Adaptive modifications of cold pain (author's transl)]

38 healthy subjects 22-28 years of age underwent the cold-pressor-test seven times on each of 21 consecutive days always at the same time of day. The subjective sensations of cold pain and the objective circulatory reactions were registered. There was observed only a very distinct subjective cold pain habituation from one exposition to the other. The habituation effect on blood pressure reaction however was of expected extent. The long term adaptation showed to have effect on the predominance of the two components of pain perception the epicritic and protopathic pain experience. Initially the cold stimulus produced an overwhelmingly protopathic sufferenig whilst at the end of the three weeks of adaptation there remained only a reduced and localized epicritic pain sensation. Typological differences of pain reactions and pain adaptation are discussed.     

Neurotensin and pain modulation

Neurotensin (NT) can produce a profound analgesia or enhance pain responses, depending on the circumstances. Recent evidence suggests that this may be due to a dose-dependent recruitment of distinct populations of pain modulatory neurons. NT knockout mice display defects in both basal nociceptive responses and stress-induced analgesia. Stress-induced antinociception is absent in these mice and instead stress induces a hyperalgesic response, suggesting that NT plays a key role in the stress-induced suppression of pain. Cold water swim stress results in increased NT mRNA expression in hypothalamic regions known to project to periaqueductal gray, a key region involved in pain modulation. Thus, stress-induced increases in NT signaling in pain modulatory regions may be responsible for the transition from pain facilitation to analgesia. This review focuses on recent advances that have provided insights into the role of NT in pain modulation.     

Advances in clinical research methodology for pain clinical trials

Pain is a ubiquitous phenomenon, but the experience of pain varies considerably from person to person. Advances in understanding of the growing number of pathophysiologic mechanisms that underlie the generation of pain and the influence of the brain on the experience of pain led to the investigation of numerous compounds for treating pain. Improved knowledge of the subjective nature of pain, the variations in the measurement of pain, the mind-body placebo effect and the impact of differences in the conduct of a clinical trial on the outcome have changed approaches to design and implement studies. Careful consideration of how these concepts affect the choice of study population, the randomization and blinding process, the measurement and collection of data, and the analysis and interpretation of results should improve the quality of clinical trials for potential pain therapies.     

丘脑中央下核在痛觉感受与痛觉调制中的作用

本结合笔的工作,综述了近年来关于丘脑中央下核（Ｓｍ）在痛觉感受与痛觉调制中作用的研究。结果表明,它可能主要与痛觉的情绪激动成分有关,而且Ｓｍ－ＶＬＯ－ＰＡＧ可能构成一个痛觉调制的通路,通过脑干下行抑制系统在脊髓水平调制伤害感受性输入,从而产生痛觉的负反馈性调节。     

Magnetic resonance imaging for chronic pain: diagnosis,manipulation, and biomarkers

Pain is a multidimensional subjective experience with biological, psychological, and social factors. Whereas acute pain can be a warning signal for the body to avoid excessive injury, long-term and ongoing pain may be developed as chronic pain. There are more than 100 million people in China living with chronic pain, which has raised a huge socioeconomic burden. Studying the mechanisms of pain and developing effective analgesia approaches are important for basic and clinical research. Recently, with the development of brain imaging and data analytical approaches, the neural mechanisms of chronic pain have been widely studied. In the first part of this review, we briefly introduced the magnetic resonance imaging and conventional analytical approaches for brain imaging data. Then, we reviewed brain alterations caused by several chronic pain disorders, including localized and widespread primary pain, primary headaches and orofacial pain, musculoskeletal pain, and neuropathic pain, and present meta-analytical results to show brain regions associated with the pathophysiology of chronic pain. Next, we reviewed brain changes induced by pain interventions, such as pharmacotherapy, neuromodulation, and acupuncture. Lastly, we reviewed emerging studies that combined advanced machine learning and neuroimaging techniques to identify diagnostic, prognostic, and predictive biomarkers in chronic pain patients.     

杏仁核参与疼痛情绪过程的研究进展

本文综述了近年来关于杏仁核参与疼痛过程的研究进展。疼痛伴随有强烈的情绪反应,而杏仁核是情绪调控中的一个关键核团。最近,越来越多的证据支持杏仁核参与痛觉的编码和调制过程。杏仁核对来自脊髓和三叉神经核的伤害性信息及皮层和丘脑的多种感觉信息进行整合,产生负性情绪,并对疼痛刺激作出相应的行为反应。同时,杏仁核也通过与导水管周围灰质、延髓头端腹内侧区及其它脑干核团的纤维联系参与镇痛过程。     

Endocannabinoids and related fatty acid derivatives in pain modulation

The brain produces at least five compounds that possess sub-micromolar affinity for cannabinoid receptors: anandamide, 2-arachidonoylglycerol, noladin ether, virodhamine, and N-arachidonoyldopamine (NADA). One function of these and/or related compounds is to suppress pain sensitivity. Much evidence supports a role of endocannabinoids in pain modulation in general, and some evidence points to the role of particular endocannabinoids. Related endogenous fatty acid derivatives such as oleamide, palmitoylethanolamide, 2-lineoylglycerol, 2-palmitoylglycerol, and a family of arachidonoyl amino acids may interact with endocannabinoids in the modulation of pain sensitivity.     

Vocal communication of simulated pain

While evidence suggests that pain cries produced by human babies and other mammal infants communicate pain intensity, whether the pain vocalisations of human adults also encode pain intensity, and which acoustic characteristics influence listeners’ perceptions, remains unexplored. Here, we investigated how trained actors communicated pain by comparing the acoustic characteristics of nonverbal vocalisations expressing different levels of pain intensity (mild, moderate and severe). We then performed playback experiments to examine whether vocalisers successfully communicated pain intensity to listeners, and which acoustic characteristics were responsible for variation in pain ratings. We found that the mean and range of voice fundamental frequency (F0, perceived as pitch), the amplitude of the vocalisation, the degree of periodicity of the vocalisation and the proportion of the signal displaying non-linear phenomena all increased with the level of simulated pain intensity. In turn, these parameters predicted increases in listeners’ ratings of pain intensity. We also found that while different voice features contributed to increases in pain ratings within each level of expressed pain, a combination of these features explained an impressive amount of the variance in listeners’ pain ratings, both across (76%) and within (31–54%) pain levels. Our results show that adult vocalisers can volitionally simulate and modulate pain vocalisations to influence listeners’ perceptions of pain in a manner consistent with authentic human infant and nonhuman mammal pain vocalisations, and highlight potential for the development of a practical quantitative tool to improve pain assessment in populations unable to self-report their subjective pain experience.     

Glutamate receptors and pain

Pain is an important survival and protection mechanism for animals. However, chronic/persistent pain may be differentiated from normal physiological pain in that it confers no obvious advantage. An accumulating body of pharmacological, electrophysiological, and behavioral evidence is emerging in support of the notion that glutamate receptors play a crucial role in pain pathways and that modulation of glutamate receptors may have potential for therapeutic utility in several categories of persistent pain, including neuropathic pain resulting from injury and/or disease of central (e.g., spinal cord injury) or peripheral nerves (e.g., diabetic neuropathy, radiculopathy) and inflammatory or joint-related pain (e.g., rheumatoid arthritis, osteoarthritis). This review focuses on the role of glutamate receptors, including both ionotropic (AMPA, NMDA and kainate) and metabotropic (mGlu1-8) receptors in persistent pain states with particular emphasis on their expression patterns in nociceptive pathways and their potential as targets for pharmacological intervention strategies.     

Conditioned pain modulation is associated with common polymorphisms in the serotonin transporter gene

Background

Variation in the serotonin transporter (5-HTT) gene (SLC6A4) has been shown to influence a wide range of affective processes. Low 5-HTT gene-expression has also been suggested to increase the risk of chronic pain. Conditioned pain modulation (CPM) - i.e. ‘pain inhibits pain’ - is impaired in chronic pain states and, reciprocally, aberrations of CPM may predict the development of chronic pain. Therefore we hypothesized that a common variation in the SLC6A4 is associated with inter-individual variation in CPM. Forty-five healthy subjects recruited on the basis of tri-allelic 5-HTTLPR genotype, with inferred high or low 5-HTT-expression, were included in a double-blind study. A submaximal-effort tourniquet test was used to provide a standardized degree of conditioning ischemic pain. Individualized noxious heat and pressure pain thresholds (PPTs) were used as subjective test-modalities and the nociceptive flexion reflex (NFR) was used to provide an objective neurophysiological window into spinal processing.

Results

The low, as compared to the high, 5-HTT-expressing group exhibited significantly reduced CPM-mediated pain inhibition for PPTs (p = 0.02) and heat-pain (p = 0.02). The CPM-mediated inhibition of the NFR, gauged by increases in NFR-threshold, did not differ significantly between groups (p = 0.75). Inhibition of PPTs and heat-pain were correlated (Spearman’s rho = 0.35, p = 0.02), whereas the NFR-threshold increase was not significantly correlated with degree of inhibition of these subjectively reported modalities.

Conclusions

Our results demonstrate the involvement of the tri-allelic 5-HTTLPR genotype in explaining clinically relevant inter-individual differences in pain perception and regulation. Our results also illustrate that shifts in NFR-thresholds do not necessarily correlate to the modulation of experienced pain. We discuss various possible mechanisms underlying these findings and suggest a role of regulation of 5-HT receptors along the neuraxis as a function of differential 5-HTT-expression.     

Ion channel therapeutics for pain

Pain is a complex disease which can progress into a debilitating condition. The effective treatment of pain remains a challenge as current therapies often lack the desired level of efficacy or tolerability. One therapeutic avenue, the modulation of ion channel signaling by small molecules, has shown the ability to treat pain. However, of the 215 ion channels that exist in the human genome, with 85 ion channels having a strong literature link to pain, only a small number of these channels have been successfully drugged for pain. The focus of future research will be to fully explore the possibilities surrounding these unexplored ion channels. Toward this end, a greater understanding of ion channel modulation will be the greatest tool we have in developing the next generation of drugs for the treatment of pain.     

Central mechanisms of pain modulation.

Bulbospinal serotonergic neurons and two physiological classes of bulbospinal nonserotonergic cells interact to modulate pain transmission. Recent studies have begun to elaborate targets of descending pain modulation other than the well-studied flexion withdrawal pathways. Site-specific, naloxone-sensitive placebo analgesia, which is hard to reconcile with current models of descending pain modulation, presents an exciting challenge to the field.     

Sensory and pharmacological modulation of pain

Traditional neurosurgical methods to control pain have been replaced by a variety of modulation techniques. The major types of modulation are pharmacological, physical, and psychological. Important advances are occurring in the development of all three modulation approaches.     

Adaptive modifications of cold pain. III. Communication: short-term experiments with 1-min-intervals (author's transl)

The subjective short-term habituation to pain-inducing cold stimuli is demonstrated for the first time by measuring the tolerated exposition time. It proves impossible to separate temporally a detection threshold of cold pain from the distress reaction level. The slope of subjective habituation is clearly dependent on the individual vegetative starting position. It is discussed why the blood pressure reaction may be used as a valid parameter for experienced intensity of a cold pain sensation only to a limited extent.     

Emotional regulation of pain: the role of noradrenaline in the amygdala

The perception of pain involves the activation of the spinal pathway as well as the supra-spinal pathway,which targets brain regions involved in affective and cognitive processes.Pain and emotions have the capacity to influence each other reciprocally;negative emotions,such as depression and anxiety,increase the risk for chronic pain,which may lead to anxiety and depression.The amygdala is a key-player in the expression of emotions,receives direct nociceptive information from the parabrachial nucleus,and is densely innervated by noradrenergic brain centers.In recent years,the amygdala has attracted increasing interest for its role in pain perception and modulation.In this review,we will give a short overview of structures involved in the pain pathway,zoom in to afferent and efferent connections to and from the amygdala,with emphasis on the direct parabrachio-amygdaloid pathway and discuss the evidence for amygdala’s role in pain processing and modulation.In addition to the involvement of the amygdala in negative emotions during the perception of pain,this brain structure is also a target site for many neuromodulators to regulate the perception of pain.We will end this article with a short review on the effects of noradrenaline and its role in hypoalgesia and analgesia.     

Barcoding human physical activity to assess chronic pain conditions

Background

Modern theories define chronic pain as a multidimensional experience – the result of complex interplay between physiological and psychological factors with significant impact on patients'' physical, emotional and social functioning. The development of reliable assessment tools capable of capturing the multidimensional impact of chronic pain has challenged the medical community for decades. A number of validated tools are currently used in clinical practice however they all rely on self-reporting and are therefore inherently subjective. In this study we show that a comprehensive analysis of physical activity (PA) under real life conditions may capture behavioral aspects that may reflect physical and emotional functioning.

Methodology

PA was monitored during five consecutive days in 60 chronic pain patients and 15 pain-free healthy subjects. To analyze the various aspects of pain-related activity behaviors we defined the concept of PA ‘barcoding’. The main idea was to combine different features of PA (type, intensity, duration) to define various PA states. The temporal sequence of different states was visualized as a ‘barcode’ which indicated that significant information about daily activity can be contained in the amount and variety of PA states, and in the temporal structure of sequence. This information was quantified using complementary measures such as structural complexity metrics (information and sample entropy, Lempel-Ziv complexity), time spent in PA states, and two composite scores, which integrate all measures. The reliability of these measures to characterize chronic pain conditions was assessed by comparing groups of subjects with clinically different pain intensity.

Conclusion

The defined measures of PA showed good discriminative features. The results suggest that significant information about pain-related functional limitations is captured by the structural complexity of PA barcodes, which decreases when the intensity of pain increases. We conclude that a comprehensive analysis of daily-life PA can provide an objective appraisal of the intensity of pain.     

谷氨酸性突触在痛觉和记忆中的突触和分子机制

谷氨酸是哺乳动物脑中的兴奋性递质。中枢神经系统的谷氨酸性突触广泛参与痛觉传递,突触可塑性和递质的调节。谷氨酸的NMDA受体参与前脑相关的学习及功能。在这篇综述中,我们提出前脑的NMDA受体通过增强谷氨酸性突触传递导致长期性的炎痛。具有增强NMDA受体功能的小鼠会产生更多的慢性痛。NMDA NR2B受体抑制剂在未来可能被用来控制人类的慢性痛。     

Galanin receptors possibly modulate the obesity-induced change in pain threshold

Pain threshold may be up-regulated or down-regulated according to gender, age, race/ethnic and psychological state. Previous studies indicated that obesity may change pain threshold, both nociceptive and antinociceptive, which resulted from obesity-reduced variation of neuroendocrine. However there is a limited understanding of its molecular mechanism underlying this variation. A lot of evidence supports that galanin increases food intake and body weight to induce obesity in animals. This peptide may also modulate nociceptive susceptibility via central galanin receptor 1 and peripheral galanin receptor 2 in dorsal root ganglion. Whereas injury and obesity may up-regulate the galanin expression and stimulate its secretion to elevate the plasma levels of subjects. Pain may increase the risk of obesity through reduced physical activity. In this review, we highlighted the multiple bilateral interrelation between obesity and pain sensitivity, between galanin and obesity and between galanin and injure-induced pain. In view of the above, we reasoned that galanin receptors possibly participated in the modulation of the obesity-induced change in pain threshold, which need further direct evidence to support as yet. This review is helpful to explore the mechanism that galanin receptors regulate the obesity-induced change of pain sensitivity and to contribute to our understanding of the relation among galanin, obesity and pain threshold.