphasized by several authors. Furthermore, a relation between a persistent pain and amygdale has been shown. Molecular biology is the new frontier in the study of neurobiology of pain. Since the entire genome has been studied, we will able to find new genes involved in specific condition such as pain, because an altered gene expression can regulate neuronal activity after inflammation or tissue damage.     

Safety of early pain relief for acute abdominal pain.

OBJECTIVES--(a) to determine the efficacy of papaveretum in treating pain when administered early to patients presenting with acute abdominal pain and (b) to assess its effect on subsequent diagnosis and management. DESIGN--Prospective, randomised, placebo controlled study. SETTING--Walsgrave Hospital, Coventry. SUBJECTS--100 consecutive patients with clinically significant abdominal pain who were admitted as emergencies to a surgical firm. INTERVENTIONS--Intramuscular injection of up to 20 mg papaveretum or an equivalent volume of saline. OUTCOME MEASURES--Pain and tenderness scores, assessment of patient comfort, accuracy of diagnosis, and management decisions. RESULTS--Median pain and tenderness scores were lower after papaveretum (pain score 8.3 in control group and 3.1 in treatment group, p < 0.0001; tenderness score 8.1 in control group and 5.1 in treatment group, p < 0.0001). Forty eight patients were deemed to be comfortable after papaveretum compared with nine after saline. Incorrect diagnoses and management decisions applied to two patients after papaveretum compared with nine patients after saline. CONCLUSION--Early administration of opiate analgesia to patients with acute abdominal pain can greatly reduce their pain. This does not interfere with diagnosis, which may even be facilitated despite a reduction in the severity of physical signs. These patients should not be denied effective treatment.