TRPV1-lineage neurons are required for thermal sensation

The ion-channel TRPV1 is believed to be a major sensor of noxious heat, but surprisingly animals lacking TRPV1 still display marked responses to elevated temperature. In this study, we explored the role of TRPV1-expressing neurons in somatosensation by generating mice wherein this lineage of cells was selectively labelled or ablated. Our data show that TRPV1 is an embryonic marker of many nociceptors including all TRPV1- and TRPM8-neurons as well as many Mrg-expressing neurons. Mutant mice lacking these cells are completely insensitive to hot or cold but in marked contrast retain normal touch and mechanical pain sensation. These animals also exhibit defective body temperature control and lose both itch and pain reactions to potent chemical mediators. Together with previous cell ablation studies, our results define and delimit the roles of TRPV1- and TRPM8-neurons in thermosensation, thermoregulation and nociception, thus significantly extending the concept of labelled lines in somatosensory coding.     

Barrels IX-proceedings

The properties of a newly developed tonic heat pain model (THPM), which makes use of pulsating contact heat, were investigated in 18 young men. The most important feature of this model is that repetitive heat pulses with an intensity of 1°C above the individual pain threshold are employed. This approach was used to tailor the tonic pain stimulation to the individual pain sensitivity. In the first of two experiments, the effects of pulse frequencies ranging from 5 to 30 pulses per minute (ppm) on ratings of pain intensity and pain unpleasantness (visual analogue scales) were examined. At all frequencies, both ratings increased steadily over the 5-min test period. Frequencies of 15 ppm or more appeared to enhance pain intensity throughout the test period compared to the lower frequencies, but did not appear to alter pain unpleasantness. This suggests that only pain intensity is influenced by slow temporal summation and that a sort of frequency threshold exists for this kind of summation. In the second experiment, the THPM was compared to a well-established form of tonic pain stimulation, the compressor test (CPT); visual analogue scales were again used, and in addition the McGill Pain Questionnaire was employed. The CPT appeared to produce stronger tonic pain than the THPM. However, as is typical with tonic pain, both tonic pain models induced relatively higher values on the affective pain dimension than on the sensory pain dimension. The time course of pain was dynamic in the CPT, with an increase followed by a plateau phase, at least in those subjects who could tolerate the CPT for more than 60 sec. In contrast, as in the first experiment, the pain ratings in the THPM were characterized by a slow and steady increase over time. Moreover, there was absolutely no indication of a dichotomy between “pain-sensitive” and “pain-tolerant” individuals in the THPM, although such a dichotomy was evident in the CPT. This implies that the distinction between pain-sensitive and pain-tolerant individuals can be made only with the CPT, and that this distinction represents individual differences in peripheral vascular reactions to cold rather than in pain perception. In conclusion, the THPM appears to produce a stable and predictable temporal pattern of tonic pain with a predominant affective component, and to be suitable for application in the majority of individuals without causing undue discomfort.     

花青素对完全弗氏佐剂诱导慢性炎性痛的镇痛作用及其机制

目的：本研究旨在探索金叶女贞果实花青素对完全弗氏佐剂（CFA）诱导慢性炎性痛的镇痛作用及其可能的中枢机制。方法：雄性SD大鼠30只随机分为三组（n=10）：正常对照组、慢性炎性痛模型组（左后足跖注射100 μl CFA）、花青素治疗组（模型+花青素90 mg·kg^-1,ig,qd）。造模前和术后第1、3、5、7、9、11、13日测量各组大鼠的体重、基础痛阈（热痛阈和机械痛阈）,左后肢足趾容积;术后第14日实验结束,分光光度计法测定血清各项生化指标,Western blot检测海马区总辣椒素受体（TRPV1）和磷酸化辣椒素受体（p-TRPV1）的表达。结果：花青素能提高模型组大鼠热痛阈和机械痛阈（P<0.05）,降低足趾肿胀度（P<0.05）,提高血清SOD水平（P<0.01）,降低血清MDA和NO含量（P<0.05）,降低大脑海马区p-TRPV1/TRPV1蛋白比例。结论：花青素灌胃14日处理对完全弗氏佐剂诱导的大鼠慢性炎性痛有镇痛作用,其机制可能与降低炎性因子释放,提高抗氧化能力和下调TRPV1磷酸化有关。     

损毁和刺激垂体对大鼠痛阈的影响

采用局限性损毁和刺激垂体的方法,以行为测痛为指标,观察大鼠垂体在痛觉调节中的作用以及地塞米松（Ｄｅｘ）对其影响。实验结果显示,损毁垂体中间叶（ＩＬ）及邻近的前叶（ＡＬ）,大鼠痛阈明显低于手术前的痛阈（Ｐ＜０．０１）。电刺激垂体的上述同样部位,大鼠痛阈明显高于手术基础值及自身假刺激值（Ｐ＜０．００１）。经Ｄｅｘ处理的动物,电刺激垂体不再引起痛阈升高。结果表明,大鼠垂体ＩＬ及靠近ＡＬ与痛调节有关,这种     

Association between ABO blood types and pain perception

Aim of the study: Pain perception is associated with different phenotypic characteristics such as sex, eye, and hair color. Hence, it is assumed that ABO blood type can also affect pain perception.

Materials and methods: In order to investigate this hypothesis, an experimental study with healthy volunteers (18–40?years) was designed. The experimental procedure included a blood type test and two rounds of pressure pain threshold assessments separated by a cold pressor test. Pressure pain threshold was assessed bilaterally at the temporalis, masseter, and deltoid muscles, where the muscle sites were randomized. Cold pressor test was conducted by immersion of participants’ non-dominant hand into iced water of 1–4?°C for 2?min.

Results: Thirty-seven healthy volunteers, distributed in the four blood type groups, completed the study. Participants with blood type B scored the highest pressure pain thresholds at the examined craniofacial muscles, while participants with blood type AB tended to score the lowest. Furthermore, participants with blood type AB displayed the highest elevation in pressure pain thresholds after cold pressor test.

Conclusions: Participants with blood type B displayed the lowest mechanical pain sensitivity and the blood type AB group exhibited the strongest conditioned pain modulation effect. These findings emphasize the necessity of considering ABO blood types in future pain research.     

苦参注射液联合普瑞巴林对脊神经结扎大鼠疼痛的影响

目的:探讨苦参注射液与普瑞巴林合用的镇痛效果,为临床用药提供实验依据。方法:通过结扎L5脊神经建立大鼠神经病理性疼痛模型。按照痛阈值将模型成功大鼠随机分为3组,分别为肌肉注射苦参注射液、口服普瑞巴林、苦参注射液和普瑞巴林联合用药。采用Von Frey纤维丝测定机械痛阈值,热板法测定热痛阈值,比较3组大鼠的机械痛阈值和热痛阈值的差异。结果:苦参注射液组大鼠机械痛镇痛效果第7天出现,热痛镇痛效果第21天出现,大鼠机械痛阈值和热痛阈值显著升高。口服普瑞巴林组大鼠机械痛阈值和热痛阈值在30分钟内显著升高,但机械痛阈值在给药第8天时下降到给药前水平,热痛阈值给药第5天时下降到给药前水平。联合使用苦参注射液和普瑞巴林,大鼠机械痛阈值和热痛阈值于给药后第1天显著升高,镇痛效果一直维持至实验结束(第28天)。结论:苦参注射液镇痛起效慢,不易产生耐受性。普瑞巴林镇痛起效快,但容易产生耐受。二者联合使用既可短时间内起到镇痛效果,并且不易产生耐受。     

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。     

A Psychophysical Comparison of Sensory and Affective Responses to Four Modalities of Experimental Pain

It is generally accepted that the sensory and affective components of pain may be differentially associated with various acute and chronic diseases, and that some treatment regimens are best directed toward certain aspects of the pain experience. In addition, experimental animal models have been described that presume to assess either the sensory-discriminative aspects of phasic pain or the affective responses associated with tonic pain. The present psychophysical experiment directly compares the perceived intensity and unpleasantness of sensations evoked by four types of experimental noxious stimuli: contact heat, electric shock, ischemic exercise, and cold-pressor pain. A novel pain measurement technique is described that incorporates unbounded magnitude-estimation/category scales; this technique allows precise ratio responses, while minimizing within- and between- subject variability. We observe that, relative to the perceived intensity of the individual stimuli, subjects consistently differentiate among the degrees of unpleasantness evoked by the four stimulus modalities. Ischemic exercise and cold-pressor pain evoke higher estimates of unpleasantness, and thus may better mimic the pain of chronic disease. The relative unpleasantness produced by contact heat is significantly less than that of the other modalities tested, and therefore contact heat stimuli may be ideally suited for assessing sensory-discriminative aspects of pain perception. Possible neurophysiological mechanisms underlying the observed differences in perceived unpleasantness are discussed in relation to the growing body of literature concerning tonic and phasic pain stimuli.     

完全弗氏佐剂诱导大鼠慢性骨盆疼痛综合征炎性痛模型的制备*

目的: 建立大鼠慢性骨盆疼痛综合征(CPPS)炎性痛模型并进行评价,为CPPS炎症引起的慢性骨盆疼痛的外周及中枢机制研究提供可靠的动物模型。方法: 将60只SD雄性大鼠随机分成空白组,假手术组和模型组,每组20只。采用向大鼠前列腺腹侧叶注射完全弗氏佐剂(CFA)的方法制备CPPS炎性痛模型。术后观察大鼠一般情况变化;分别于造模后7 d,14 d,21 d,28 d,35 d测定大鼠足底和阴囊热刺激疼痛阈值;取材后前列腺组织称重计算前列腺指数;显微镜下观察大鼠前列腺组织病理变化并用半定量法评价前列腺组织损伤程度,以评价模型是否成功。结果: 模型成功17只,成模率为85%。与空白组和假手术组比较,造模后大鼠的活动度、毛发光泽度降低,排尿量增加。足底和阴囊热刺激疼痛阈值显著降低并可稳定维持1个月以上(P＜0.01)。前列腺湿重和前列腺指数均显著性提高(P＜0.01)。前列腺组织肉眼可见明显水肿,与周围组织粘连严重;镜下可见腺腔萎缩,间质内大量炎性细胞浸润。结论: 利用向大鼠前列腺腹侧叶注射CFA的方法,可成功复制CPPS炎性痛模型,这将为后续CPPS发病机制的研究,特别是疼痛行为与潜在炎症和神经损伤之间的机制联系提供有价值的工具。     

The effect of stimulus number on the stability of responses for an extensive heat pain test

Background.?The use of relatively lower stimulus presentation numbers in quantitative sensory testing may influence the computation accuracy of participants’ discriminability. The minimum trial number for obtaining a stabilized participant discrimination ability was determined.

Materials and methods.?Twelve participants’ ability to discriminate between noxious heat stimuli pairs (45°C/46°C, 46°C/47°C, and 47°C/48°C) was assessed using a six-category confidence rating scale. Heat stimuli were administered to the forearm. Two conditions with presentation numbers of 17 trials per stimulus (representing the median number of trials in previous studies) and 40 trials per stimulus (used in a previous study with a similar protocol) were used.

Results and discussion.?Participants’ discriminability stabilized at approximately the 20th trial based on the lowest frequency of indeterminate and non-model conforming results under both conditions. A simple linear regression model showed a statistically significant positive relationship between discriminability for the two conditions (slope?=?0.65, p?<?0.001; constant?=?0.33, p?=?0.02; r^2?=?0.51). As a rule of thumb, approximately 20 trials per stimulus intensity could be used to obtain a stabilized discriminability outcome.     

中枢催产素在电针镇痛中的作用

本工作以钾离子透入法引起大鼠甩尾反应的电流强度(mA)为痛反应指标,观察了侧脑室注射催产素(OT)及抗催产素血清(AOTS)对大鼠痛阈和电针镇痛效应的影响。注射50 ngOT 后80min 内,大鼠痛阈比注药前增加20—38%。与注射生理盐水组的痛阈相比有非常明显的增高(p<0.01—0.001),侧脑室注射 OT 后电针期内,痛阈增加139—234%,与生理盐水电针组相比,有显著差异(P<0.05—0.01)。OT 的剂量在25—100ng 范围内,其增强电针镇痛效应有明显的剂量-效应关系。注射 AOTS 后,电针镇痛应明显低于注射正常兔血清(NRS)组(p<0.05—0.01)。上述结果表明,侧脑室注射 OT,既可提高痛阈又可明显地增强电针镇痛效应,而用 AOTS消除内源性 OT 的作用后,电针镇痛效应明显降低。这提示,中枢神经系统内的 OT 在电针镇痛过程中,发挥一定的作用     

一种刺激内脏大神经的慢性测痛方法

用聚四氟乙烯绝缘多股银丝作双极电极,埋置于左侧大内脏神经上,以刺激大内脏神经引起行为反应所需的最小电流强度作为内脏痛觉阈值。刺激参数为短串单相方波,串长500ms,波宽1ms,频率40Hz,强度为每隔5s递增约0.1mA,至出现行为反应时停止。30只家兔121次测试,内脏痛阈均值为1.16±0.056mA。在18只家兔中每只兔测定12次痛阈,其阈值相当稳定,波动在0.07mA 之间,用随机区组方差分析无显著意义。在14只家兔中静脉注射芬坦尼(20μg/kg),5min 后阈值升高显著,维持15min,其后渐趋恢复。作者认为,本方法可用于测定内脏痛阈的实验研究。