We acknowledge funding support by K23 AT008477 (Kong), NIH K23 DA031808 (Johnson), and the Chris Redlich Endowment in Pain Research (Mackey, Dixon).

1.时间总和协议<ol><li>设备<ol><li>热脉冲传递和地点: <ol><li>使用圆形热电极，直径为2.9厘米这个热电极具有驱动的微处理器，自动化控制系统，并且，能够迅速的温度变化的珀尔帖元件。放置在受试者的鱼际热电极，并使用手套以固定的位置。 </li></ol></li><li>计算机接口: <ol><li>接口热电极上能精确控制温度交付一台笔记本电脑的软件程序。根据表1中所列的规格预编程的适当热刺激的协议的各个阶段（训练1和仅2中，作为最优化和最终的试验遵循相同的脉冲结构作为训练2）。 </li><li>通过选择合适的软件，每个阶段的热刺激计划执行热脉冲的传递，调节温度和打击"ST艺术"在用户界面上。 </li></ol></li><li>疼痛分级设备: <ol><li>使用电脑视觉模拟评分（科瓦斯）。 注:科瓦斯是表示视觉模拟评分法（VAS）单杠上移动杠杆的盒子。它是一个附属于主热电极。 </li></ol></li></ol></li><li>训练<ol><li>上定义科瓦斯视觉模拟评分（VAS）: <ol><li>目前科瓦斯的参与者和定义对VAS锚固点:0表示没有疼痛，10表示最剧烈的疼痛可想而知。确定该参与者为舒适左右移动自如的杠杆。 </li></ol></li><li>定义第二疼痛: <ol><li>指导参与者把重点放在第二疼痛从热脉冲。定义第二疼痛为"一个缓慢的，灼热，疼痛的疼痛大约需要热脉冲后的一个第二位。" </li></ol></li><li>从单一的热脉冲（训练试验1）率第二疼痛:<ol><li>在固定参与者的鱼际的热电极。指导参与者使用科瓦斯从通过热电极每个交付的单脉率第二疼痛。 </li><li>通过点击软件菜单上的"开始"按钮，开始在笔记本电脑上的预编程测试。每个加热脉冲持续时间0.5秒具有10秒（ 参照图1）的刺激间间隔。顺序地增加每表2中的加热脉冲的基线和峰温度。 </li><li>密切观察参与者的评级的第二疼痛。只要参与率的第二次痛苦比2/10以上，按软件上的停止按钮停止训练试验1。取下热电极，记录最后的热脉冲参数（ 即基线和峰值温度）。 </li></ol></li><li>从TS试验（训练试验2）疼痛率持续: <ol><li>固定在对面的手热电极。通知PARTICIPA新台币它们将接受一系列的快速10脉冲。指示参与者率仅第二疼痛，而不是着眼于快热痛的感觉，马上随每个脉冲（第疼痛）。解释给参与者，该第二疼痛可能增加，减少，或保持每个脉冲之间是相同的。 </li><li>开始在笔记本电脑上预先编程的测试。使用来自上述步骤1.2.3记录最后的基准和峰值温度。保持在0.5秒的脉冲宽度，并在2秒（ 图2）的刺激间间隔。开关的手，直到参与者舒适的评价第二疼痛持续响应快速的热脉冲必要时重复这种训练试验。 </li></ol></li></ol></li><li>优化<ol><li>定义P1，P max和TS E: <ol><li>在峰值温度下的从第一脉冲递送后约2秒定义P1作为疼痛等级（参照图3）。 11 </SUP&gt; 21 注:TS E是疼痛P1和最大疼痛（P 最大 ）之间的估计差值。 </li></ol></li><li>调整脉冲温度。旨在通过根据图4顺序地调节峰和基线温度达到30和70/100之间的TS 即 注: 见图。 4为优化算法。 </li><li>安全热电极:使用外科手套，保证热电极，以参与者的鱼际。交换机的每个审判之间的手。 </li><li>提供热脉冲:指导参与者只能从热脉冲评价他们的第二疼痛。确认参加者准备开始，然后启动预编程测试的笔记本电脑。 </li><li>迭代:重复步骤1.3.2 -1.3.4直到参与者的疼痛评级为P1是&lt;50/100 VAS和TS E是VAS 30/100和70/100之间。进行不超过5更优化试验和确保有每个审判之间的3分钟休息。从最后的审判作为最后的参数采用参数。 </li></ol></li><li>最终审判<ol><li>休息的优化试验和最终试验间5分钟。重复1.3.3和1.3.4。使用上述步骤1.3.5最终的参数。有与会者休息3分钟，然后再重复。 </li></ol></li></ol> 2.空调疼痛调制协议<ol><li>概述和设备: <ol><li>测试刺激:30秒校准到6选自10疼痛（耐热-6）接触的热（由与上述相同的热电极递送）。见2.2的详细信息。 </li><li>条件刺激: <ol><li>构造使用具有穿孔的分隔壁上的一个透明的塑料盒，并用冰和水的一侧，只是水​​的其他填充它冷水浴中。轻轻搅动然后插入温度计只水侧，以确保温度为10℃是稳定的。 </li><li>如果无法获得稳定的温度，附加水电泵到一边用冰不断循环水，以保持稳定的温度。开启泵并确保水侧温度是在10℃下是稳定的。 </li></ol></li><li>时序和计算CPM: <ol><li>在调节冷水浴的最后30秒施加试验刺激参与者一次与前一次。 CPM计算在之前和期间冷浴的最后30秒采用的热刺激6的疼痛程度的差异。 </li></ol></li></ol></li><li>用于校准热6: <ol><li>通过加热快速上升估算热6: <ol><li>固定热电极到参与者的非优势手的鱼际。在32℃下开始，提高温度以每秒0.3℃的速率。 注:升速度较慢用于优先激活C纤维20，其负责CPM。 12 </li><li>停止磨片从未参加者达到热耐受性或C最高51°。指导参与者的热量斜坡期间连续打分疼痛。重复3次，并计算平均温度在那里的痛苦评级是6/10。 </li></ol></li><li>精阈值:应用热火-6和指导参与率的痛苦。如果评级是5和7/10之间，继续2.3.2。如果是&gt; 7或&lt;5，应用一系列30秒的热热刺激的参与者（每次刺激之间交替手），从44°C至49°C，并在0.5-1℃的增量变化，直到该评级是5-7之间，允许30秒每间刺激休息。 </li><li>最终化热6和预处理的评级，测试刺激: <ol><li>结束精阈值，一旦参与者的疼痛评级是5和7/10之间。注:使用此最后，区域内疼痛为预处理测试刺激的CPM的计算的评级。也，记录最终热6导致这种等级的温度。 </li></ol></li></ol></li><li> CPM协议<ol><li>前置条件测试刺激按照步骤2.2.3。 </li><li>条件刺激: <ol><li>在10℃下施加在冷水浴对侧脚2分钟。指导参与者在0，30和90 s到率由冷水浴的痛苦。 </li></ol></li><li>重复条件刺激试验过程中的刺激: <ol><li>在冷水浴的最后30秒应用从细阈值（2.2.3），以再次对同一只手的最终热6刺激。指导参加者在30秒的热刺激，这也是120秒冷水浴月底结束时率从热6的痛苦。 注:CPM计算为在疼痛分级之前报告的测试刺激的差异和冷水浴中。 </li></ol></li></ol></li></ol>

<ol>
	<li>Pizzo, P. A., Clark, N. M. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Alleviating+suffering+101--pain+relief+in+the+United+States.">Alleviating suffering 101--pain relief in the United States.</a> N Engl J Med. 366 (3), 197-199 (2012).</li><li>Backonja, M. M., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Value+of+quantitative+sensory+testing+in+neurological+and+pain+disorders:+NeuPSIG+consensus.">Value of quantitative sensory testing in neurological and pain disorders: NeuPSIG consensus.</a> Pain. 154 (9), 1807-1819 (2013).</li><li>Arendt-Nielsen, L., Yarnitsky, D. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Experimental+and+clinical+applications+of+quantitative+sensory+testing+applied+to+skin,+muscles+and+visera.">Experimental and clinical applications of quantitative sensory testing applied to skin, muscles and visera.</a> J Pain. 10 (6), 556-572 (2009).</li><li>Cruz-Almeida, Y., Fillingim, R. B. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Can+quantitative+sensory+testing+move+us+closer+to+mechanism-based+pain+management?.">Can quantitative sensory testing move us closer to mechanism-based pain management?.</a> Pain Med. 15 (1), 61-72 (2014).</li><li>Curatolo, M., Arendt-Nielsen, L., Petersen-Felix, S. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Evidence,+mechanisms,+and+clinical+implications+of+central+hypersensitivity+in+chronic+pain+after+whiplash+injury.">Evidence, mechanisms, and clinical implications of central hypersensitivity in chronic pain after whiplash injury.</a> Clin J Pain. 20 (6), 469-476 (2004).</li><li>Kong, J. T., Schnyer, R. N., Johnson, K. A., Mackey, S. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Understanding+central+mechanisms+of+acupuncture+analgesia+using+dynamic+quantitative+sensory+testing:+a+review.">Understanding central mechanisms of acupuncture analgesia using dynamic quantitative sensory testing: a review.</a> Evid Based Complement Alternat Med. 2013, 187182 (2013).</li><li>Price, D. D. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Characteristics+of+second+pain+and+flexion+reflexes+indicative+of+prolonged+central+summation.">Characteristics of second pain and flexion reflexes indicative of prolonged central summation.</a> Exp. Neurol. 37 (2), 371-387 (1972).</li><li>Price, D. D., Hu, J. W., Dubner, R., Gracely, R. H. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Peripheral+suppression+of+first+pain+and+central+summation+of+second+pain+evoked+by+noxious+heat+pulses.">Peripheral suppression of first pain and central summation of second pain evoked by noxious heat pulses.</a> Pain. 3 (1), 57-68 (1977).</li><li>Arendt-Nielsen, L., Petersen-Felix, S. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Wind-up+and+neuroplasticity:+is+there+a+correlation+to+clinical+pain?.">Wind-up and neuroplasticity: is there a correlation to clinical pain?.</a> Eur J Anaesthesiol Suppl. 10, 1-7 (1995).</li><li>Eide, P. K. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Wind-up+and+the+NMDA+receptor+complex+from+a+clinical+perspective.">Wind-up and the NMDA receptor complex from a clinical perspective.</a> Eur J Pain. 4 (1), 5-15 (2000).</li><li>Kong, J. T., Johnson, K. A., Balise, R. R., Mackey, S. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Test-retest+reliability+of+thermal+temporal+summation+using+an+individualized+protocol.">Test-retest reliability of thermal temporal summation using an individualized protocol.</a> J Pain. 14 (1), 79-88 (2013).</li><li>Le Bars, D. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=The+whole+body+receptive+field+of+dorsal+horn+multireceptive+neurones.">The whole body receptive field of dorsal horn multireceptive neurones.</a> Brain Res Brain Res Rev. 40 (1-3), 29-44 (2002).</li><li>Pud, D., Granovsky, Y., Yarnitsky, D. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=The+methodology+of+experimentally+induced+diffuse+noxious+inhibitory+control+(DNIC)-like+effect+in+humans.">The methodology of experimentally induced diffuse noxious inhibitory control (DNIC)-like effect in humans.</a> Pain. 144 (1-2), 16-19 (2009).</li><li>Yarnitsky, D., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Recommendations+on+terminology+and+practice+of+psychophysical+DNIC+testing.">Recommendations on terminology and practice of psychophysical DNIC testing.</a> Eur J Pain. 14 (4), 339 (2010).</li><li>Anderson, R. J., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Temporal+summation+of+second+pain:+Variability+in+responses+to+a+fixed+protocol.">Temporal summation of second pain: Variability in responses to a fixed protocol.</a> Eur J Pain. , (2012).</li><li>Wilson, H., Carvalho, B., Granot, M., Landau, R. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Temporal+stability+of+conditioned+pain+modulation+in+healthy+women+over+four+menstrual+cycles+at+the+follicular+and+luteal+phases.">Temporal stability of conditioned pain modulation in healthy women over four menstrual cycles at the follicular and luteal phases.</a> Pain. 154 (12), 2633-2638 (2013).</li><li>Backonja, M. M., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Quantitative+sensory+testing+in+measurement+of+neuropathic+pain+phenomena+and+other+sensory+abnormalities.">Quantitative sensory testing in measurement of neuropathic pain phenomena and other sensory abnormalities.</a> Clin J Pain. 25 (7), 641-647 (2009).</li><li>Price, D. D., Dubner, R. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Mechanisms+of+first+and+second+pain+in+the+peripheral+and+central+nervous+systems.">Mechanisms of first and second pain in the peripheral and central nervous systems.</a> J Invest Dermatol. 69 (1), 167-171 (1977).</li><li>Van Hees, J., Gybels, J. C. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=nociceptor+activity+in+human+nerve+during+painful+and+non+painful+skin+stimulation.">nociceptor activity in human nerve during painful and non painful skin stimulation.</a> J Neurol Neurosurg Psychiatry. 44 (7), 600-607 (1981).</li><li>Treede, R. D., Meyer, R. A., Raja, S. N., Campbell, J. N. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Evidence+for+two+different+heat+transduction+mechanisms+in+nociceptive+primary+afferents+innervating+monkey+skin.">Evidence for two different heat transduction mechanisms in nociceptive primary afferents innervating monkey skin.</a> J Physiol. 483 (Pt 3), 747-758 (1995).</li><li>Mauderli, A. P., Vierck, C. J., Cannon, R. L., Rodrigues, A., Shen, C. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Relationships+between+skin+temperature+and+temporal+summation+of+heat+and+cold+pain.">Relationships between skin temperature and temporal summation of heat and cold pain.</a> J Neurophysiol. 90 (1), 100-109 (2003).</li><li>Granot, M., Granovsky, Y., Sprecher, E., Nir, R. R., Yarnitsky, D. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Contact+heat-evoked+temporal+summation:+tonic+versus+repetitive-phasic+stimulation.">Contact heat-evoked temporal summation: tonic versus repetitive-phasic stimulation.</a> Pain. 122 (3), 295-305 (2006).</li><li>Eisenberg, E., Midbari, A., Haddad, M., Pud, D. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Predicting+the+analgesic+effect+to+oxycodone+by+'static'+and+'dynamic'+quantitative+sensory+testing+in+healthy+subjects.">Predicting the analgesic effect to oxycodone by 'static' and 'dynamic' quantitative sensory testing in healthy subjects.</a> Pain. 151 (1), 104-109 (2010).</li><li>Granovsky, Y., Yarnitsky, D. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Personalized+pain+medicine:+the+clinical+value+of+psychophysical+assessment+of+pain+modulation+profile.">Personalized pain medicine: the clinical value of psychophysical assessment of pain modulation profile.</a> Rambam Maimonides Med J. 4 (4), e0024 (2013).</li><li>Yarnitsky, D., Granot, M., Nahman-Averbuch, H., Khamaisi, M., Granovsky, Y. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Conditioned+pain+modulation+predicts+duloxetine+efficacy+in+painful+diabetic+neuropathy.">Conditioned pain modulation predicts duloxetine efficacy in painful diabetic neuropathy.</a> Pain. 153 (6), 1193-1198 (2012).</li><li>van Wijk, G., Veldhuijzen, D. S. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Perspective+on+diffuse+noxious+inhibitory+controls+as+a+model+of+endogenous+pain+modulation+in+clinical+pain+syndromes.">Perspective on diffuse noxious inhibitory controls as a model of endogenous pain modulation in clinical pain syndromes.</a> J Pain. 11 (5), 408-419 (2010).</li><li>Granot, M., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Determinants+of+endogenous+analgesia+magnitude+in+a+diffuse+noxious+inhibitory+control+(DNIC)+paradigm:+do+conditioning+stimulus+painfulness,+gender+and+personality+variables+matter?.">Determinants of endogenous analgesia magnitude in a diffuse noxious inhibitory control (DNIC) paradigm: do conditioning stimulus painfulness, gender and personality variables matter?.</a> Pain. 136 (1-2), 142-149 (2008).</li><li>Raphael, K. G., Janal, M. N., Anathan, S., Cook, D. B., Staud, R. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Temporal+summation+of+heat+pain+in+temporomandibular+disorder+patients.">Temporal summation of heat pain in temporomandibular disorder patients.</a> J Orofac Pain. 23 (1), 54-64 (2009).</li><li>Robinson, M. E., Bialosky, J. E., Bishop, M. D., Price, D. D., George, S. Z. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Supra-threshold+scaling,+temporal+summation,+and+after-sensation:+relationships+to+each+other+and+anxiety/fear.">Supra-threshold scaling, temporal summation, and after-sensation: relationships to each other and anxiety/fear.</a> J Pain Res. 3, 25-32 (2010).</li><li>Bernaba, M., Johnson, K. A., Kong, J. T., Mackey, S. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Conditioned+pain+modulation+is+minimally+influenced+by+cognitive+evaluation+or+imagery+of+the+conditioning+stimulus.">Conditioned pain modulation is minimally influenced by cognitive evaluation or imagery of the conditioning stimulus.</a> J Pain Res. 7, 689-697 (2014).</li></ol>

The authors have no conflicts of interests or any financial interests to disclose.

该议定书中的关键步骤该TS协议包括按时间顺序的关键步骤如下:多步训练（使用视觉模拟评分评价疼痛，从一个单一的加热脉冲的第二疼痛评级，并从快速加热脉冲串等级第二疼痛）;脉冲温度优化;在2-3试验，优化温度取得TS。与大多数心理的措施，参加培训万分危急确保痛苦的评级是在各试验一致，并尽可能准确。优化步骤是同样重要的，其中两个基线和峰值脉冲的温度被调节，使得第一加热脉冲的评级是小于5/10，和所述近似TS为7 3之间。 CPM的关键步骤包括视觉模拟评分疼痛分级培训，获得热火-6慢热坡道，确认热-6和精细阈值，如果necess元，应用冷水浴对侧肢体远端，并在冷水浴的最后30秒重新应用证实热6。到TS协议类似，两者的训练和热刺激的个性化（热-6）是在CPM协议的关键。另外，从经验以及从文献，在冷浴的最后30秒的重复热-6刺激是关键的，并产生比较冷浴后施加热刺激的CPM更大幅值。 26然而，鉴于有些个人不能在10摄氏度容忍冷加压的全部2分钟，这可能是合理考虑条件刺激完成后立即施加测试刺激在所有个人数据收集标准化。 修改和故障排除与TS协议的最常见的问题是，得到的TS无力，这可能是由于3主要原因。第一，也是最常见的是，疼痛评级从第一热脉冲可以是如此强大，它淹没在与随后的脉冲（TS）的疼痛的任何增加的感知。尽量减少此问题的最佳方法是优化TS的大小之前遵循协议，并依次减少基线和峰刺激温度，直到第一脉冲的疼痛评级是小于5（满分10分）。第二个原因，相对于第一个，是当与会者在即使在最高温度设定在10个脉冲的结束任何感知没有痛苦。在这种情况下，可以考虑由1或2℃提高基线脉冲温度。有时，一个人可能只是有一个很难识别和评价第二疼痛，可能是由于外周和中枢的因素。未经第二疼痛可靠感知，这是非常难以捕捉的TS。在这种情况下，我们发现温度的最好的一套，一个individual可容忍和记录TS为零。 一个成功的CPM协议中最常见的障碍是热6的不稳定性和无法容忍2分钟冷浴（10℃）。使用精细阈值在当前的协议，通过调整，以解决第一个问题的热刺激温度逐步直至疼痛评分为5和7对于第二个问题之间，注意，文献表明的抑制作用从条件刺激是饱和。 27因此，即使一个人不能他或她的脚保持冷浴2分钟，应该与此强烈痛苦的冷的刺激会出现足够的CPM效果。修改协议来记录在冷水浴浸没脚的持续时间和该参与者后立即将热刺激他或她的脚从冷水浴撤出。 CPM随后的疼痛分级热刺激的疼痛评级HEA之前减去计算ŧ刺激冷水浴后立即应用（未过程中，当一般的协议表示）。 技术的局限性这种方法也不是没有局限性。第一，尽管我们最大的努力，我们不能（分别为1遗漏参与者TS和1 CPM，）征求TS和CPM的每一个人。此，部分地，可能是由于大之间的个体差异在这些参数。 5，15，16，28，29然而，成功率为94％，这比从文献中引用的50-60％的成功率更好。 22，28二，研究者应该用这种方法，因为我们使用不同的热脉冲温度每INDI产生TS产生的TS不同个人之间演绎时要谨慎维杜阿尔。因此，横截面样品中比较的TS时，应考虑这两个在TS的幅度和在用于产生它的温度的差异。个性化的TS的方法是最适合于纵向研究，其中，重点是在同一个体加班的变化。因为同样的条件刺激用于所有个体和只在个体热6的疼痛知觉的变化被记录，而不是热-6-疼痛原始分数相同关注并不适用于个性化的CPM。尽管此方法允许TS和CPM的广泛采集，它相比于使用通用参数的方法需要更多的时间。最后，该技术需要一个有经验的操作者和高级热试验机，这两者都是不立即适应繁忙临床设置实用。我们鼓励今后的努力简化的方法。 关于到现有的技术意义。/另类方法我们的个体化​​TS和CPM参数的方法旨在消除地板和天花板效应影响，由于周边散热灵敏度变化。该方法介绍了我们组的两个更广泛的捕捉和时间效率的目标公布以前的方法改善。 11，30个体化的TS和CPM的优点是捕获上升的状态和下降疼痛处理在一个宽范围的个人，由此允许使用这些参数作为合理的测量结果为纵向研究的能力。 掌握技术后，未来的应用方向或今后的研究应着重补充修改，以节省时间，在人口众多的TS和CPM数据采集表征个体这些参数谁是无痛苦VS那些历代志的范围集成电路的疼痛，以及在TS和CPM响应于除了卷起装置和DNIC特定的生理过程的多样性的相关性。

在国际疼痛研究学会（IASP）疼痛定义为"一种不愉快的感觉和情绪体验。"慢性疼痛是指疼痛持续超过6个月。慢性疼痛是在美国一个显著的问题，影响在$ 635十亿每年成本向上100多万美国成年人。 1由于疼痛的主观性质，很难让研究者和临床医生客观地衡量一个人的痛苦经历（S），因此使得它具有挑战性的评估和治疗疼痛。出于这个原因，我们开发的标准化测试，以尽可能客观地量化疼痛是很重要的。一个这样的测试是QST，其中标准化感官刺激施用到由被检者定级。 2有静态和动态QST。前者通常评估到感觉阈值或单个刺激的等级，而后者评估了响应于一些刺激。 3日前，动态QST已经获得了，因为它提供了机会来探测传入伤害性信号的中央处理越来越多的关注。 4，5，6 动态QST的两个关键组成部分是时间总和（TS）和空调疼痛调制（CPM）。时间总和指疼痛从重复的，伤害性刺激增加的感知。 TS是卷起，在脊髓神经元继发增加显示烧制由于重复的C-光纤输入的现象行为相关。 7,8一般来说，TS可以通过使用各种伤害性刺激，如热，电，和触觉方法（ 即压力或针眼）诱导的，条件是重复刺激的频率大于0.3Hz更大，C的固有频率-纤维秒。 9,10许多研究人员使用重复的热脉冲生成生产和规范有毒热刺激，因为容易的TS。 11 CPM是指现象"痛抑制痛"，其中第二次伤害性刺激的存在降低了从最初的有害刺激的疼痛感觉。 12初始有害刺激，这是之前和之后（或期间），第二刺激的应用测量，被称为测试刺激。测试激励可以是热，电或触觉。这里热刺激经常被用来作为测试刺激，因为其在调整和标准化的缓解。 13第二刺激，称为条件刺激，通常由施加到远侧末端冷或热水浴中。 13 CPM是行为的归属关系Ø˚F弥漫有毒抑制控制（DNIC），一种生理现象，其中输入来自从异位场由C-纤维介导的所有传入刺激的脑干弥漫抑制外周C纤维的结果。 12,14 虽然TS和CPM都有反映状态和中枢性疼痛处理变化的潜力，局限性同时存在。 4，5。例如，因为在个人热灵敏度大可变性，通用刺激的应用可以导致测试的个体的高达50％的缺乏的TS。 11，15同样，热测试刺激往往造成了很可能导致CPM测试不可能的，由于地板或天花板效应广泛不同的疼痛评级。 16因此，捕捉TS和CPM广义上的协议，广告甫一热刺激是需要个人。为TS，我们调整加热脉冲的温度，以便他们可以生成在疼痛评分与每个相继脉冲充分提高;而对于CPM，我们在调整热测试刺激中度疼痛（6出10），为每个单独的使有足够的疼痛分级仍可能调理刺激后应用存在。 对于所有的精神物理学检查，在适当的评级疼痛刺激的参与者的培训是这些行为测试的准确性和再现性是至关重要的。 17当多个刺激被以较快的速度呈现，并且在CPM的情况下，当两个不同的刺激被同时施加到参加者。这是TS特别相关。此外，从热脉冲的TS，它培养参与者进行评分C-纤维介导的第二疼痛（慢，燃烧，通常是普热后亮起大约1秒钟就显得尤为重要LSE），而不是最初的阵痛（由A-δ纤维介导，并与热脉冲立即来吧）。 18,19这是较少在CPM一个问题，因为刺激有（&gt; 30秒）更长和C-纤维介导的感觉会支配在这些情况下有毒感知。 19，20在下面的协议，我们将在参与者的细节适当的培训。

<table><tbody><tr><td>Medoc Pathway CHEPS system</td><td>Medoc Advanced Medical Systems&amp;nbsp;&amp;nbsp;</td><td></td><td>This system includes the machine to generate contact heat (Pathway), the thermode capable of rapid temperature change (CHEPS), and the Medoc software.&amp;nbsp;</td></tr><tr><td>CoVAS accessory hardware with the CHEPS systems</td><td>Medoc Advanced Medical Systems&amp;nbsp;&amp;nbsp;</td><td></td><td>This device is a Medoc accessory that allows real-time pain rating by the participant.&amp;nbsp;</td></tr><tr><td>Laptop Computer</td><td>Lenovo</td><td></td><td>This is the computer that runs the Medoc software and communicates with the Pathway machine.&amp;nbsp;</td></tr><tr><td>Glove</td><td>Kimberly-Clark</td><td></td><td>Gloves are used to secure the thermode on the participant&#039;s thenar eminence.&amp;nbsp;</td></tr><tr><td>Clear plastic box with a perforated dividing wall - filled with Ice and water</td><td></td><td></td><td>This box provides the cold water bath for the CPM task.&amp;nbsp;</td></tr><tr><td>Aquarium pump&amp;nbsp;</td><td>Aquarium Systems Micro-Jet pump MC 450</td><td></td><td>This pump circulates water, to maintain stable, even temperature in the cold water bath.&amp;nbsp;</td></tr><tr><td>Infrared Thermometer</td><td>Exergen Temporal Scanner, model TAT 2000&amp;nbsp;</td><td></td><td>To monitor constantly the temperature of the water bath.&amp;nbsp;</td></tr><tr><td>Stop Watch</td><td>Any handheld stop watch or stop watch built into a smartphone</td><td></td><td>To prompt the participant to rate pain at specific time pointds during the CPM task.&amp;nbsp;</td></tr></tbody></table>

dynamic quantitative sensory testing to characterize central pain processing

Central facilitation and modulation of incoming nociceptive signals play an important role in the perception of pain. Disruption in central pain processing is present in many chronic pain conditions and can influence responses to specific therapies. Thus, the ability to precisely describe the state of central pain processing has profound clinical significance in both prognosis and prediction. Because it is not practical to record neuronal firings directly in the human spinal cord, surrogate behavior tests become an important tool to assess the state of central pain processing. Dynamic QST is one such test, and can probe both the ascending facilitation and descending modulation of incoming nociceptive signals via TS and CPM, respectively. Due to the large between-individual variability in the sensitivity to noxious signals, standardized TS and CPM tests may not yield any meaningful data in up to 50% of the population due to floor or ceiling effects. We present methodologies to individualize TS and CPM so we can capture these measures in a broader range of individuals than previously possible. We have used these methods successfully in several studies at the lab, and data from one ongoing study will be presented to demonstrate feasibility and potential applications of the methods.

在正在进行的临床试验中，我们执行患者深表型慢性轴向腰痛，我们包括动态QST作为评估的一个组成部分。下面的表3总结了其中使用上述确切TS和CPM协议的第15例患者的基线数据。需要注意的是该数据包括患者＃19，因为不是所有的19例患者招募出现了对自己的评价，由于日程安排冲突和其他情况。 图5可视地显示在TS和CPM数据侧由端来揭示这些患者中枢性疼痛处理的变化的图案。 如上图所示，采用个性化的优化方案，我们与0-10 VAS规模平均2.7获得TS在鱼际。我们能够获得TS在所有19名学员除参加1，谁是不能够可靠地识别秒OND疼痛无需从最初的阵痛由感觉所淹没。参与者13需要早退因此没有接受植物检疫任务。否则，所有的18名学员展示CPM，其中平均约为3.1。我们成功地实现在大多数的学科一定程度的TS和CPM;并且TS和CPM的幅度与从文献一致。 13，15，22 此外，如在图4中显示出，TS和CPM的同时测量可导致对患者的在中枢性疼痛处理信息的洞察力。把它放在简体而言，高TS可能表示异常增强上升便利而低CPM建议受损降痛觉传递的抑制作用。例如，参加10，显示出7.7（满分10分）的高TS，同时参加18魔trated一个基本上不存在的CPM（-0.5 / 10）。几个先驱研究表明，中枢性疼痛处理，例如不同的配置文件可以预测术后慢性疼痛的发展的不同的速率，并以对特定中枢性疼痛途径起作用的药物不同的反应。 4，23，24，25在这里此例中，这是合理的推测，参与者10可能给加巴喷丁，钙通道阻断剂响应而参与者18，谁具有受损的CPM可能向度洛西汀，血清素-去甲肾上腺素再摄取抑制剂响应。显然还需要更多的数据和研究来验证假设。介入审判正在进行中，并会评估这些背痛患者的反应真药和假电。这里介绍的个体QST方法将允许我们准确地和纵向地跟踪在TS和CPM的变化许多个人尽可能。 <img alt="图1" src="/files/ftp_upload/54452/54452fig1.jpg" /> 图1.单热脉冲用于训练试验1.每个热普乐持续0.5秒，是除了10秒从下一个热脉冲。每个脉冲的基线和峰温度根据表2逐渐增加。只要参与者感觉到任何的脉冲，达到训练试验1的终点第二疼痛而导致的第二疼痛感觉被记录，并在训练试验2.使用脉冲的温度设置<a href="http://ecsource.jove.com/files/ftp_upload/54452/54452fig1large.jpg" target="_blank">，请点击这里查看一个更大的版本这个数字。</a> <img alt="图2" src="/files/ftp_upload/54452/54452fig2.jpg" /> 图2.热脉冲串用于培训TRIAL 2，优化并最终TS试验。十热脉冲，每0.5秒长，且2秒分开，在一个标准的TS试验被递送。 <img alt="图3" src="/files/ftp_upload/54452/54452fig3.jpg" /> 图3.定义P1，P max和TSË。 P1:从第一脉冲的第二疼痛评级; {P MAX:最大额定值的整个10脉冲串的第二疼痛; TS E:时间总和的估计的大小。 <a href="http://ecsource.jove.com/files/ftp_upload/54452/54452fig3large.jpg" target="_blank">请点击此处查看该图的放大版本。</a> <img alt="图4" src="/files/ftp_upload/54452/54452fig4.jpg" /> 图4.算法单独优化时间总和。这里的目标是找到基线和峰值脉冲的温度导致在预计吨emporal总和（TSE）3进出10 VAS 7之间。如果TSE低于目标，用C顺序1°增加峰值和基线的温度。如果TSE是上述目标，用C顺序1°减少基线和峰值温度。上述算法之前，应先热脉冲的肯定疼痛评级是由小（0.5-1°C）的增量减少基线和峰值脉冲温度≤5。 <a href="http://ecsource.jove.com/files/ftp_upload/54452/54452fig4large.jpg" target="_blank">请点击此处查看该图的放大版本。</a> <img alt="图5" src="/files/ftp_upload/54452/54452fig5.jpg" /> 图5.从正在进行的临床试验TS和CPM型材患者。在第一19例来自正在进行的临床试验慢性腰痛的TS和CPM的基线测量。相对的TS和CPM幅度的各种图案揭示于百分之电位差拉尔疼痛处理。 <a href="http://ecsource.jove.com/files/ftp_upload/54452/54452fig5large.jpg" target="_blank">请点击此处查看该图的放大版本。</a> <table border="1" fo:keep-together.within-page="1" fo:keep-with-next.within-page="always"><tbody><tr><td> 审讯 </td><td> 脉冲＃ </td><td> 刺激持续时间 </td><td> 峰峰值ISI </td><td> 斜率 </td><td> 基准温度 </td><td> 最高温度 </td></tr><tr><td>训练试验1 </td><td> 1个脉冲</td><td> 0.5秒</td><td> 10秒</td><td> 40℃/秒</td><td>变量（ 见表2） </td><td>变量（ 见表2） </td></tr><tr><td>训练试验2 </td><td> 10个脉冲</td><td> 0.5秒</td><td> 2秒</td><td> 40℃/秒</td><td>从训练试验1 </td><td>从训练试验1 </td></tr><tr><td>优化试验</td><td> 10个脉冲</td><td> 0.5秒</td><td> 2秒</td><td> 40℃/秒</td><td>先从训练试验1临时工</td><td>先从训练试验1临时工</td></tr><tr><td>最终审判</td><td> 10个脉冲</td><td> 0.5秒</td><td> 2秒</td><td> 40℃/秒</td><td>个性化</td><td>个性化</td></tr></tbody></table> 表1:用于TS协议热刺激的规格（包括训练试验）。 <table border="1" fo:keep-together.within-page="1" fo:keep-with-next.within-page="always"><tbody><tr><td> 脉冲数 </td><td> 基线温度（℃） </td><td> 峰温度（℃） </td></tr><tr><td> 1 </td><td> 36 </td><td> 45 </td></tr><tr><td> 2 </td><td> 36 </td><td> 46 </td></tr><tr><td> 3 </td><td> 37 </td><td> 47 </td></tr><tr><td> 4 </td><td> 38 </td><td> 48 </td></tr><tr><td>五</td><td> 39 </td><td> 49 </td></tr><tr><td> 6 </td><td> 40 </td><td> 50 </td></tr><tr><td> 7 </td><td> 41 </td><td> 51 </td></tr><tr><td> 8 </td><td> 42 </td><td> 51 </td></tr><tr><td> 9 </td><td> 43 </td><td> 51 </td></tr><tr><td> 10 </td><td> 44 </td><td> 51 </td></tr></tbody></table> 表2: 温度设置用于捕捉第二疼痛在训练试验1.参见图1与这些温度参数传递单热脉冲的形状。 <table border="1" fo:keep-together.within-page="1" fo:keep-with-next.within-page="always"><tbody><tr><td> SUBJ ID </td><td>碱基T </td><td>山顶ŧ </td><td> TS </td><td>热6 </td><td> CPM </td></tr><tr><td></td><td>摄氏</td><td>摄氏</td><td> VAS </td><td>摄氏</td><td> VAS </td></tr><tr><td> 1 </td><td></td><td></td><td> 0 </td><td> 44 </td><td> 4.4 </td></tr><tr><td> 2 </td><td> 41 </td><td> 51 </td><td> 0.43 </td><td> 47.6 </td><td> 4.717 </td></tr><tr><td> 3 </td><td> 40 </td><td> 50 </td><td> 0.5 </td><td> 44.7 </td><td> 4.42 </td></tr><tr><td> 4 </td><td> 38 </td><td> 49 </td><td> 0.45 </td><td> 44 </td><td> 4.355 </td></tr><tr><td>五</td><td> 42 </td><td> 51 </td><td> 3.287 </td><td> 44 </td><td> 4.0713 </td></tr><tr><td> 6 </td><td> 44 </td><td> 51 </td><td> 0.415 </td><td> 45.5 </td><td> 4.5085 </td></tr><tr><td> 7 </td><td> 44 </td><td> 51 </td><td> 4.2495 </td><td> 45.5 </td><td> 4.12505 </td></tr><tr><td> 8 </td><td> 41 </td><td> 51 </td><td> 2.575 </td><td> 45 </td><td> 4.2425 </td></tr><tr><td> 9 </td><td> 44 </td><td> 51 </td><td> 3.435 </td><td> 48 </td><td> 4.4565 </td></tr><tr><td> 10 </td><td> 43 </td><td> 51 </td><td> 7.713 </td><td> 44 </td><td> 3.6287 </td></tr><tr><td> 11 </td><td> 39 </td><td> 51 </td><td> 4.59 </td><td> 42.5 </td><td> 3.791 </td></tr><tr><td> 12 </td><td> 39 </td><td> 49 </td><td> 5.395 </td><td> 43.3 </td><td> 3.7905 </td></tr><tr><td> 13 </td><td> 44 </td><td> 51 </td><td> 2.165 </td><td></td><td> 0 </td></tr><tr><td> 14 </td><td> 39 </td><td> 49 </td><td> 2.55 </td><td> 44.1 </td><td> 4.155 </td></tr><tr><td> 15 </td><td> 40 </td><td> 51 </td><td> 4.0635 </td><td> 44 </td><td> 3.99365 </td></tr><tr><td> 16 </td><td> 42 </td><td> 51 </td><td> 3.45665 </td><td> 45.5 </td><td> 4.204335 </td></tr><tr><td> 17 </td><td> 40 </td><td> 51 </td><td> 0.953 </td><td> 46.1 </td><td>4.5147 </td></tr><tr><td> 18 </td><td> 37.5 </td><td> 49 </td><td> 0.21 </td><td> 45.5 </td><td> 4.529 </td></tr><tr><td> 19 </td><td> 40 </td><td> 51 </td><td> 2.2135 </td><td> 46.6 </td><td> 4.43865 </td></tr></tbody></table> 表3.从正在进行的临床试验TS和CPM的结果。参见图4为TS和CPM从并排绘制边露出痛苦调制谱相同的参与者。

Watch this Scientific Journal Video about Dynamic Quantitative Sensory Testing to Characterize Central Pain Processing at JoVE.com

Dynamic Quantitative Sensory Testing to Characterize Central Pain Processing

By assessing pain in response to repetitive or different types of standardized stimuli, dynamic quantitative sensory testing (QST) can reveal changes in the central processing of pain. We present methods to optimize and individualize two dynamic QST measures: temporal summation (TS) and conditioned pain modulation (CPM).

动态定量感觉测试表征中央疼痛处理

Central facilitation and modulation of incoming nociceptive signals play an important role in the perception of pain. Disruption in central pain ...

dynamic-quantitative-sensory-testing-to-characterize-central-pain

Research

JoVE Journal

Neuroscience

16.9K 次观看.  Stanford University School of Medicine. By assessing pain in response to repetitive or different types of standardized stimuli, dynamic quantitative sensory testing (QST) can reveal changes in the central processing of pain. We present methods to optimize and individualize two dynamic QST measures: temporal summation (TS) and conditioned pain modulation (CPM).

视频: Dynamic Quantitative Sensory Testing to Characterize Central Pain Processing

Acute and Chronic Tactile Sensory Testing after Spinal Cord Injury in Rats

Spinal cord injury (SCI) impairs sensory systems causing allodynia1-8. To identify cellular and molecular causes of allodynia, sensitive and valid sensory testing in rat SCI models is needed. However, until recently, no single testing approach had been validated for SCI so that standardized methods have not been implemented across labs. Additionally, available testing methods could not be implemented acutely or when severe motor impairments existed, preventing studies of the development of SCI-induced allodynia3. Here we present two validated sensory testing methods using von Frey Hair (VFH) monofilaments which quantify changes in tactile sensory thresholds after SCI4-5. One test is the well-established Up-Down test which demonstrates high sensitivity and specificity across different SCI severities when tested chronically5. The other test is a newly-developed dorsal VFH test that can be applied acutely after SCI when allodynia develops, prior to motor recovery4-5. Each VFH monofilament applies a calibrated force when touched to the skin of the hind paw until it bends. In the up-down method, alternating VFHs of higher or lower forces are used on the plantar L5 dermatome to delineate flexor withdrawal thresholds. Successively higher forces are applied until withdrawal occurs then lower force VFHs are used until withdrawal ceases. The tactile threshold reflects the force required to elicit withdrawal in 50% of the stimuli. For the new test, each VFH is applied to the dorsal L5 dermatome of the paw while the rat is supported by the examiner. The VFH stimulation occurs in ascending order of force until at least 2 of 3 applications at a given force produces paw withdrawal. Tactile sensory threshold is the lowest force to elicit withdrawal 66% of the time. Acclimation, testing and scoring procedures are described. Aberrant trials that require a retest and typical trials are defined. Animal use was approved by Ohio State University Animal Care and Use Committee.

We describe two tactile sensory testing methods for acute or chronic periods of spinal cord injury in rats. These validated procedures can detect the development and maintenance of allodynia-like sensations.

在大鼠脊髓损伤后的急性和慢性触觉测试

Spinal cord injury (SCI) impairs sensory systems causing allodynia1-8. To identify cellular and molecular causes of allodynia, sensitive and valid sensory ...

科研

医学

Chronic Constriction of the Sciatic Nerve and Pain Hypersensitivity Testing in Rats

Chronic neuropathic pain, resulting from damage to the central or peripheral nervous system, is a prevalent and debilitating condition, affecting 7-18% of the population1,2. Symptoms include spontaneous (tingling, burning, electric-shock like) pain, dysaesthesia, paraesthesia, allodynia (pain resulting from normally non-painful stimuli) and hyperalgesia (an increased response to painful stimuli). The sensory symptoms are co-morbid with behavioural disabilities, such as insomnia and depression. To study chronic neuropathic pain several animal models mimicking peripheral nerve injury have been developed, one of the most widely used is Bennett and Xie's (1988) unilateral sciatic nerve chronic constriction injury (CCI)3 (Figure 1). Here we present a method for performing CCI and testing pain hypersensitivity.
CCI is performed under anaesthesia, with the sciatic nerve on one side exposed by making a skin incision, and cutting through the connective tissue between the gluteus superficialis and biceps femoris muscles. Four chromic gut ligatures are tied loosely around the sciatic nerve at 1 mm intervals, to just occlude but not arrest epineural blood flow. The wound is closed with sutures in the muscle and staples in the skin. The animal is then allowed to recover from surgery for 24 hrs before pain hypersensitivity testing begins.
For behavioural testing, rats are placed into the testing apparatus and are allowed to habituate to the testing procedure. The area tested is the mid-plantar surface of the hindpaw (Figure 2), which falls within the sciatic nerve distribution. Mechanical withdrawal threshold is assessed by mechanically stimulating both injured and uninjured hindpaws using an electronic dynamic plantar von Frey aesthesiometer or manual von Frey hairs4. The mechanical withdrawal threshold is the maximum pressure exerted (in grams) that triggers paw withdrawal. For measurement of thermal withdrawal latency, first described by Hargreaves et al (1988), the hindpaw is exposed to a beam of radiant heat through a transparent glass surface using a plantar analgesia meter5,6. The withdrawal latency to the heat stimulus is recorded as the time for paw withdrawal in both injured and uninjured hindpaws. Following CCI, mechanical withdrawal threshold, as well as thermal withdrawal latency in the injured paw are both significantly reduced, compared to baseline measurements and the uninjured paw (Figure 3). The CCI model of peripheral nerve injury combined with pain hypersensitivity testing provides a model system to investigate the effectiveness of potential therapeutic agents to modify chronic neuropathic pain. In our laboratory, we utilise CCI alongside thermal and mechanical sensitivity of the hindpaws to investigate the role of neuro-immune interactions in the pathogenesis and treatment of neuropathic pain.

Due to the simplicity of surgery and the robust behavioural outcome, chronic constriction of the sciatic nerve is one of the pre-eminent animal models of neuropathic pain. Within 24 hrs following surgery, pain hypersensitivity is established and can be quantitatively measured using a von Frey aesthesiometer (mechanical test) and plantar analgesia meter (thermal test).

慢性缩窄大鼠坐骨神经疼痛过敏测试

Chronic neuropathic pain, resulting from damage to the central or peripheral nervous system, is a prevalent and debilitating condition, affecting 7-18% of ...

Determining Pain Detection and Tolerance Thresholds Using an Integrated, Multi-Modal Pain Task Battery

Human pain models are useful in the assessing the analgesic effect of drugs, providing information about a drug&#39;s pharmacology and identify potentially suitable therapeutic populations. The need to use a comprehensive battery of pain models is highlighted by studies whereby only a single pain model, thought to relate to the clinical situation, demonstrates lack of efficacy. No single experimental model can mimic the complex nature of clinical pain. The integrated, multi-modal pain task&#160;battery presented here encompasses the electrical stimulation task, pressure stimulation task, cold pressor task, the UVB inflammatory model which includes a thermal task and a paradigm for inhibitory conditioned pain modulation. These human pain models have been tested for predicative validity and reliability both in their own right and in combination, and can be used repeatedly, quickly, in short succession, with minimum burden for the subject and with a modest quantity of equipment. This allows a drug to be fully characterized and profiled for analgesic effect which is especially useful for drugs with a novel or untested mechanism of action.

Human pain models are valuable tools used to assess the analgesic potential of novel compounds and predict their clinical efficacy, especially when used in an integrated manner. Although implementation of these models is complex, with proper execution, the pain models described in this protocol can provide predictive and reliable results.

确定疼痛的检测和容忍阈值使用集成的，多模式疼痛任务电池

Human pain models are useful in the assessing the analgesic effect of drugs, providing information about a drug&#39;s pharmacology and identify ...

行为学

A Protocol of Manual Tests to Measure Sensation and Pain in Humans

Numerous qualitative and quantitative techniques can be used to test sensory nerves and pain in both research and clinical settings. The current study demonstrates a quantitative sensory testing protocol using techniques to measure tactile sensation and pain threshold for pressure and heat using portable and easily accessed equipment. These techniques and equipment are ideal for new laboratories and clinics where cost is a concern or a limiting factor. We demonstrate measurement techniques for the following: cutaneous mechanical sensitivity on the arms and legs (von-Frey filaments), radiant and contact heat sensitivity (with both threshold and qualitative assessments using the Visual Analog Scale (VAS)), and mechanical pressure sensitivity (algometer, with both threshold and the VAS). The techniques and equipment described and demonstrated here can be easily purchased, stored, and transported by most clinics and research laboratories around the world. A limitation of this approach is a lack of automation or computer control. Thus, these processes can be more labor intensive in terms of personnel training and data recording than the more sophisticated equipment. We provide a set of reliability data for the demonstrated techniques. From our description, a new laboratory should be able to set up and run these tests and to develop their own internal reliability data.

The goal of this procedure is to demonstrate a battery of quantitative techniques for sensory and pain measurement in humans. The equipment and techniques described are commonly found in pain clinics or are easy to obtain.

手动测试的协议来衡量感觉和疼痛人类

Numerous qualitative and quantitative techniques can be used to test sensory nerves and pain in both research and clinical settings. The current study ...

Psychophysically-anchored, Robust Thresholding in Studying Pain-related Lateralization of Oscillatory Prestimulus Activity

In perceptual studies, it is often important to objectively assess the equality of delivered stimulation across participants or to quantify the intra-individual sensation magnitude that is evoked by stimulation over multiple trials. This requires a robust mapping of stimulus magnitude to perceived intensity and is commonly achieved by psychophysical estimation methods such as the staircase procedure. Newer, more efficient procedures like the QUEST algorithm fit a psychophysical function to the data in real time while at the same time maximizing the efficiency of data collection. A robust estimate of the threshold intensity between painful and nonpainful perceptions can then be used to reduce the influence of variations in sensory input in subsequent analyses of oscillatory brain activity. By stimulating at a constant threshold intensity determined by an adaptive estimation procedure, the variance in the ratings can be directly attributed to perceptual processes. Oscillatory activity can then be contrasted between &#34;pain&#34; and &#34;no-pain&#34; trials directly, yielding activity that closely relates to perceptual classification processes in nociception.

Psychophysical methods such as the QUEST estimation procedure can efficiently yield robust estimates of the stimulation intensity at which nonpainful sensations transition into painful sensations. By stimulating repeatedly at the threshold intensity, the variability in rating responses can directly be attributed to perceptual classifications in subsequent analyses.

在研究疼痛相关振荡Prestimulus活动偏侧Psychophysically锚，乐百氏阈值

In perceptual studies, it is often important to objectively assess the equality of delivered stimulation across participants or to quantify the ...

Determining heat and mechanical pain threshold in inflamed skin of human subjects

In a previous article in the Journal of Visualized Experiments we have demonstrated skin microdialysis techniques for the collection of tissue-specific nociceptive and inflammatory biochemicals in humans. In this article we will show pain-testing paradigms that are often used in tandem with microdialysis procedures. Combining pain tests with microdialysis provides the critical link between behavioral and biochemical data that allows identifying key biochemicals responsible for generating and propagating pain.
Two models of evoking pain in inflamed skin of human study participants are shown. The first model evokes pain with aid of heat stimuli. Heat evoked pain as described here is predominantly mediated by small, non-myelinated peripheral nociceptive nerve fibers (C-fibers). The second model evokes pain via punctuated pressure stimuli. Punctuated pressure evoked pain is predominantly mediated by small, myelinated peripheral nociceptive nerve fibers (A-delta fibers). The two models are mechanistically distinct and independently examine nociceptive processing by the two major peripheral nerve fiber populations involved in pain signaling.
Heat pain is evoked with aid of the TSA II, a commercially available thermo-sensory analyzer (Medoc Advanced Medical Systems, Durham, NC). Stimulus configuration and delivery is handled with aid of specific software. Thermodes vary in size and shape but in principle consist of a metal plate that can be heated or cooled at various rates and for different periods of time. Algorithms assessing heat-evoked pain are manifold. In the experiments shown here, study participants are asked to indicate at what point they start experiencing pain while the thermode in contact with skin is heated at a predetermined rate starting at a temperature that does not evoke pain. The thermode temperature at which a subject starts experiencing pain constitutes the heat pain threshold.
Mechanical pain is evoked with punctuated probes. Such probes are commercially available from several manufacturers (von Frey hairs). However, the accuracy of von Frey hairs has been criticized and many investigators use custom made punctuated pressure probes. In the experiments shown here eight custom-made punctuated probes of different weights are applied in consecutive order, a procedure called up-down algorithm, to identify perceptional deflection points, i.e., a change from feeling no pain to feeling pain or vice versa. The average weight causing a perceptional deflection constitutes the mechanical pain threshold.

Algorithms assessing heat and mechanical pain thresholds in experimentally inflamed skin of human study subjects are shown. The two pain testing paradigms independently examine nociceptive processing by the two major peripheral nerve fiber populations transmitting pain, i.e., non-myelinated C fibers and small myelinated A-delta fibers.

确定人类受试者皮肤发炎的热和机械痛阈

In a previous article in the Journal of Visualized Experiments we have demonstrated skin microdialysis techniques for the collection of tissue-specific ...

生物学

Chronic Post-Ischemia Pain Model for Complex Regional Pain Syndrome Type-I in Rats

Complex regional pain syndrome type-I (CRPS-I) is a neurological disease that causes severe pain among patients and remains an unresolved medical condition. However, the underlying mechanisms of CRPS-I have yet to be revealed. It is known that ischemia/reperfusion is one of the leading factors that causes CRPS-I. By means of prolonged ischemia and reperfusion of the hind limb, the rat chronic post-ischemia pain (CPIP) model has been established to mimic CRPS-I. The CPIP model has become a well-recognized animal model for studying the mechanisms of CRPS-I. This protocol describes the detailed procedures involved in the establishment of the rat model of CPIP, including anesthesia, followed by ischemia/reperfusion of the hind limb. Characteristics of the rat CPIP model are further evaluated by measuring the mechanical and thermal hypersensitivities of the hind limb as well as the nocifensive responses to acute capsaicin injection. The rat CPIP model exhibits several CRPS-I-like manifestations, including hind limb edema and hyperemia in the early stage after establishment, persistent thermal and mechanical hypersensitivities, and increased nocifensive responses to acute capsaicin injection. These characteristics render it a suitable animal model for further investigation of the mechanisms involved in CRPS-I.

Provided here is a protocol that details steps to establish an animal model of chronic post-ischemia pain (CPIP). This is a well-recognized model mimicking human complex regional pain syndrome type-I. Mechanical and thermal hypersensitivities are further evaluated, as well as capsaicin-induced nocifensive behaviors observed in the CPIP rat model.

大鼠复杂区域疼痛综合征I型慢性缺血后疼痛模型

Complex regional pain syndrome type-I (CRPS-I) is a neurological disease that causes severe pain among patients and remains an unresolved medical ...

Measuring Changes in Tactile Sensitivity in the Hind Paw of Mice Using an Electronic von Frey Apparatus

Measuring inflammation-induced changes in thresholds of hind paw withdrawal from mechanical pressure is a useful technique to assess changes in pain perception in rodents. Withdrawal thresholds can be measured first at baseline and then following drug, venom, injury, allergen,&#160;or otherwise evoked inflammation by applying an accurate force on very specific areas of the skin. An electronic von Frey apparatus allows precise assessment of mouse hind paw withdrawal thresholds that are not limited by the available filament sizes in contrast to classical von Frey measurements. The ease and rapidity of measurements allow for incorporation of assessment of tactile sensitivity outcomes in diverse models of rapid-onset inflammatory and neuropathic pain as multiple measurements can be taken within a short time period. Experimental measurements for individual rodent subjects can be internally controlled against individual baseline responses and exclusion criteria easily established to standardize baseline responses within and across experimental groups. Thus, measurements using an electronic von Frey apparatus represent a useful modification of the well-established classical von Frey filament-based assays for rodent mechanical allodynia that may also be applied to other nonhuman mammalian models.

Electronic von Frey measurements are an effective and improved alternative to classical von Frey filaments, as they allow rapid and precise measurement of changes in rodent mechanical withdrawal thresholds to continuously applied pressure stimuli before and after an inflammatory event.

Measuring inflammation-induced changes in thresholds of hind paw withdrawal from mechanical pressure is a useful technique to assess changes in pain ...

神经科学

Back Mechanical Sensitivity Assessment in the Rat for Mechanistic Investigation of Chronic Back Pain

Low back pain is the leading cause of disability worldwide, with dramatic personal, economic, and social consequences. To develop novel therapeutics, animal models are needed to examine the mechanisms and effectiveness of novel therapies from a translational perspective. Several rodent models of back pain are used in current investigations. Surprisingly, however, no standardized behavioral test was validated to assess mechanical sensitivity in back pain models. This is critical to confirm that animals with presumed back pain present local hypersensitivity to nociceptive stimuli, and to monitor sensitivity during interventions designed to relieve back pain. The objective of this study is to lay down a simple and accessible test to assess mechanical sensitivity in the back of rats. A test cage was fabricated specifically for this method; length x width x height: 50 x 20 x 7 cm, having a stainless-steel mesh on the top. This test cage allows the application of mechanical stimuli to the back. To perform the test, the back of the animal is shaved in the region of interest, and the test area is marked to repeat the test on different days, as needed. The mechanical threshold is determined with Von Frey filaments applied to the paraspinal muscles, utilizing the up-down method described previously. The positive responses include (1) muscle twitching, (2) arching (back extension), (3) rotation of the neck (4) scratching or licking the back, and (5) escaping. This behavioral test (Back Mechanical Sensitivity (BMS) test) is useful for mechanistic research with rodent models of back pain for the development of therapeutic interventions for the prevention and management of back pain.

To develop novel therapeutic interventions for the prevention and management of back pain, animal models are required to examine the mechanisms and effectiveness of these therapies from a translational perspective. The present protocol describes the BMS test, a standardized method to assess back mechanical sensitivity in the rat.

大鼠背部机械敏感性评估用于慢性背痛的机制研究

Low back pain is the leading cause of disability worldwide, with dramatic personal, economic, and social consequences. To develop novel therapeutics, ...

A Quantitative Sensory Testing Paradigm to Obtain Measures of Pain Processing in Patients Undergoing Breast Cancer Surgery

Chronic pain following surgery, persistent postsurgical pain, is an important highly prevalent condition contributing to significant symptom burden and lower quality of life. Persistent postsurgical pain is relatively refractory to treatment hence generating a high need for preventive strategies and treatments. Therefore, the identification of patients at risk of developing persistent pain is an area of active ongoing research. Recently it was demonstrated that peri-operative disruptions in central pain processing may be able to predict persistent postsurgical pain at long term follow-up in breast cancer patients. The aim of the current report is to present a short protocol to obtain pain thresholds to different stimuli at multiple sites and a measure of endogenous analgesia in breast cancer patients. We have used this method successfully in a clinical context and detail some representative results from a clinical study.

Persistent postsurgical pain may be related to changes in pain processing. By assessing pain in response to standardized stimuli, changes in pain processing can be elucidated. We present methods to obtain pain thresholds to different stimuli and a measure of endogenous analgesia in patients undergoing breast cancer surgery.

一种定量感官检测方法在乳腺癌手术患者疼痛处理中的研究

Chronic pain following surgery, persistent postsurgical pain, is an important highly prevalent condition contributing to significant symptom burden and ...