中枢胰高血糖素样肽-1介导的奖赏环路对肥胖的影响概述

脑干孤束核(NTS)中的胰高血糖素样肽-1(GLP-1)近年来在调控食欲、改善肥胖等方面受到广泛关注。这一效应涉及多条神经环路，其中奖赏环路是近几年的研究热点之一。中脑多巴胺能(DA)奖赏系统调控摄食的核团主要有腹侧被盖区(VTA)、伏隔核(NAc)和弓状核(ARC)。这些区域存在大量GLP-1受体(GLP-1R),当受体被激活后，出现食物摄入量的减少。了解其中的神经生物学机制对进一步探索肥胖及相关疾病的治疗方法具有重要意义。本文以神经环路的角度作为切入点，分别阐述了中枢GLP-1通过直接或间接的神经投射调控奖赏环路，进而抑制摄食、改善肥胖的研究进展。     

脊髓背角星形胶质细胞内PAPR-1/TNF-α通路参与脊神经结扎模型大鼠神经病理性痛的机制研究

目的观察PAPR-1/TNF-α信号通路在脊神经结扎模型大鼠脊髓背角星形胶质细胞内的表达情况,并探究其与神经病理性痛的发生发展关系。方法将大鼠第5腰神经(L5)进行结扎构建慢性神经病理性痛模型,Von-Frey细丝检测各组大鼠的机械性痛阈值,免疫组织化学染色和Western blot技术半定量和定量分析脊髓背角内PAPR-1和TNF-α的表达情况。结果与正常组相比,假手术组大鼠疼痛阈值未见显著改变(P0.05),脊神经结扎后大鼠的术侧后足的疼痛阈值显著降低,差异具有统计学意义(P0.05),且在术后2周内,疼痛阈值均保持在较低水平。免疫荧光组织化学染色结果显示,PAPR-1和TNF-α主要表达于脊髓背角内星形胶质细胞中,Western blot结果进一步显示,造模后大鼠脊髓背角内GFAP、PAPR-1及TNF-α水平显著高于正常组和假手术组(P0.05)。结论 PAPR-1/TNF-α信号通路主要表达于脊髓背角内星形胶质细胞中,且在慢性神经病理性痛的维持阶段保持较高表达水平,可能参与了慢性痛的发生和发展,临床治疗中具有一定的理论参考意义。     

NR2B参与脊髓损伤致慢性疼痛的机制研究

目的:研究N-甲基-D-天冬氨酸(NMDA)受体2B型受体(NR2B)参与脊髓损伤后慢性神经病理性痛的机制。方法:制作脊髓半横断大鼠模型,von Frey纤维丝测量机械性刺激缩足阈值变化,Western Blot观察脊髓背角NR2B表达时程变化;同时采用行为药理学方法,鞘内给予NR2B特异性拮抗剂ifenprodil,观察对机械性刺激缩足阈值及NR2B表达的影响。结果:脊髓半横断术后大鼠双侧后足出现触诱发痛状态,NR2B在腰段脊髓双侧背角表达上调。鞘内给予ifenprodil逆转了大鼠的痛敏状态,伴随着NR2B在脊髓背角表达下调。结论:NR2B可能参与脊髓损伤后慢性神经病理性痛的发生发展,特异性拮抗NR2B可能是临床治疗脊髓损伤致慢性神经病理性痛的潜在策略。     

内质网应激介导的JNK通路在大鼠神经病理性疼痛中的作用

目的:检测内质网应激介导的JNK通路在坐骨神经慢性压迫(CCI)模型大鼠中的作用。方法:SD雄性大鼠随机分为假手术组(sham)和模型组(CCI)。CCI前、后1、3、5、7、14 d测定大鼠的热痛敏和机械痛敏;CCI后14 d,免疫组织化学检测大鼠脊髓背角内葡萄糖调节蛋白78(GRP78)、p-JNK、caspase-3和胶质纤维酸性蛋白(GFAP)的表达;TUNEL法检测脊髓背角内的细胞凋亡。结果:与假手术组相比,模型组的热痛敏和机械痛敏在术后均明显下降,脊髓背角内GRP78、p-JNK、caspase-3和GFAP的表达均增高,凋亡染色阳性细胞数目也较多。结论:内质网应激介导的p-JNK途径参与了神经病理性疼痛模型大鼠脊髓背角内神经元凋亡,可能与星形胶质细胞的活化有关。     

炎性痛大鼠脊髓背角内神经激肽B受体的动态变化

目的：观察神经激肽B受体（NK3）与大鼠髓内伤害性信息和调控的可能关系。方法：用免疫组织化学技术观察完全弗氏佐剂（CFA）诱发慢性性大鼠脊髓背角神经激肽B受体的运动变化。结果：炎症侧腰髓氏脊髓背角NKB受体样免疫反应结构的染色强度有明显升高,背角浅层尤为显著。经进观察与图像分析有明,注射CFA2d后脊髓背角内免疫染色强度即开始升高21d左右抵达高峰,28d后渐恢复至正常水平。结论NKB受体可能参与炎性慢性痛状态下伤害性信息在脊髓水平的传递与整合过程.     

8-O-乙酰山栀子苷甲酸通过抑制脊髓背角JNK的磷酸化水平改善大鼠炎性痛的研究

目的:探究8-O-乙酰山栀子苷甲酸(8-O-acetyl-SM,8-Oa S)对于慢性炎性痛模型大鼠痛行为及脊髓背角星形胶质细胞内c-Jun氨基酸末端激酶(c-Jun N-terminal kinase,JNK)磷酸化水平的影响。方法:运用大鼠足底注射完全弗式佐剂(complete Freund’s adjuvant,CFA)的方法建立慢性炎性痛模型;通过腹膜腔注射8-Oa S进行干预;采用von Frey丝测定大鼠足底50%机械性缩足反射阈值;应用免疫荧光组织化学染色法观察大鼠腰膨大节段脊髓背角胶质纤维酸性蛋白(glial fibrillary acidic protein,GFAP)及磷酸化的JNK(phosphorylatedc-Jun N-terminal kinase,p JNK)表达;应用Western Blot方法对大鼠脊髓背角内GFAP、JNK以及p-JNK的表达水平进行定量分析。结果:(1)行为学结果显示:与对照组相比,CFA模型大鼠机械性痛阈明显降低(P0.01),腹膜腔注射8-Oa S可有效提高CFA诱导的机械性痛阈值(P0.05);(2)免疫荧光染色结果显示:CFA模型脊髓背角内GFAP的表达量明显高于正常组,且p JNK基本表达于星形胶质细胞内;(3)Western Blot结果显示:与对照组相比,CFA造模后7 d脊髓背角内GFAP和p JNK表达明显上调,腹膜腔给予8-Oa S可以显著下调CFA诱导的脊髓背角内GFAP和p JNK的水平(P0.01)。结论:腹膜腔内给予8-Oa S可有效提高炎性痛大鼠的机械性痛阈,其机制是通过下调脊髓背角星形胶质细胞内JNK信号通路的磷酸化水平进而抑制星形胶质细胞的激活。     

p-ERK1/2-AP-1通路在姜黄素抗大鼠糖尿病神经病理性痛中的作用

目的: 观察p-ERK1/2-AP-1通路在姜黄素(Cur)抗大鼠糖尿病神经病理性痛(DNP)中的作用。方法: 雄性SD大鼠96只,随机分为4组(n=24):正常对照组、DNP组、DNP+溶剂组(DNP+Sol组)和DNP+Cur 100 mg/kg组(DNP+Cur组)。除正常对照组外,其余各组采用腹腔注射链唑霉素75 mg/kg的方法制备DNP模型,造模成功后每天1次腹腔注射相应的溶剂或Cur,持续2周。于造模前2 d、造模后14 d、腹腔给药后3、7、14 d时测定机械缩足痛阈(MWT)、热缩足潜伏期(TWL)和非空腹尾静脉血糖值,取脊髓腰膨大及L₄/L₅背根神经节(DRG),采用免疫组化及Western blotting法测定脊髓背角和DRG p-ERK1/2的表达,电泳迁移率变动分析AP-1的表达。结果: 与正常对照组相比,DNP组各时点MWT降低、TWL缩短;血糖值升高;脊髓背角及DRG p-ERK1/2均出现表达上调(P<0.05);脊髓背角AP-1表达上调(P<0.05)。与DNP组相比,DNP+Cur组在给药后7 d MWT回升、TWL延长;在给药后14 d脊髓背角及DRG p-ERK1/2、脊髓背角AP-1表达下调(P<0.05),但并不影响血糖水平。结论: Cur可减轻大鼠糖尿病神经病理性痛,其机制可能与抑制脊髓背角和DRG神经元p-ERK1/2-AP-1通路激活有关。     

腹外侧眶皮层内给予谷氨酸抑制福尔马林诱发的大鼠脊髓背角Fos表达

目的:观察腹外侧眶皮层(ventrolateral orbital cortex,VLO)内微量注射谷氨酸对大鼠后爪注射福尔马林诱发的腰段脊髓背角Fos表达的抑制效应以及该效应是否通过中脑导水管周围灰质(PAG)下行抑制系统介导。方法:免疫组织化学染色技术。结果:(1)VLO内微量注射谷氨酸(100nmol/0.5μl)明显抑制大鼠后爪注射福尔马林诱发的脊髓背角Fos表达,与注射生理盐水相比,差异显著(P0.001),并且这种抑制效应可被VLO内预先注射非选择性谷氨酸受体拮抗剂kynurenic acid(2nmol/0.5μl)所翻转,与单独注射谷氨酸相比差异显著(P0.001),但与注射生理盐水相比无显著差异(P0.05);(2)双侧腹外侧PAG内微量注射局麻剂利多卡因(0.2nmol/0.5μl)可以明显阻断VLO内微量注射谷氨酸(100nmol/0.5μl)对大鼠脊髓背角Fos表达的抑制效应,与单独注射谷氨酸相比差异显著(P0.001),而双侧腹外侧PAG内微量注射生理盐水不影响VLO内微量注射谷氨酸对大鼠脊髓背角Fos表达的抑制效应(P0.05)。结论:VLO内谷氨酸可能通过其受体激活PAG脑干下行抑制系统在脊髓水平抗炎性持续性伤害感受效应。     

大鼠脊髓环氧合酶在皮下注射蜜蜂毒诱发的持续性自发痛、原发性痛敏的发生和在脊髓c-fos蛋白表达中的作用

本实验用鞘内给药的方法对非选择性环氧合酶 1/ 2抑制剂吲哚美辛 (indomethacin,Indo)和选择性环氧合酶 2抑制剂Etodolac对蜜蜂毒诱致的自发缩足行为、原发性 (热和机械性 )痛敏和脊髓背角 c-fos蛋白表达的效果进行了观察 ,发现 :(1)预先用吲哚美辛和 Etodolac处理均可剂量依赖性地抑制自发缩足行为的发生 ,提示脊髓环氧合酶 2 (但不能完全排除环氧合酶 1)在长时程、持续性自发痛的诱导中具有重要作用 ;(2 )与上述结果不同 ,预先用吲哚美辛和 Etodolac处理对蜜蜂毒注入部位热刺激潜伏期缩短和机械性刺激阈值的下降无抑制作用 ,提示脊髓环氧合酶在原发性热和机械痛敏的诱导不起任何作用 ;(3 )上述两种药物的同样处理对脊髓背角 c-fos蛋白的表达均具有显著抑制作用 ,但通过对背角浅、深层细胞分别记数分析显示两种环氧合酶抑制剂只对浅层具有抑制作用 ,而对深层则无。以上结果提示 ,脊髓环氧合酶参与介导蜜蜂毒组织损伤后持续性自发痛的发生 ,但不参与原发性热和机械性痛敏的发生 ;背角浅层 c-fos阳性神经元可能不参与介导原发性痛敏的发生。     

大鼠脊髓神经元对福尔马林痛刺激的反应及氯胺酮的调节

目的：研究大鼠脊髓对福尔马林痛刺激的反应及氯胺酮的影响。方法：采用福尔马林致痛模型、c-fos基因免疫组化法和NADPH-d组化技术。SD大鼠30只，分为福尔马林致痛组、痛刺激前和后腹腔注射氯胺酮组及相应对照组，取脊髓切片。结果：(1)痛刺激后，刺激侧脊髓背角出现大量Fos免疫样阳性(FLI)神经元，其中部分为FLI／NOS双标记神经元；(2)痛刺激之前或之后给予氯胺酮，背角各层FLI神经元和FLI／NOS双标记神经元的数量均显著减少。结论：同侧相应脊髓节段的某些神经元参与了化学性致痛信息的传导和调控，氯胺酮通过抑制这些神经元的活动而产生抗伤害作用。此作用与抑制脊髓内NOS阳性神经元的活性有关。     

Pain and Effusion and Quadriceps Activation and Strength

Context:

Quadriceps dysfunction is a common consequence of knee joint injury and disease, yet its causes remain elusive.

Objective:

To determine the effects of pain on quadriceps strength and activation and to learn if simultaneous pain and knee joint effusion affect the magnitude of quadriceps dysfunction.

Design:

Crossover study.

Setting:

University research laboratory.

Patients or Other Participants:

Fourteen (8 men, 6 women; age = 23.6 ± 4.8 years, height = 170.3 ± 9.16 cm, mass = 72.9 ± 11.84 kg) healthy volunteers.

Intervention(s):

All participants were tested under 4 randomized conditions: normal knee, effused knee, painful knee, and effused and painful knee.

Main Outcome Measure(s):

Quadriceps strength (Nm/kg) and activation (central activation ratio) were assessed after each condition was induced.

Results:

Quadriceps strength and activation were highest under the normal knee condition and differed from the 3 experimental knee conditions (P < .05). No differences were noted among the 3 experimental knee conditions for either variable (P > .05).

Conclusions:

Both pain and effusion led to quadriceps dysfunction, but the interaction of the 2 stimuli did not increase the magnitude of the strength or activation deficits. Therefore, pain and effusion can be considered equally potent in eliciting quadriceps inhibition. Given that pain and effusion accompany numerous knee conditions, the prevalence of quadriceps dysfunction is likely high.Key Words: arthrogenic muscle inhibition, central activation failure, voluntary activation, muscles

Key Points

• Knee pain and effusion resulted in arthrogenic muscle inhibition and weakness of the quadriceps.
• The simultaneous presence of pain and effusion did not increase the magnitude of quadriceps dysfunction.
• To reduce arthrogenic muscle inhibition and improve muscle strength, clinicians should employ interventions that target removing both pain and effusion.

Quadriceps weakness is a common consequence of traumatic knee joint injury^1,2 and chronic degenerative knee joint conditions.^3,4 Arthrogenic muscle inhibition (AMI), a neurologic decline in muscle activation, results in quadriceps weakness and hinders rehabilitation by preventing gains in strength.⁵ The inability to reverse AMI and restore muscle function can lead to decreased physical abilities,⁶ biomechanical deficits,⁷ and possibly reinjury.⁵ Furthermore, researchers^8,9 have suggested that quadriceps weakness resulting from AMI may place patients at risk for developing osteoarthritis in the knee. In light of the substantial influence of quadriceps AMI on these clinically relevant outcomes, we need to improve our understanding of the factors that contribute to this neurologic decline in muscle activity so efforts to target and reverse it can be implemented and gains in strength can be achieved more easily.Joint injury and disease are accompanied by numerous sequelae (ie, pain, swelling, tissue damage, inflammation), so ascertaining which one ultimately leads to neurologic muscle dysfunction is difficult. Whereas a joint effusion can result in AMI,^10–12 the effects of pain are less understood despite many clinicians attributing AMI to pain. Using techniques that introduce knee pain without accompanying injury may provide insights into the role of pain in eliciting AMI.The degree of knee joint damage may play a role in the quantity of AMI that manifests. Hurley et al^13,14 demonstrated that quadriceps AMI, measured using an interpolated-twitch technique, was greater in patients with extensive traumatic knee injury (eg, fractured tibial plateau, ruptured medial collateral ligament, and medial meniscectomy) than patients with isolated joint trauma (ie, isolated anterior cruciate ligament [ACL] rupture). Similarly, patients with more knee joint symptoms (ie, greater number of symptoms and increased severity of symptoms) may present with greater magnitudes of quadriceps inhibition. Recently, investigators¹⁵ have suggested that patients with more pain display less quadriceps strength, supporting this tenet. Given that effusion and pain often present simultaneously with joint injuries and diseases, such as ACL injury and osteoarthritis, examining both the isolated and cumulative effects of these sequelae appears warranted to determine if they influence the magnitude of muscle inhibition.Experimental joint-effusion and pain models are safe and effective experimental methods that allow for the isolated examination of their effects on muscle function. The effusion model, whereby sterile saline is injected directly into the knee joint capsule,⁷ produces a clinically relevant magnitude of the joint effusion that may be present with traumatic injury. Effusion is thought to activate group II afferents responding to stretch or pressure,^16–18 which in turn may facilitate group Ib interneurons and result in quadriceps AMI.⁵ The pain model involves injecting hypertonic saline into the infrapatellar fat pad to produce anteromedial knee pain similar to that described in patients with patellofemoral pain syndrome.¹⁹ Pain is considered to initiate AMI through activation of group III and IV afferents that act as nocioceptors to signal damage or potential damage to joint structures.^16–18 The firing of these afferents then may lead to facilitation of group Ib interneurons, the flexion reflex, or the gamma loop, ultimately resulting in quadriceps inhibition.²⁰ Thus, these models allow us to create symptoms that are associated with knee injury and have the added benefit of providing a way to examine their effects in isolation.Therefore, the purpose of our study was to determine the effects of pain on quadriceps strength and activation and to learn if simultaneous pain and knee joint effusion would affect the magnitude of quadriceps dysfunction. We hypothesized that pain alone would result in quadriceps inhibition and that the magnitude of inhibition would be greater when effusion and pain were present simultaneously.     

即早基因c-fos与脑血管病及学习记忆

即早基因c-fos是广泛存在于原核细胞和真核细胞的高度保守基因.在正常情况下,c-fos基因参与细胞生长、分化、信息传递、学习和记忆等生理过程,而在病理情况下c-fos基因表达及调控变化与多种疾病的发生和发展有关.C-fos在中枢神经系统的某些部位可有基础水平的表达,但表达很低,当受到如脑缺血、脑出血、痫性发作、应激等刺激后,其在数十分钟内做出反应,在对外界刺激-转录耦联的信忠传递过程中起着核内第三信使的重要作用.     

Opportunities and challenges in the prevention and control of cancer and other chronic diseases: children's diet and nutrition and weight and physical activity

OBJECTIVE: The purpose of this article is to review the role of behavioral research in disease prevention and control, with a particular emphasis on lifestyle- and behavior-related cancer and chronic disease risk factors--specifically, relationships among diet and nutrition and weight and physical activity with adult cancer, and tracking developmental origins of these health-promoting and health-compromising behaviors from childhood into adulthood. METHOD: After reviewing the background of the field of cancer prevention and control and establishing plausibility for the role of child health behavior in adult cancer risk, studies selected from the pediatric published literature are reviewed. Articles were retrieved, selected, and summarized to illustrate that results from separate but related fields of study are combinable to yield insights into the prevention and control of cancer and other chronic diseases in adulthood through the conduct of nonintervention and intervention research with children in clinical, public health, and other contexts. RESULTS: As illustrated by the evidence presented in this review, there are numerous reasons (biological, psychological, and social), opportunities (school and community, health care, and family settings), and approaches (nonintervention and intervention) to understand and impact behavior change in children's diet and nutrition and weight and physical activity. CONCLUSIONS: Further development and evaluation of behavioral science intervention protocols conducted with children are necessary to understand the efficacy of these approaches and their public health impact on proximal and distal cancer, cancer-related, and chronic disease outcomes before diffusion. It is clear that more attention should be paid to early life and early developmental phases in cancer prevention.