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.     

内源性痛觉调制系统的双向调节

近年来在内源性痛觉调制系统的调控机制方面取得了重大进展。脑干的羟胺能通路和去甲肾上腺素能通路共同构成了控制脊髓水平伤害性信息传递的下行调控系统。在组织损伤和炎症后,疼痛下行调节系统在功能上表现出可塑性。脑干的下行抑制及易化系统是同时被激活的,抑制及易化通路之间的相互平衡是影响脊髓兴奋性增高及痛觉过敏形成的关键。当下行抑制及易化调节系统的失衡并引起的内源性易化系统的效应增高时,非伤害性刺激也可被感觉为疼痛。     

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.     

主动运动和被动运动的镇痛效果及其镇痛机制

主动运动和被动运动可以有效缓解各种急性疼痛和慢性疼痛,且主动运动诱发的镇痛效果强于运动参数相似的被动运动.文章在讨论运动镇痛机制的基础上,探讨了主、被动运动镇痛效果存在差异的原因.具体来说,通过比较两种运动传导运动信息的下行通路和传导躯体感觉/本体感觉的上行通路,论述了主、被动运动在生理(外周神经系统和中枢神经系统)和心理(情绪和认知)层面上镇痛机制的异同.由于被动运动缺少运动下行控制且肌肉激活程度小,其在外周镇痛物质含量和皮层水平上对疼痛的调控弱于主动运动.此外,被动运动相比主动运动不易诱发积极情绪,较难转移对疼痛的注意力,缺乏身体掌控感并拥有较低的身体归属感,进而导致较弱的镇痛效果.最后,文章指出了目前本领域研究的局限性,并对运动镇痛未来的研究方向和方法提出了建议.     

大鼠脊髓内甲啡肽、亮啡肽和甲七肽在镇痛和电针镇痛中的不同作用

1.给大鼠脊髓蛛网膜下腔注射甲啡肽200—800nmol引起与剂量相关的镇痛效应。注射脑啡肽降解酶抑制剂Thiorphan 50nmol或Benatin 300nmol可加强电针镇痛,注射甲啡肽抗体则可对抗电针镇痛。这些资料说明内源性甲啡肽确实在痛觉调制系统中起着重要作用。 2.脊髓蛛网膜下腔注射亮啡肽800nmol使痛阈升高44％,其镇痛效应尚不及200nmol甲啡肽的作用(痛闻升高61％);注射甲七肽10-200nmol未见痛阈明显改变。注射亮啡肽或甲七肽抗体并不能对抗电针镇痛;注射甲七肽降解酶抑制剂Captopril 1000nmol也不能加强电针镇痛。这些资料说明,脊髓中的亮啡肽和甲七肽存痛觉调制中可能不起重要作用。     

内源性大麻素系统对皮层下运动中枢的调控作用

以往研究已证明,内源性大麻素系统广泛存在于中枢和外周神经组织中,并作为逆向信号分子在突触信号传递中发挥重要调节作用。本文就内源性大麻素系统对皮层下运动中枢的调控作用及相关机制进行综述,以期系统地论述皮层下运动中枢在躯体运动、动作选择和运动技能学习等高级神经活动过程中的突触和神经环路机制,并为相关疾病的治疗和靶向药物开发提供理论依据。     

手术截断小鼠尾末端诱发的痛觉过敏和吗啡镇痛效应

手术截断小鼠尾末端可诱发长期性的痛觉过敏和吗啡镇痛效应变化。这种长期性的变化可能是由于中枢神经系统的神经可塑性变化引起的(从脊髓背角到皮层)。在截尾5周后,小鼠后肢和余下的尾端出现痛敏反应。低剂量吗啡可诱发热板的易化反应。这些可塑性变化能延长至5周,因此小鼠的截尾模型可以用于研究截肢后的中枢性长期性的可塑性变化。     

皮层内刺激或冷冻阻滞体感Ⅰ区对猴的操作式条件反射和针刺镇痛作用的影响

为了研究皮层体感Ⅰ区(S_Ⅰ 区)在痛觉的产生和调制以及在针刺镇痛中的作用,以皮肤伤害性刺激引起的操作式条件反射为痛指标,用钨丝微电极记录神经元的电活动和进行皮层内刺激,并用冰盐水进行皮层局部阻滞,在10只清醒的、可以活动的猕猴上进行了实验观察。刺激皮层 S_Ⅰ 区对感受野部位皮肤痛阈可产生明显的影响。在51次实验中有46次引起了痛阈的变化,仅有5次未见明显的变化。在13次对非感受野的皮肤痛阈的影响的实验中,10次未见变化,仅有3次出现轻度变化。皮层内刺激效应往往在刺激开始就出现,并延续到刺激的全过程。停止刺激后痛阈的恢复约需4—6分钟。皮层内刺激对针刺镇痛效应的影响与其对皮肤痛阈的影响有极为密切的关系,即皮层内刺激使皮肤痛阈下降者往往是对抗针刺的镇痛效应,而使皮肤痛阈升高者往往是加强针刺的镇痛效应。在12次冷冻皮层 S_Ⅰ 区的实验中全部都表现为使感受野皮肤痛阈的升高。去冷冻后约需3—8分钟才由抑制状态回复到原来水平。而对非感受野皮肤痛阈影响的8次实验中,有6次没有产生任何影响。本实验的结果表明,皮层体感区对痛觉是有一定的调制作用,当其受到电刺激或冷冻阻滞时,均可使相应部位的皮肤痛阈降低或升高,同时还能对抗或加强针刺的镇痛效应。     

皮层蛋白介导斑马鱼(Danio rerio)原肠化细胞运动

在胚胎发育过程中, 细胞运动对指导原肠期胚胎细胞的时空定位并决定其发育命运具有核心作用, 然而活体状态下原肠化过程中细胞运动的调控机制目前并不清楚. 微丝结合蛋白皮层蛋白(cortactin)是微丝核化过程的重要调控分子, 它通过激活微丝相关蛋白2/3复合物(Arp2/3 complex)促进微丝在细胞前导缘区域迅速组装, 从而直接作用于细胞运动. 为阐明斑马鱼(Danio rerio)原肠化细胞运动的分子调控机制, 本研究首先检测了皮层蛋白在斑马鱼胚胎发育过程的表达水平. Western blotting分析证明皮层蛋白在斑马鱼原肠期胚胎中大量表达; 整装胚胎抗体染色结果表明在斑马鱼原肠化过程中, 皮层蛋白主要分布于胚胎背侧胚盾区域的细胞中, 在发生活跃运动的上皮层细胞和下皮层细胞中含量较高;在亚细胞水平, 皮层蛋白和Arp2/3复合物共同定位于运动的皮层区域, 并在细胞连接处也有大量分布. 此外, 研究还发现皮层蛋白在发育中的中枢神经系统中表达量较高. 本研究结果首次表明皮层蛋白和Arp2/3复合物介导的微丝聚合参予了斑马鱼原肠化细胞运动, 并在中枢神经系统发育中扮演重要角色.     

大鼠脊髓蛛网膜下腔注射5-羟色胺和吗啡的镇痛作用

本工作利用大鼠脊髓蛛网膜下腔注射的方法,观察了在脊髓水平5-HT 和吗啡的镇痛作用及其相互关系。结果如下:(1)脊髓蛛网膜下腔注射 200μg 5-HT 或10μg吗啡可产生明显的镇痛作用,并分别被 5-HT受体阻断剂肉桂硫胺和阿片受体阻断剂纳洛酮所对抗。(2)单纯使用肉桂硫胺可产生痛敏。纳洛酮对痛阈无明显影响。(3)5-HT 镇痛作用不能被大剂量纳洛酮(10mg/kg,sc)阻断。吗啡镇痛作用则可被脊髓蛛网膜下腔注射肉桂硫胺所削弱。后一效应可能与肉桂硫胺本身可引起痛敏有关。上述结果表明,在脊髓水平5-HT 和吗啡可通过各自的受体产生镇痛作用,两者间无明显依赖关系。5-HT 可能有紧张性活动,内源性阿片肽似不存在紧张性作用。     

Investigation on the effectiveness of abdominal hollowing home-exercises using a portable ultrasound: Randomized controlled trial

We used a 3-arm randomized control trial to investigate whether abdominal hollowing (AH) home exercise using pocket-sized ultrasonography (US)—miruco (AH with miruco group)—was more effective than conventional AH home exercise using abdominal palpation and or also a wait-and-see approach (control group) to improve isolated control of the transversus abdominis (TrA) muscle during AH. We randomized 60 participants with low back pain into the three groups equally. Primary outcome measures for the US group were percentage of change in TrA thickness and excursion of the edge of the TrA fascia during AH when the thickness of the internal or external oblique muscles increased. Score on the Oswestry Disability Index (ODI) was a secondary outcome measure. The intervention period was 1 week, followed by 1 week without intervention. As a result, we found no statistically significant interaction effect (P > .05) in changes of the primary outcome measures from baseline for each follow-up period. The AH with miruco group had a statistically lower ODI (P = .036) than did the control group after the intervention. Results indicate a limited benefit for use of the miruco in AH home exercise to improve isolated control of the TrA muscle during AH.     

Minimising pain in farm animals: the 3S approach – ‘Suppress,Substitute, Soothe’

Recently, the French National Institute for Agricultural Research appointed an expert committee to review the issue of pain in food-producing farm animals. To minimise pain, the authors developed a ‘3S’ approach accounting for ‘Suppress, Substitute and Soothe’ by analogy with the ‘3Rs’ approach of ‘Reduction, Refinement and Replacement’ applied in the context of animal experimentation. Thus, when addressing the matter of pain, the following steps and solutions could be assessed, in the light of their feasibility (technical constraints, logistics and regulations), acceptability (societal and financial aspects) and availability. The first solution is to suppress any source of pain that brings no obvious advantage to the animals or the producers, as well as sources of pain for which potential benefits are largely exceeded by the negative effects. For instance, tail docking of cattle has recently been eliminated. Genetic selection on the basis of resistance criteria (as e.g. for lameness in cattle and poultry) or reduction of undesirable traits (e.g. boar taint in pigs) may also reduce painful conditions or procedures. The second solution is to substitute a technique causing pain by another less-painful method. For example, if dehorning cattle is unavoidable, it is preferable to perform it at a very young age, cauterising the horn bud. Animal management and constraint systems should be designed to reduce the risk for injury and bruising. Lastly, in situations where pain is known to be present, because of animal management procedures such as dehorning or castration, or because of pathology, for example lameness, systemic or local pharmacological treatments should be used to soothe pain. These treatments should take into account the duration of pain, which, in the case of some management procedures or diseases, may persist for longer periods. The administration of pain medication may require the intervention of veterinarians, but exemptions exist where breeders are allowed to use local anaesthesia (e.g. castration and dehorning in Switzerland). Extension of such exemptions, national or European legislation on pain management, or the introduction of animal welfare codes by retailers into their meat products may help further developments. In addition, veterinarians and farmers should be given the necessary tools and information to take into account animal pain in their management decisions.     

Non-invasive assessment of animal exercise stress: real-time PCR of GLUT4, COX2, SOD1 and HSP70 in avalanche military dog saliva

Exercise has been shown to increase mRNA expression of a growing number of genes. The aim of this study was to assess if mRNA expression of the metabolism- and oxidative stress-related genes GLUT4 (glucose transporter 4), COX2 (cyclooxygenase 2), SOD1 (superoxide dismutase 1) and HSP70 (heat shock protein 70) in saliva changes following acute exercise stress in dogs. For this purpose, 12 avalanche dogs of the Italian Military Force Guardia di Finanza were monitored during simulation of a search for a buried person in an artificial avalanche area. Rectal temperature (RT) and saliva samples were collected the day before the trial (T0), immediately after the descent from a helicopter at the onset of a simulated avalanche search and rescue operation (T1), after the discovery of the buried person (T2) and 2 h later (T3). Expressions of GLUT4, SOD1, COX2 and HSP70 were measured by real-time PCR. The simulated avalanche search and rescue operation was shown to exert a significant effect on RT, as well as on the expression of all metabolism- and oxidative stress-related genes investigated, which peaked at T2. The observed expression patterns indicate an acute exercise stress-induced upregulation, as confirmed by the reductions in expression at T3. Moreover, our findings indicate that saliva is useful for assessing metabolism- and oxidative stress-related genes without the need for restraint, which could affect working dog performance.     

普拉提运动对慢性下腰痛患者的疼痛和腰椎功能的影响

为了揭示普拉提运动对慢性下腰痛患者的疼痛和腰椎功能的影响,本研究选择2017年1月至2018年6月在医院确诊并接受治疗的64例慢性下腰痛患者作为研究对象,根据运动疗法分为对照组(悬吊训练法)和观察组(悬吊训练法结合普拉提运动),采用视觉模拟评分(VAS)评价患者的疼痛程度,采用Oswestry功能障碍指数(ODI)评价患者的腰椎功能障碍情况,采用运动情境动机量表(SSIMS)评价患者的运动参与动机。研究显示,治疗后观察组的VAS评分显著低于对照组(p=0.043)。观察组治疗后的ODI总评分显著低于对照组(p=0.026),观察组患者治疗后的疼痛、生活自理、提物、行走和站立5个维度评分显著低于对照组(p<0.05)。SSIMS量表的4个维度中,鉴别原则得分最高,其次为内部动机,然后是外部调节,最后为缺乏动机。本研究结果提示,普拉提运动可显著降低下腰痛患者的疼痛程度,并改善腰椎功能。此外,普拉提运动具有较好的患者认可度和喜爱度,值得在临床和运动康复训练中应用。     

Cannabis, pain, and sleep: lessons from therapeutic clinical trials of Sativex, a cannabis-based medicine

Cannabis sativa L. has been utilized for treatment of pain and sleep disorders since ancient times. This review examines modern studies on effects of Delta9-tetrahydrocannabinol (THC) and cannabidiol (CBD) on sleep. It goes on to report new information on the effects on sleep in the context of medical treatment of neuropathic pain and symptoms of multiple sclerosis, employing standardized oromucosal cannabis-based medicines containing primarily THC, CBD, or a 1 : 1 combination of the two (Sativex). Sleep-laboratory results indicate a mild activating effect of CBD, and slight residual sedation with THC-predominant extracts. Experience to date with Sativex in numerous Phase I-III studies in 2000 subjects with 1000 patient years of exposure demonstrate marked improvement in subjective sleep parameters in patients with a wide variety of pain conditions including multiple sclerosis, peripheral neuropathic pain, intractable cancer pain, and rheumatoid arthritis, with an acceptable adverse event profile. No tolerance to the benefit of Sativex on pain or sleep, nor need for dosage increases have been noted in safety extension studies of up to four years, wherein 40-50% of subjects attained good or very good sleep quality, a key source of disability in chronic pain syndromes that may contribute to patients' quality of life.     

Behavioral and immunohistochemical investigations of the effects of phytoestrogens on pain, analgesia, and inflammation: Gender dependency

The effects of long-term administration of the phytoestrogens (PEs) genistein (Gen) and naringenin (Nar) on nociception, imflammatory hyperalgesia, and metamizol-induced analgesia, the efficacy of PEs vs 17β-E to modulate nociception, as well as the gender dependency of PE effects, and NOS and TH (NO synthase and tyrosine hydroxylase, respectively) expression in the periaqueductal gray (PAG) were studied in gonadectomized female and male rats. The paw pressure, tail flick, and hot plate tests, incapacitance test, and plethismometry were employed for in vivo studies. For in vitro studies, immuno-or histochemical staining of NOS and TH expression in PAG were applied. Data revealed that PEs, like 17β-E, decreased nociceptive thresholds in both sexes, but more significantly in female rats. Genistein intensified carrageenan-induced exudative inflammatory reaction and modulated metamizol-induced analgesia. Long-term PE administration resulted in gender-specific alterations of NO and TH expression. The effects of PEs might be correlated with gender-specific 17β-E-like action in male and female individuals. The results suggest that, similarly to other estrogen-like compounds, PEs can play a significant role in the individualization of analgesic therapy. Neirofiziologiya/Neurophysiology, Vol. 38, No. 4, pp. 350–353, July–August, 2006.     

Zonisamide: Antihyperalgesic efficacy,the role of serotonergic receptors on efficacy in a rat model for painful diabetic neuropathy

Aims

The purpose of this study was to compare the changes of antihyperalgesic effectiveness of zonisamide (25 and 50 mg/kg), an antiepileptic drug, on the early and late phases of neuropathy and to investigate the role of serotonergic descending inhibitory pain pathways in antihyperalgesic effectiveness of zonisamide in the streptozotocin-induced rat model for painful diabetic neuropathy.

Main methods

The hot-plate and tail-immersion, to determine thermal thresholds, and paw pressure withdrawal tests, to determine mechanical thresholds, were performed as hyperalgesia tests. To investigate the role of serotonergic pathway, 1 mg/kg ketanserin (5-HT_2A/2C antagonist) and ondansetron (serotonin 5-HT₃ receptor antagonist) were used.

Key findings

Zonisamide enhanced pain thresholds significantly in the 3rd, 6th and 8th weeks as the reference drugs morphine (5 mg/kg) and carbamazepine (32 mg/kg, tested only in the 3rd week). There were no observed differences on the potency of antihyperalgesic effect between weeks and between doses. Each antagonist reversed the effect of zonisamide in the hot-plate and tail-immersion tests significantly, but, relatively in the paw pressure withdrawal tests.

Significance

These results support the role for zonisamide in the management of diabetic neuropathic pain in all phases. Serotonin 5-HT_2A/2C and 5-HT₃ receptors are involved in the antihyperalgesic effect of zonisamide by enhancement of thermal threshold, and partially by mechanical threshold, so they may not mediate mechanical hyperalgesia in diabetic neuropathy.     

Whole-body vibration mediates mechanical hypersensitivity through Aβ-fiber and C-fiber thermal sensation in a chronic pain model

Whole-body vibration (WBV), which is widely used as a type of exercise, involves the use of vibratory stimuli and it is used for rehabilitation and sports performance programmes. This study aimed to investigate the effect of WBV treatment in a chronic pain model after 10 WBV sessions. An animal model (chronic pain) was applied in 60 male Wistar rats (±180 g, 12 weeks old) and the animals were treated with low intensity exercise (treadmill), WBV (vibrating platform), and a combined treatment involving both. The controls on the platform were set to a frequency of 42 Hz with 2 mm peak-to-peak displacement, g ≈ 7, in a spiral mode. Before and after the vibration exposure, sensitivity was determined. Aβ-fibers-mediated mechanical sensitivity thresholds (touch-pressure) were measured using a pressure meter. C-fibers-mediated thermal perception thresholds (hot pain) were measured with a hot plate. After each session, WBV influenced the discharge of skin touch-pressure receptors, reducing mechanical sensitivity in the WBV groups (P < 0.05). Comparing the conditions “before vs. after”, thermal perception thresholds (hot pain) started to decrease significantly after the third WBV session (P < 0.05). WBV decreases mechanical hyperalgesia after all sessions and thermal sensitivity after the third session with the use of WBV.