Activation of pain by sumatriptan

OBJECTIVE: To demonstrate that sumatriptan may induce activation or aggravation of pain at sites of inflammation caused by trauma or disease. METHODS: Case reports from the national pharmaco vigilancecenters of 2 countries, The Netherlands and New Zealand, are presented. These reports come from programs that use 2 methodologies to monitor drugs for adverse reactions: spontaneous reporting and a prospective observational cohort study. The potential mechanisms for pain production by sumatriptan are discussed in detail. RESULTS: Thirteen case reports of activation of pain by sumatriptan following injury and 8 associated with inflammatory diseases are presented. Most patients had one or more positive rechallenges. This type of reaction occurred at a higher rate with the subcutaneous formulation than with the oral preparation. Pain mostly was severe but short-lasting; pain was prolonged in some patients with inflammatory disease. CONCLUSIONS: A strong association has been demonstrated between the use of sumatriptan and the production of pain at sites of inflammation, and there is a plausible pharmacological mechanism for this reaction. Pain activation may be a class effect of the selective serotonergic agonists used in the treatment of migraine.     

Diffuse optical tomography of pain and tactile stimulation: activation in cortical sensory and emotional systems

Using diffuse optical tomography (DOT), we detected activation in the somatosensory cortex and frontal brain areas following tactile (brush) and noxious heat stimulation. Healthy volunteers received stimulation to the dorsum of the right hand. In the somatosensory cortex area, tactile stimulation produced a robust, contralateral to the stimulus, hemodynamic response with a weaker activation on the ipsilateral side. For the same region, noxious thermal stimuli produced bilateral activation of similar intensity that had a prolonged activation with a double peak similar to results that have been reported with functional MRI. Bilateral activation was observed in the frontal areas, oxyhemoglobin changes were positive for brush stimulation while they were initially negative (contralateral) for heat stimulation. These results suggest that based on the temporal and spatial characteristics of the response in the sensory cortex, it is possible to discern painful from mechanical stimulation using DOT. Such ability might have potential applications in a clinical setting in which pain needs to be assessed objectively (e.g., analgesic efficacy, pain responses during surgery).     

Localization of sensorimotor cortical rhythms induced by tactile stimulation using spatially filtered MEG

We applied the synthetic aperture magnetometry (SAM) spatial filtering method to localize sensorimotor mu (8-14 Hz) and beta (15-35 Hz) rhythms following tactile (brush) stimulation. Neuromagnetic activity was recorded from 10 adult subjects. Transient brush stimuli were applied separately to the right index finger, medial right toe and lower right lip. Differential images of mu and beta band source power were created for periods during (event-related desynchronization; ERD) or following (event-related synchronization; ERS) tactile stimulation, relative to prestimulus baseline activity. Mu ERD to finger brushing was localized to the contralateral somatosensory cortex and was organized somatotopically. Mu ERS, however, was not consistently observed for each subject. Beta ERD was consistently localized to sensory cortical areas and organized somatotopically in the post-central gyrus (SI), and beta ERS was observed to be organized motorotopically in the precentral gyrus (MI). Longer duration (2-3 s) stimulation of the index finger also produced beta ERS in the primary motor cortex, and its time course demonstrated that these oscillatory changes are an off-response to the termination of the presented sensory stimulus. Interestingly, lip and toe stimulation also produced post-stimulus increases in beta rhythms in the bilateral motor hand areas for all subjects, suggesting that common neural systems in the primary motor cortex are activated during tactile stimulation of different body regions.     

The cerebellum contributes to somatosensory cortical activity during self-produced tactile stimulation.

We used fMRI to examine neural responses when subjects experienced a tactile stimulus that was either self-produced or externally produced. The somatosensory cortex showed increased levels of activity when the stimulus was externally produced. In the cerebellum there was less activity associated with a movement that generated a tactile stimulus than with a movement that did not. This difference suggests that the cerebellum is involved in predicting the specific sensory consequences of movements and providing the signal that is used to attenuate the sensory response to self-generated stimulation. In this paper, we use regression analyses to test this hypothesis explicitly. Specifically, we predicted that activity in the cerebellum contributes to the decrease in somatosensory cortex activity during self-produced tactile stimulation. Evidence in favor of this hypothesis was obtained by demonstrating that activity in the thalamus and primary and secondary somatosensory cortices significantly regressed on activity in the cerebellum when tactile stimuli were self-produced but not when they were externally produced. This supports the proposal that the cerebellum is involved in predicting the sensory consequences of movements. In the present study, this prediction is accurate when tactile stimuli are self-produced relative to when they are externally produced, and is therefore used to attenuate the somatosensory response to the former type of tactile stimulation but not the latter.     

Patterns of cortical reorganization parallel impaired tactile discrimination and pain intensity in complex regional pain syndrome

In the complex regional pain syndrome (CRPS), several theories proposed the existence of pathophysiological mechanisms of central origin. Recent studies highlighted a smaller representation of the CRPS-affected hand on the primary somatosensory cortex (SI) during non-painful stimulation of the affected side. We addressed the question whether reorganizational changes can also be found in the secondary somatosensory cortex (SII). Moreover, we investigated whether cortical changes might be accompanied by perceptual changes within associated skin territories. Seventeen patients with CRPS of one upper limb without the presence of peripheral nerve injuries (type I) were subjected to functional magnetic resonance imaging (fMRI) during electrical stimulation of both index fingers (IFs) in order to assess hemodynamic signals of the IF representation in SI and SII. As a marker of tactile perception, we tested 2-point discrimination thresholds on the tip of both IFs. Cortical signals within SI and SII were significantly reduced contralateral to the CRPS-affected IF as compared to the ipsilateral side and to the representation of age- and sex-matched healthy controls. In parallel, discrimination thresholds of the CRPS-affected IF were significantly higher, giving rise to an impairment of tactile perception within the corresponding skin territory. Mean sustained, but not current pain levels were correlated with the amount of sensory impairment and the reduction in signal strength. We conclude that patterns of cortical reorganization in SI and SII seem to parallel impaired tactile discrimination. Furthermore, the amount of reorganization and tactile impairment appeared to be linked to characteristics of CRPS pain.     

Common cortical network for first and second pain

We measured, with whole-scalp magnetoencephalography, evoked fields from 10 healthy subjects to 1-ms thulium-laser stimuli that selectively activated nociceptive nerve fibers. The stimuli were delivered to the dorsum of the subject's left hand. The earliest cortical responses peaked at 165 +/- 7 ms, agreeing with the conduction velocity of Adelta-fibers. To stimulate unmyelinated C-fibers, we modified the method of Bragard et al. [Bragard, D., Chen, A.C., Plaghki, L., 1996. Direct isolation of ultra-late (C-fibre) evoked brain potentials by CO2 laser stimulation of tiny cutaneous surface areas in man. Neurosci. Lett. 209, 81-84], by decreasing the total energy of the laser beam and by restricting the size of the stimulated skin area to 0.2-0.3 mm2. The earliest cortical responses to these stimuli peaked at 811 +/- 14 ms. Bilateral activation of the SII cortices was detected in all 10 subjects to Adelta and in 8 subjects to C stimuli, emphasizing the importance of the SII cortex in processing of pain. Additional activation was observed in the posterior parietal cortex (PPC), probably related to sensorimotor coordination targeted to produce precise motor acts that reduce or prevent the pain; the PPC activation may have been accentuated by the required continuous evaluation of the perceived pain. In contrast to some earlier studies, we did not observe activation of the primary somatosensory cortex (SI). Additional activations to both types of stimuli were detected in the cingulate cortex (three subjects) and in the bilateral insular cortex (two subjects). These results implicate that the nociceptive inputs mediated by the Adelta- and C-fibers are processed in a common cortical network in different time windows. Reliable temporospatial characterization of cortical responses to first and second pain offers a unique tool for basic and clinical neuroscience to study the two distinctive pain fiber systems at cortical level.     

Cortical representation of dermatomes: MEG-derived maps after tactile stimulation

Mechanical stimulation of skin receptors is known to evoke cortical responses arising from the somatosensory cortex. Here we present a magnetoencephalographic (MEG) study where dermatomal somatosensory-evoked fields (DSSEFs) were recorded after mechanical stimulation of sacral (S1), lumbar (L3), thoracic (Th7), and cervical (C4) dermatomes in three healthy volunteers. All MEG measurements were repeated in order to test the replicability of the results. DSSEFs were successfully measured and modeled in all three participants. The topography and temporal dynamics of cortical responses derived after stimulation of each dermatome are described. We found that cortical-evoked responses can be reliably recorded using MEG after mechanical stimulation of dermatomes when a sufficiently large skin region within the dermatome is stimulated. Primary sensory cortex response (SI) to each of the four dermatomes was replicable and showed stability over time. The MEG-derived individual maps of activation confirm the somatotopic representation of dermatomes in primary sensory cortex and the utility of MEG recordings in disentangling the interactions between primary and secondary sensory cortex during somatic perception.     

前列地尔注射液对老年患者外周静脉血管疼痛刺激的研究

目的研究前列地尔注射液（商品名凯时）在静脉注射和静脉滴注时对老年患者外周静脉血管的疼痛刺激。方法选取100例使用凯时治疗的老年患者,随机进入观察组和对照组,观察组46例,采用静脉推注凯时,对照组54例采用静脉滴注凯时,观察两种注射方式对外周静脉血管的疼痛刺激。结果凯时在静脉推注时对老年患者外周静脉血管的疼痛刺激较弱,疼痛持续时间较短;在静脉滴注时发生疼痛刺激反应较强,疼痛持续时间较长,两种注射方法不良反应发生率比较差异有统计学意义（P〈0．05）。结论老年患者使用凯时治疗时宜静脉推注。     

Tactile discrimination, but not tactile stimulation alone, reduces chronic limb pain

Chronic pain is often associated with reduced tactile acuity. A relationship exists between pain intensity, tactile acuity and cortical reorganisation. When pain resolves, tactile function improves and cortical organisation normalises. Tactile acuity can be improved in healthy controls when tactile stimulation is associated with a behavioural objective. We hypothesised that, in patients with chronic limb pain and decreased tactile acuity, discriminating between tactile stimuli would decrease pain and increase tactile acuity, but tactile stimulation alone would not. Thirteen patients with complex regional pain syndrome (CRPS) of one limb underwent a waiting period and then 2 weeks of tactile stimulation under two conditions: stimulation alone or discrimination between stimuli according to their diameter and location. There was no change in pain (100 mm VAS) or two-point discrimination (TPD) during a no-treatment waiting period, nor during the stimulation phase (p > 0.32 for both). Pain and TPD were lower after the discrimination phase [mean (95% CI) effect size for pain VAS = 27 mm (14–40 mm) and for TPD = 5.7 mm (2.9–8.5 mm), p < 0.015 for both]. These gains were maintained at three-month follow-up. We conclude that tactile stimulation can decrease pain and increase tactile acuity when patients are required to discriminate between the type and location of tactile stimuli.     

Activation of the external anal and urethral sphincter muscles by repetitive transcranial cortical stimulation during spine surgery

OBJECTIVE: Clinical utility of high intensity repetitive transcranial electrical stimulation (rTES) to elicit a response in external anal and urethral sphincter muscles was investigated in 23 patients undergoing spine surgery. METHODS: During surgery, motor evoked potentials (MEPs) were recorded from external anal sphincter (EAS), external urethral sphincter (EUS), and tibialis anterior (TA) muscles following high voltage rTES under total intravenous anesthesia. RESULTS: No neurologic sequelae occurred during or after the rTES of the motor cortex. Onset latency for the EAS muscle was 20.2 +/- 3.5 msec which was not significant compared to the EUS muscle latency at 19.9 +/- 1.8 msec. The average electrical intensity to evoke EAS response was 789 +/- 78 volts compared to the 831 +/- 11 volts of the EUS muscle. Waveform latency for the TA muscle was robust in all cases while the latencies for EAS and EUS were not always clear. CONCLUSIONS: This preliminary study shows that intraoperative MEP monitoring of the external anal and urethral muscles is feasible method in particular in circumstances where bowel and bladder function are at risk of an inadvertent injury due to surgical manipulation.     

硬膜外植入式皮质刺激脑卒中患者提高神经网络功能

背景：硬膜外植入式皮质刺激兼顾了经颅磁刺激、经颅直流电刺激、硬膜下皮质刺激和深部脑刺激的优点,可显著改善脑卒中后的肢体运动与语言功能。 目的：综述近年来有关硬膜外植入式皮质刺激在脑卒中康复中的研究及其临床应用。 方法：由第一作者应用计算机检索1995年1月至2014年4月PubMed数据库及中国期刊全文数据库文献,检索关键词为“cortical stimulation,extradural motor cortex stimulation,extradural cortical implants,extraduralcorticalstimulation,stroke,rehabilitation;皮质刺激,硬膜外电刺激,硬膜外皮质植入,硬膜外皮质刺激,脑卒中,康复”。纳入有关硬膜外植入式皮质刺激在脑卒中后运动与言语障碍中应用的文章。结果与结论：硬膜外皮质刺激是植入式皮质刺激,其优势是侵入性小、高度精确性和经硬膜与大脑密切接触,对缺乏有效治疗的脑卒中慢性期运动和语言障碍患者来说,这有可能是一种新的治疗方法。硬膜外皮质刺激通过促进神经可塑性、促进病灶周围结构与功能改变、提高神经网络功能、促进大脑半球间功能平衡及增加感觉输入来改善脑卒中后的肢体运动功能与语言功能。     

Activation of excitatory amino acid receptors may mediate the folate-induced stimulation of locomotor activity after bilateral injection into the rat nucleus accumbens

Folic acid (FA) and 5-formyltetrahydrofolic acid (FTHF) have been shown previously to produce a marked stimulation of locomotor activity after bilateral injection into the rat nucleus accumbens. This study was designed to determine whether the hypermotility response produced by the folates is mediated through the activation of excitatory amino acid receptors in the nucleus accumbens. Although FA stimulated locomotor activity, pteroic acid, a congener of FA that lacks the glutamate moiety, was ineffective, suggesting that the glutamate portion of the molecule is essential for the hypermotility response. The N-methyl-D-aspartic acid (NMDA) receptor antagonists, D-alpha-aminoadipic acid, DL-alpha-epsilon-diaminopimelic acid and MgCl2, at doses that attenuated NMDA-induced hypermotility, were ineffective in decreasing the folate-induced hypermotility response. This behavioral observation is consistent with the biochemical observation that the folates, at a 1 mM concentration, were unable to stimulate the release of [3H]acetylcholine from striatal slices, a model system that is sensitive to the activation of NMDA receptors. In contrast to the ineffectiveness of the NMDA antagonists in inhibiting the response to the folates, the antagonist, glutamic acid diethylester, which inhibited the response to quisqualic acid, but not NMDA, also inhibited the response to both FA and FTHF. Two recently characterized dipeptides, gamma-D-glutamylaminomethylsulfonic acid and gamma-D-glutamyltaurine, antagonized the stimulation of locomotor activity produced by quisqualic acid, FA and FTHF. However, these dipeptides also inhibited the response to NMDA, suggesting that these compounds are not able to distinguish between quisqualate and NMDA receptors in the nucleus accumbens.(ABSTRACT TRUNCATED AT 250 WORDS)     

Needle temperature effect on pain ratings after injection

OBJECTIVES: Little research regarding appropriate immunization administration technique for adults has been carried out. Pain is a leading cause of self-deferral from immunizations. The purpose of this study was to determine whether administering intramuscular injections using cold needles would decrease patients' perceived pain and have an effect on the immune response elicited by the vaccine. METHODS: Eighty participants received an injection of influenza vaccine in 1 arm and a saline injection in the other using a cold or room temperature needle in a double-blind fashion assigned at random. Participants rated their pain after each injection using a standard visual pain scale bounded by no pain and most painful injection ever. Vaccine antibody response was measured using hemagglutination inhibition assays. RESULTS: Overall, pain scores after influenza vaccine administration were quite low (34.2+/-2.5 mm). The mean pain score for influenza vaccine was not different using cold or room temperature needles (cold 32.2 mm+/-3.20 vs. room temperature 36.0 mm+/-3.80; t=0.76; P=0.450). The mean pain scores for saline injections did not differ (room temperature 23.7 mm+/-3.19 vs. cold 25.2+/-2.95; t=-0.34; P=0.73). Individuals receiving injections with cold needles had less bruising (0/40 vs. 5/40; P<0.02) at the injection site, but incidences of pain and erythema were similar. The use of cold needles for vaccine administration had no effect on antibody response. CONCLUSIONS: Pain after influenza vaccine administration is generally mild. Use of cold needles may not be worth pursuing for injections associated with mild pain. However, it may be worthwhile to explore using cold needles as an analgesic with more painful injections.     

非药物干预缓解成人肌内注射引起注射部位疼痛的网状Meta分析

目的:对多种缓解成人肌内注射引起的注射部位疼痛的非药物干预方法进行效果评估。方法:计算机检索PubMed、the Cochrane Library、EMbase、Web of Science、PsycINFO、万方、中国知网和中国生物医学文献数据库中有关非药物干预缓解成人肌内注射疼痛的随机对照试验,检索时间均为建库至2020年3月31日。按照纳入和排除标准筛选文献、评价纳入研究的偏倚风险并从中提取数据,采用Stata 14.0展现各研究之间的网状关系,并进行发表偏倚分析;通过累积排序概率图下面积呈现每个干预方法成为最佳干预的可能性。结果:共纳入15项RCT,涉及1180例病人、12种非药物干预措施。Meta分析结果显示,在减轻成人注射过程中疼痛方面,穴位按压优于常规注射。其余10种干预方法(两针头法、指压、使用shot blocker、Z径路、留置气泡、使用buzzy、综合干预、注射体位、伪穴按压、Z路径+留置气泡)的相关研究较少,尚不能确定其改善注射疼痛效果;但根据潜在有效性优劣结果排序提示,使用buzzy工具>使用shot blocker工具>皮肤牵拉、加压伴肌肉快速松解综合干预>伪穴按压>Z路径+留置气泡>两针头法>注射体位>注射点指压>Z径路法>留置气泡>常规注射。结论:现有证据表明穴位按压是缓解成人肌内注射部位疼痛的有效方式,但尚不能确定其余10种干预方法在缓解成人肌内注射引起的注射部位疼痛的有效性,建议开展更多研究以证实其潜在效果。     

皮质脊髓投射决定触觉和神经病理性触痛的敏感性

当前的躯体感觉感知模型强调感觉信息加工处理的过程是从初级感觉神经元经脊髓再传递到大脑。人们普遍认为心理对感知的影响是发生在脑内某些局部区域。本文主要研究脊髓水平的感觉信息的传入是否直接接受来自大脑皮质的、自上而下的控制。尽管皮质脊髓束(CST)传统上被视为主要运动通路,但是有一群源自初级和次级躯体感觉皮层的皮质脊髓神经元(CSN)通过CST轴突直接投射到脊髓背角。躯体感觉中CSN活性的降低或CST的横断都会选择性地损害小鼠对轻触觉刺激的行为反应,但不改变对伤害性刺激的行为反应。此外,以上对CSN的操控极大地减轻了外周神经病理性疼痛中由触觉引发的异常性疼痛(Allodynia)。触觉刺激可以激活躯体感觉CSN,进而通过其皮质脊髓投射促进通过轻触诱发的脊髓背角深层的胆囊收缩素阳性的中间神经元的活动。这种由触觉驱动的脊髓-皮质-脊髓前馈反射致敏环路对于在触觉诱发的异常性疼痛条件下募集脊髓伤害性神经元非常重要。以上研究结果表明,脊髓中正常和病理条件下的触觉信息处理过程直接接受来自皮层的操控,并为神经病理性疼痛的治疗开辟了新思路。     

Corneal pain evoked by thermal stimulation

The thermal sensitivity of the eyelid and cornea was compared using an automated apparatus to produce stimulus pulses of known magnitude and duration over the range 33--45 degrees C. Subjects reported only temperature sensation when the skin of the upper eyelid was tested; however, corneal stimulation in the same subjects was always perceived as nociceptive. The possibility that other ocular tissues may be involved in the pain responses was shown to be unlikely by direct experimentation or by calculation of heat flow in those tissues. Cornea and eyelid thresholds were compared in relationship to the structural and physical properties of these tissues. It was found that the nerve endings of the corneal epithelium are less sensitive to temperature change when compared to the thermal receptors of the eyelid. It is concluded that the cornea is useful for the experimental study of pain.     

Therapeutic extradural cortical stimulation for central and neuropathic pain: a review.

OBJECTIVE: Extradural cortical stimulation is a recent addition to the armamentarium of functional neurosurgery. This article reviews results of treatment of chronic central and neuropathic pain. CONCLUSIONS: It is concluded that extradural cortical stimulation may be effective in several refractory cases.