综述与专论: 内脏痛实验动物模型的研究进展

内脏痛是内脏器官受到机械性牵拉、炎症、痉挛、应激和缺血等刺激所致的疼痛，是一种临床上常见病症。与躯体痛相比，内脏痛的产生、维持和调控机制更为复杂，因此是目前疼痛基础研究领域中的重点和难点之一。建立符合临床内脏疾病病理生理学特征的实验动物模型对研究内脏痛的产生、维持、调控机制及筛选相关内脏疾病的治疗药物具有重要意义。目前内脏痛动物模型主要按照造模刺激方式进行分类，分为炎性内脏痛模型、电刺激性内脏痛模型、机械扩张性内脏痛模型及缺血性内脏痛模型等，且每种动物模型具有不同特点。本文就近年来内脏痛基础研究中常用的实验动物模型的制备及特点做一简要综述，以期为研究者选择合适的内脏痛动物模型提供参考，为更深入研究内脏痛的复杂机制及筛选相关治疗药物奠定基础。     

多模式术后镇痛在腹腔镜结肠手术中的应用

目的:理论上联合使用不同机制镇痛药较镇痛药单独使用镇痛效果更完善,在妇科、骨科等手术中已有结论;笔者观察比较腹腔镜结肠手术术使用单一止痛药及联合使用不同机制镇痛药在术后镇痛的效果以及各自不良反应的发生率。方法:择期腹腔镜结肠手术患者90例,随机分为3组,每组30例。A组使用地佐辛+氟比洛酚酯行术后镇痛为多模式镇痛组;B组使用地佐辛行术后镇痛;C组使用氟比洛酚酯行术后镇痛。记录每组术后4、8、12、24 h视觉模糊评分(VAS)及术后不良反应包括嗜睡、躁动、恶心呕吐的发生率。结果:A组术后4 h、8 h的VAS评分低于B、C两组,差异有显著性,A组无嗜睡及躁动发生,发生呕吐1例,不良反应发生率A组低于B、C两组,差异有显著性。结论:地佐辛+氟比洛酚酯联合用药可安全有效应用于腹腔镜结肠手术术后镇痛,是一种有效的多模式术后镇痛方式,在减弱疼痛的放大效应及对中枢神经的作用两方面起效,因而较单独使用地佐辛及氟比洛酚酯有更好的镇痛效果,且不良反应低于单独使用地佐辛及氟比洛酚酯。     

Phasic and Tonic Pain Differentially Impact the Interruptive Function of Pain

The interruptive effect of painful experimental stimulation on cognitive processes is a well-known phenomenon. This study investigated the influence of pain duration on the negative effects of pain on cognition. Thirty-four healthy volunteers performed a rapid serial visual presentation task (RSVP) in which subjects had to detect (visual detection task) and count the occurrence of a target letter (working memory task) in two separate sessions while being stimulated on the left volar forearm with either short (2 sec) or long (18 sec) painful heat stimuli of equal subjective intensity. The results show that subjects performed significantly worse in the long pain session as indexed by decreased detection and counting performance. Interestingly, this effect on performance was also observed during control trials of the long pain session in which participants did not receive any painful stimulation. Moreover, subjects expected long painful stimulation to have a greater impact on their performance and individual expectation correlated with working memory performance. These findings suggest that not only the length of painful stimulation but also its expected ability to impair cognitive functioning might influence the interruptive function of pain. The exact relevance of expectation for the detrimental effects of pain on cognitive processes needs to be explored in more detail in future studies.     

Design and Assessment of a Potent Sodium Channel Blocking Derivative of Mexiletine for Minimizing Experimental Neuropathic Pain in Several Rat Models

Physical or chemical damage to peripheral nerves can result in neuropathic pain which is not easily alleviated by conventional analgesic drugs. Substantial evidence has demonstrated that voltage-gated Na⁺ channels in the membrane of damaged nerves play a key role in the establishment and maintenance of pathological neuronal excitability not only of these peripheral nerves but also in the second- and third-order neurons in the pain pathway to the cerebral cortex. Na⁺ channel blocking drugs have been used in treating neuropathic pain with limited success mainly because of a preponderance of side-effects. We have developed an analogue of mexiletine which is approximately 80 times more potent than mexiletine in competing with the radioligand, ³H-batrachotoxinin for binding to Na⁺ channels in rat brain membranes and also it is much more lipophilic than mexiletine which should enhance its uptake into the brain to block the increased expression of Na⁺ channels on second- and third-order neurons of the pain pathway. This analogue, HFI-1, has been tested in three different rat models of neuropathic pain (formalin paw model, ligated spinal nerve model and contusive spinal cord injury model) and found to be more effective in reducing pain behaviours than mexiletine.     

Pain Threshold and Arthritis

Pain threshold was measured in 106 patients with rheumatoid arthritis, 50 with ankylosing spondylitis, and 50 normal controls using Keele''s algometer. In rheumatoid arthritis patients with a low pain threshold had more severe pain for a greater part of the day and required more tablets for pain relief. In ankylosing spondylitis the pain threshold was higher and was not related to pain or analgesic requirements. There was no evidence that pain threshold affected the course or outcome of rheumatoid arthritis in any way.     

苦参碱对神经病理性大鼠背根神经节P2X3受体、疼痛行为学和疼痛阈值的影响

摘要 目的：探讨苦参碱对神经病理性大鼠背根神经节P2X3受体、疼痛行为学和疼痛阈值的影响。方法：选择Sprague-Dawley雄性大鼠30只,随机分为3组,包括模型组、试验组和假手术组。于大鼠造模成功1 d后,试验组给予30 mg/（kgod）的剂量在腹腔注射苦参碱溶液,1次/d;给予假手术组和模型组腹腔注射等量浓度为0.9 %的氯化钠溶液,1次/d,共14 d。进行自发疼痛行为学评分检测、机械痛阈值检测、热痛阈值检测、P2X2和P2X3mRNA相对表达量检测、P2X2和P2X3蛋白表达水平检测,以及氧化应激指标水平检测。结果：术后模型组与试验组自发性疼痛行为学评分与假手术组比均升高,自术后第5天起,与模型组比,试验组自发性疼痛行为学评分明显低于模型组（P<0.05）;自术后第3天起,相较于假手术组,模型组机械痛阈值、热痛阈值显著下降,相较于模型组,试验组自术后第5天起机械痛阈值、热痛阈值显著上升（均P<0.05）;术后第14天试验组与假手术组机械痛阈值、热痛阈值对比无差异（P>0.05）;模型组P2X2和P2X3mRNA、P2X2及P2X3蛋白比假手术组和试验组高（均P<0.05）,试验组和假手术组P2X2、P2X3mRNA、P2X2及P2X3蛋白比较无差异（P>0.05）;干预前及干预1、2周后模型组大鼠脊髓组织SOD比假手术组低,MDA比假手术组高;试验组大鼠脊髓组织SOD比模型组高,MDA比模型组低（均P<0.05）。结论：苦参碱可有效缓解神经病理性痛的所引发的机械痛觉和热痛觉,镇痛作用较好,机制可能在于其可使大鼠背根神经元中P2X2、P2X3受体下降相关,同时其在抑制神经病理性大鼠脊髓组织氧化应激反应方面有一定的作用,与其在对神经病理性痛大鼠脊髓组织神经元凋亡的抑制有密切关系。     

经颅电刺激镇痛研究的现状及展望

经颅电刺激技术是一种非侵入性神经调控方法,因其具有卓越的安全性、良好的患者依从性以及高度便携性等特点,被视为一种潜在的非药物镇痛手段。然而,目前对于经颅电刺激镇痛效果的研究结果不一致且镇痛机制尚未完全阐明。本文通过系统归纳总结3种主要的经颅电刺激技术——经颅直流电刺激、经颅交流电刺激和经颅随机噪声刺激——在镇痛领域的研究进展,评估了这些技术对短时、急性和慢性疼痛的镇痛效果,并深入剖析了其潜在的镇痛机制。同时,本文系统讨论了既往研究的局限性,并对未来研究提出了一系列切实可行的建议,如借助电场模拟技术实现个性化刺激以克服不同个体头部解剖结构差异的影响、应用多位点刺激和深部脑刺激技术来拓展刺激脑区、搭建经颅电刺激技术同步神经影像平台以制定个体特异性的刺激方案并深入揭示其镇痛机制、探索与其他治疗技术的联合应用以提高疗效等。这些建议的实施将有助于解决当前研究中存在的问题,充分发挥经颅电刺激在疼痛治疗中的临床价值,最终实现患者疼痛的缓解。     

下行疼痛易化系统在吗啡耐受机制中的作用

吗啡是临床上常用的一种阿片类镇痛药物,广泛用于治疗各种类型疼痛,但是长期应用吗啡会造成吗啡耐受,从而限制了吗啡的临床应用。吗啡耐受的机制十分复杂,近年来的研究表明下行疼痛易化系统参与了吗啡耐受,本文拟对近年来此方面的研究进行综述。     

帕瑞昔布钠在术后镇痛中应用的研究进展

手术方式的不断完善和创新,对术后镇痛提出了更高要求。非甾体抗炎药为我国临床术后镇痛常用的一类药物,近年来应用范围仍在不断扩大,但总结长期术后镇痛用药经验发现,传统的非甾体抗炎药易引起胃肠道毒性反应和血小板抑制,因此迫切需要寻找一种安全、有效的术后镇痛药物。帕瑞昔布钠是一种环氧合酶-2(COX-2)特异性抑制剂,注射使用,可用于术后不同程度疼痛的短期治疗,近年来已被临床实践证实具有良好的疗效和较高的安全性。本文结合已经发表的临床研究报道对该药物在术后镇痛中的应用进展进行综述,旨在对该药物的作用机制、疗效、安全性有一个系统性的认识。     

下行疼痛易化系统在吗啡耐受机制中的作用

吗啡是临床上常用的一种阿片类镇痛药物,广泛用于治疗各种类型疼痛,但是长期应用吗啡会造成吗啡耐受,从而限制了吗啡的临床应用。吗啡耐受的机制十分复杂,近年来的研究表明下行疼痛易化系统参与了吗啡耐受,本文拟对近年来此方面的研究进行综述。     

A review of pain assessment techniques and pharmacological approaches to pain relief after bovine castration: Practical implications for cattle production within the United States

Castration of male calves destined for beef production is a common livestock management practice in the United States amounting to approximately 7 million procedures per year. Recently there has been renewed interest in identifying methods to reduce pain associated with dehorning and castration. Although several studies have reported that analgesic drug administration prior to castration attenuates plasma cortisol response, there are currently no compounds specifically approved for pain relief in livestock in the U.S. Validated pain assessment tools are needed to support regulatory approval of analgesic compounds. This may include use of accelerometers, videography, heart rate variability determination, electroencephalography, thermography and plasma neuropeptide measurement to assess behavioral, physiological and neuroendocrine changes associated with a pain response. Extra-label drug use (ELDU) for pain relief is regulated under the Animal Medicinal Drug Use Clarification Act (AMDUCA) and requires that drugs be administered by or under the supervision of a veterinarian. Agents that may provide preemptive analgesia include local anesthetics, nonsteroidal anti-inflammatory drugs (NSAIDs), opioids, α2-agonists, and N-methyl d-aspartate (NMDA) receptor antagonists. A review of the published literature suggests that a significant decrease in plasma cortisol concentration after castration was associated with preemptive administration of a NSAID and local anesthesia. Local anesthesia alone tended to decrease peak plasma cortisol concentrations more than NSAIDs. However NSAIDs alone tended to decrease the area under the plasma cortisol-time curve more than local anesthesia alone. These findings suggest that multimodal analgesic regimens that extend into the post-operative period are more effective at mitigating pain and distress associated with castration than a single drug modality. Regulatory approval of safe and cost effective analgesic compounds with convenient routes of administration is needed for routine use of pain relieving drugs to be considered as standard practice at the time of castration.     

Evaluation of Anti-Hyperalgesic and Analgesic Effects of Two Benzodiazepines in Human Experimental Pain: A Randomized Placebo-Controlled Study

Background and Aims

Compounds that act on GABA-receptors produce anti-hyperalgesia in animal models, but little is known on their effects in humans. The aim of this study was to explore the potential usefulness of GABA-agonism for the control of pain in humans. Two agonists at the benzodiazepine-binding site of GABA_A-receptors (clobazam and clonazepam) were studied using multiple experimental pain tests. Positive results would support further investigation of GABA agonism for the control of clinical pain.

Methods

In a randomized double-blind crossover design, 16 healthy male volunteers received clobazam 20 mg, clonazepam 1 mg and tolterodine 1 mg (active placebo). The area of static hyperalgesia after intradermal capsaicin injection was the primary endpoint. Secondary endpoints were: area of dynamic hyperalgesia, response to von Frey hair stimulation, pressure pain thresholds, conditioned pain modulation, cutaneous and intramuscular electrical pain thresholds (1, 5 and 20 repeated stimulation), and pain during cuff algometry.

Results

For the primary endpoint, an increase in the area of static hyperalgesia was observed after administration of placebo (p<0.001), but not after clobazam and clonazepam. Results suggestive for an anti-hyperalgesic effect of the benzodiazepines were obtained with all three intramuscular pain models and with cuff algometry. No effect could be detected with the other pain models employed.

Conclusions

Collectively, the results are suggestive for a possible anti-hyperalgesic effect of drugs acting at the GABA_A-receptors in humans, particularly in models of secondary hyperalgesia and deep pain. The findings are not conclusive, but support further clinical research on pain modulation by GABAergic drugs. Because of the partial results, future research should focus on compounds acting selectively on subunits of the GABA complex, which may allow the achievement of higher receptor occupancy than unselective drugs. Our data also provide information on the most suitable experimental models for future investigation of GABAergic compounds.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT01011036","term_id":"NCT01011036"}}NCT01011036     

疼痛管理对老年髋部骨折患者术后的影响

目的:临床分析疼痛管理应用于老年髋部骨折术后的影响。方法:选取我院2012年3月至2013年3月收治的50例老年髋部骨折患者,按照随机分配的方法,将其分为研究组与对照组,每组25例,对照组给予常规管理模式,研究组在常规管理模式基础上,给予规范化的疼痛管理,主要包含合理评估与应用镇痛药物、健康教育、个性化管理等管理内容,对比两组的管理效果。结果:经过管理后,研究组的疼痛评分入院时(2.792.79±0.69)、手术当日(2.39±0.93)、术后1d时(2.39±0.59)、术后3d(1.67±0.46)、出院时(1.29±0.46)明显优于对照组的入院时(2.39±1.13)、手术当日(2.49±1.10)、术后1d时(2.24±0.54)、术后3d(2.49±0.67)、出院时(1.94±0.50),两组疼痛评分对比,存在显著性差异(P0.05);研究组Barthel指数评分入院时(32.24±4.88)、出院时(45.24±7.85)明显优于对照组入院时(33.24±8.33)、出院时(38.49±7.95),两组对比存在显著性差异(P0.05)。研究组住院时间明显短于对照组,两组对比存在显著性差异(P0.05)。结论:针对老年髋部骨折患者,给予规范化的疼痛管理,可有效降低术后疼痛,使患者的生活能力显著增强,有利于患者早日康复,值得临床推广应用。     

Pyrrolinone derivatives as a new class of P2X3 receptor antagonists Part 2: Discovery of orally bioavailable compounds

Some P2X3 receptor antagonists have been developed as new therapeutic drugs for pain. We discovered a novel chemotype of P2X3 receptor antagonists with a pyrrolinone skeleton. Because of SAR studies to improve bioavailability of lead compound 2, compound (R)-24 was identified, which showed an analgesic effect against neuropathic pain by oral administration. We constructed a human P2X3 homology model as a template for the zebrafish P2X4 receptor, which agreed with SAR studies of pyrrolinone derivatives.     

TNS-evoked long loop effects.

Local analgesia can be produced by transcutaneous electrical stimulation of peripheral nerves. This is used in the treatment of chronic pain states. Its clinical effectiveness depends on two points; namely (1) the stimulation has to be perceptible, and (2) paresthesias elicited by TNS must be localized in the area of pain. To verify this in healthy subjects we produced an experimental pain by radiant heating of the skin and tested the analgesic effect of TNS. TNS stimuli parameters (duration, amplitude and frequency) were determined so that double blind conditions were given. Stimulation with small rectangular pulses showed the best analgesic effect especially at a stimulation rate of 100 Hz. The stimulation of various nerves showed that most of the analgesic effects depend on spinal level mechanisms but probably long loop effects are involved.     

A Novel Magnetic Stimulator Increases Experimental Pain Tolerance in Healthy Volunteers - A Double-Blind Sham-Controlled Crossover Study

The ‘complex neural pulse’^TM (CNP) is a neuromodulation protocol employing weak pulsed electromagnetic fields (PEMF). A pioneering paper reported an analgesic effect in healthy humans after 30 minutes of CNP-stimulation using three nested whole head coils. We aimed to devise and validate a stimulator with a novel design entailing a multitude of small coils at known anatomical positions on a head cap, to improve applicability. The main hypothesis was that CNP delivery with this novel device would also increase heat pain thresholds. Twenty healthy volunteers were enrolled in this double-blind, sham-controlled, crossover study. Thirty minutes of PEMF (CNP) or sham was applied to the head. After one week the other treatment was given. Before and after each treatment, primary and secondary outcomes were measured. Primary outcome was heat pain threshold (HPT) measured with thermal quantitative sensory testing. Other outcomes were warmth detection threshold, and aspects of cognition, emotion and motor performance. As hypothesized heat pain threshold was significantly increased after the PEMF stimulation. All other outcomes were unaltered by the PEMF but there was a trend level reduction of cognitive performance after PEMF stimulation as measured by the digit-symbol substitution task. Results from this pilot study suggest that our device is able to stimulate the brain and to modulate its function. This is in agreement with previous studies that used similar magnetic field strengths to stimulate the brain. Specifically, pain control may be achieved with PEMF and for this analgesic effect, coil design does not appear to play a dominant role. In addition, the flexible configuration with small coils on a head cap improves clinical applicability.

Trial Registration

Dutch Cochrane Centre NTR1093     

Antinociceptive effect of amitriptyline in mice of acute pain models

Tricyclic antidepressant drugs induce antinociceptive effect and suggest that their analgesic action could be related to the monoaminergic activity of the drugs. The analgesic activity of amitriptyline was observed in mouse models of acute pain. Mice were divided into different groups and were given amitriptyline in different doses alone and in combination with morphine. Reaction time in Hot-Plate and Tail-Flick tests was observed. Results showed that amitriptyline had antinociceptive effect in acute pain state in experimental models. Amitriptyline in combination with morphine had better analgesic effect than the morphine alone in Hot-Plate test.     

The Striatum and Pain Modulation

The aim of this review was to give a general aspect of the sensorial function of the striatum related to pain modulation, which was intensively studied in our laboratory. We analyse the effect of electrical and chemical stimulation of the striatum on the orofacial pain, especially that produced by tooth pulp stimulation of the lower incisors. We demonstrated specific sites within the nucleus which electrical or chemical stimulation produced inhibition of the nociceptive jaw opening reflex. This analgesic action of the striatum was mediated by activation of its dopamine D₂ receptors and transmitted through the indirect pathways of the basal ganglia and the medullary dorsal reticular nucleus (RVM) to the sensorial nuclei of the trigeminal nerve. Its mechanism of action was by inhibition of the nociceptive response of the second order neurons of the nucleus caudalis of the V par.     

Effects of Sensory Behavioral Tasks on Pain Threshold and Cortical Excitability

Background/Objective

Transcutaneous electrical stimulation has been proven to modulate nervous system activity, leading to changes in pain perception, via the peripheral sensory system, in a bottom up approach. We tested whether different sensory behavioral tasks induce significant effects in pain processing and whether these changes correlate with cortical plasticity.

Methodology/Principal Findings

This randomized parallel designed experiment included forty healthy right-handed males. Three different somatosensory tasks, including learning tasks with and without visual feedback and simple somatosensory input, were tested on pressure pain threshold and motor cortex excitability using transcranial magnetic stimulation (TMS). Sensory tasks induced hand-specific pain modulation effects. They increased pain thresholds of the left hand (which was the target to the sensory tasks) and decreased them in the right hand. TMS showed that somatosensory input decreased cortical excitability, as indexed by reduced MEP amplitudes and increased SICI. Although somatosensory tasks similarly altered pain thresholds and cortical excitability, there was no significant correlation between these variables and only the visual feedback task showed significant somatosensory learning.

Conclusions/Significance

Lack of correlation between cortical excitability and pain thresholds and lack of differential effects across tasks, but significant changes in pain thresholds suggest that analgesic effects of somatosensory tasks are not primarily associated with motor cortical neural mechanisms, thus, suggesting that subcortical neural circuits and/or spinal cord are involved with the observed effects. Identifying the neural mechanisms of somatosensory stimulation on pain may open novel possibilities for combining different targeted therapies for pain control.     

经皮穴位电刺激治疗术后疼痛的研究进展

术后疼痛是术后常见的一种伤害性疼痛,随着舒适化医疗的倡导,经皮穴位电刺激因其无创、安全等优点受到关注。经皮穴位电刺激是将经皮神经电刺激与针灸穴位理论相结合的一种方法,虽有研究证实其频率、波形、强度、刺激时间的设定及不同穴位的配伍对镇痛效果均可产生较大的影响,但在规范化方面仍有不足。本文总结其使用方法及镇痛疗效,以期对经皮穴位电刺激应用于临床提供最优参数及穴位配伍,使之规范化,从而发挥出最佳镇痛效果。