Pain genes

Pain, which afflicts up to 20% of the population at any time, provides both a massive therapeutic challenge and a route to understanding mechanisms in the nervous system. Specialised sensory neurons (nociceptors) signal the existence of tissue damage to the central nervous system (CNS), where pain is represented in a complex matrix involving many CNS structures. Genetic approaches to investigating pain pathways using model organisms have identified the molecular nature of the transducers, regulatory mechanisms involved in changing neuronal activity, as well as the critical role of immune system cells in driving pain pathways. In man, mapping of human pain mutants as well as twin studies and association studies of altered pain behaviour have identified important regulators of the pain system. In turn, new drug targets for chronic pain treatment have been validated in transgenic mouse studies. Thus, genetic studies of pain pathways have complemented the traditional neuroscience approaches of electrophysiology and pharmacology to give us fresh insights into the molecular basis of pain perception.     

Pain genetics: past, present and future

Chronic pain is a classic example of gene × environment interaction: inflammatory and/or nerve injuries are known or suspected to be the etiology of most chronic pain syndromes, but only a small minority of those subjected to such injuries actually develop chronic pain. Once chronic pain has developed, pain severity and analgesic response are also highly variable among individuals. Although animal genetics studies have been ongoing for over two decades, only recently have comprehensive human twin studies and large-scale association studies been performed. Here, I review recent and accelerating progress in, and continuing challenges to, the identification of genes contributing to such variability. Success in this endeavor will hopefully lead to both better management of pain using currently available therapies and the development and/or prioritizing of new ones.     

Does experimental pain response vary across the menstrual cycle? A methodological review

The findings on sex differences in human experimental pain research are inconsistent. One possible factor contributing to the inconsistent findings is the female hormonal cycle, as hormone levels may affect pain sensitivity. A number of studies suggest that women's responses to experimentally evoked pain vary across the menstrual cycle. However, at least an equal number of studies suggest a lack of variability. The purpose of this article is to review the literature with emphasis on what we believe could be the reasons for the inconsistent findings, namely, differences in populations sampled, timing of experimental sessions across the menstrual cycle, and nomenclature used to identify the time (phases) in the cycle when measurements were done, nature of the pain stimuli chosen, and outcomes measured. These inconsistencies and other methodological problems associated with most experimental pain studies make it difficult to draw inferences from this literature. For the science to improve, replication of significant findings using standardized timing of sessions, pain stimulus procedures, outcomes, and hormonal assessment is necessary.     

Changes in pain sensitivity following spinal manipulation: A systematic review and meta-analysis

Spinal manipulation (SMT) is commonly used for treating individuals experiencing musculoskeletal pain. The mechanisms of SMT remain unclear; however, pain sensitivity testing may provide insight into these mechanisms. The purpose of this systematic review is to examine the literature on the hypoalgesic effects of SMT on pain sensitivity measures and to quantify these effects using meta-analysis. We performed a systematic search of articles using CINAHL, MEDLINE, PsycINFO, and SPORTDiscus from each databases' inception until May 2011. We examined methodological quality of each study and generated pooled effect size estimates using meta-analysis software. Of 997 articles identified, 20 met inclusion criteria for this review. Pain sensitivity testing used in these studies included chemical, electrical, mechanical, and thermal stimuli applied to various anatomical locations. Meta-analysis was appropriate for studies examining the immediate effect of SMT on mechanical pressure pain threshold (PPT). SMT demonstrated a favorable effect over other interventions on increasing PPT. Subgroup analysis showed a significant effect of SMT on increasing PPT at the remote sites of stimulus application supporting a potential central nervous system mechanism. Future studies of SMT related hypoalgesia should include multiple experimental stimuli and test at multiple anatomical sites.     

Autologous adipose tissue grafting for the management of the painful scar

Background aimsThere is currently no definitive treatment for the painful scar. Autologous adipose tissue grafting (AATG) as a treatment option for scars has become increasingly popular and there is now an abundance of evidence in the literature that supports its application. Some studies suggest that human adipose tissue is a rich source of multipotent mesenchymal stromal cells. To our knowledge, there is currently no systematic literature review to date that examines the effectiveness of AATG for reducing pain in scars. Our novel systematic review aims to examine clinical studies on the use of AATG in the treatment of the painful scar.MethodsA literature search was performed using the following databases: PubMed, Cumulative Index to Nursing and Allied Health Literature, Web of Science, Medline, Cochrane library and Embase. The following key words and search terms were used: adipose stem cells, scar, pain, autologous fat grafting, scar management and neuropathic pain. Human interventional studies using autologous adipose tissue grafting for the treatment of painful scars including case series, case-control, cohort studies and randomized controlled trials were reviewed.ResultsA total of 387 studies were found and 18 studies from January 1990 to January 2019 were identified as relevant for the purpose of this systematic review. Two studies were evidence level V, seven were evidence level IV, six were evidence level III, two were evidence level II and one was level I. A total of 337 scars were assessed in 288 patients for improvement in pain after scar treatment using adipose tissue grafting. An improvement in the analgesic effect was recorded in 12 of the 18 studies with adipose tissue grafting. A total of 233 of the 288 treated subjects responded with reduction in pain, whereas the rest did not. We carried out a pooled analysis of the studies and observed an odds ratio of 3.94 (P = 0.00001) when comparing pain reduction to no change in pain.ConclusionsWe conclude that AATG is a promising and safe modality for the treatment of the painful scar. There is an abundance of low-level evidence to support its use as an alternative treatment but there is a lack of high-level evidence at present to support its standard use. Future long-term randomized controlled trials with analgesic scores as the primary outcome measures are required to assess long-term efficacy.     

Synthesis and evaluation of 2-amido-3-carboxamide thiophene CB₂ receptor agonists for pain management

SAR studies on a series of thiophene amide derivatives provided CB(2) receptor agonists. The activity of the compounds was characterized by radioligand binding determination, multiple functional assays, ADME, and pharmacokinetic studies. A representative compound with selectivity for CB(2) over CB(1) effectively produced analgesia in behavioral models of neuropathic, inflammatory, and postsurgical pain. Control experiments using a CB(2) antagonist demonstrated the efficacy in the pain models resulted from CB(2) agonism.     

Effect of pulsed electromagnetic field therapy on experimental pain: A double-blind,randomized study in healthy young adults

ABSTRACT

Previous studies suggested that pulsed electromagnetic field (PEMF) therapy can decrease pain. To date, however, it remains difficult to determine whether the analgesic effect observed in patients are attributable to a direct effect of PEMF on pain or to an indirect effect of PEMF on inflammation and healing. In the present study, we used an experimental pain paradigm to evaluate the direct effect of PEMF on pain intensity, pain unpleasantness, and temporal summation of pain. Twenty-four healthy subjects (mean age 22 ± 2 years; 9 males) participated in the experiment. Both real and sham PEMF were administered to every participant using a randomized, double-blind, cross-over design. For each visit, PEMF was applied for 10 minutes on the right forearm using a portable device. Experimental pain was evoked before (baseline) and after PEMF with a 9 cm² Pelletier-type thermode, applied on the right forearm (120 s stimulation; temperature individually adjusted to produce moderate baseline pain). Pain intensity and unpleasantness were evaluated using a 0–100 numerical pain rating scale. Temporal summation was evaluated by comparing pain intensity ratings obtained at the end of tonic nociceptive stimulation (120 s) with pain intensity ratings obtained after 60 s of stimulation. When compared to baseline, there was no change in pain intensity and unpleasantness following the application of real or sham PEMF. PEMF did not affect temporal summation. The present observations suggest that PEMF does not directly influence heat pain perception in healthy individuals.     

A Literature Review of Factors Associated With Pain From Fine Needle Aspiration Biopsy of Thyroid Nodules

ObjectiveThyroid nodules are common, being detected in 19% to 67% of the population. A fine needle aspiration biopsy (FNAB) is recommended for suspicious thyroid nodules to rule out malignancy; however, the procedure can be painful for subsets of patients. It remains unclear what factors are more likely to be associated with pain during FNAB. This literature review aimed to investigate patient-, procedure-, and analgesic-related factors that affect pain levels during thyroid nodule FNAB.MethodsPredefined inclusion and exclusion criteria were set to search the Embase, MEDLINE, CINAHL, and Cochrane databases. The articles evaluating the factors affecting pain during FNAB were assessed for inclusion. The primary outcome of interest was scores evaluating pain level during FNAB.ResultsTwenty-two studies were included. The studies were a mix of cohort studies, randomized controlled trials, and clinical controlled trials. Under patient-related factor, nodule calcification was associated with increasing pain. The procedure-related factors potentially increasing pain included the number of needle passes and utilization of the aspiration technique (as opposed to capillary action), perpendicular needle placement (as opposed to parallel), and not using safety devices. Larger needle size, type of biopsy, operator expertise, and patient education did not appear to be correlated with pain. Subcutaneous lidocaine appeared to provide better pain relief than a topical analgesic.ConclusionWith increasing use of FNAB as the diagnostic test of choice for assessing thyroid nodules, understanding patient-, procedure-, and analgesic-related factors associated with optimal patient satisfaction is imperative.     

Pain centers--organization and outcome.

Pain treatment centers have evolved at a rapid rate, but they differ in their complexity and services provided. Patients, as well as primary care physicians, have difficulty in identifying the appropriate center for a specific problem. Guidelines for pain centers have recently been proposed by the International Association for the Study of Pain, along with an attempt at their accreditation. Outcome studies from pain centers have proliferated, with a wide range of treatment programs being reported. Comprehensive multidisciplinary pain centers using the rehabilitation medicine approach are effective in decreasing disability and increasing the productivity of patients with chronic, disabling pain.     

Proteomic analysis of differential protein expression in neuropathic pain and electroacupuncture treatment models

Acupuncture has long been used for pain relief. Although recent studies have shown that acupuncture can reduce neuropathic pain, the mechanism of this effect is not clear and little information is available regarding proteins that are involved in the development of neuropathic pain and the effects of acupuncture. We have developed an animal model for neuropathic pain using young adult male Sprague-Dawley rats. The model was confirmed by behavioral tests. Electroacupuncture (EA) treatment was applied to Zusanli (ST36) of neuropathic pain model to examine the analgesic effect of EA. The protein expression profile of the hypothalamus in both neuropathic pain and EA treatment models was analyzed using two-dimensional electrophoresis-based proteomics. We detected thirty-six proteins that were differentially expressed in the neuropathic pain model compared with normal rats and that restored to normal expression levels after EA treatment. Twenty-one of these proteins were identified in the MS-FiT database and are involved in a number of biological processes, including inflammation, enzyme metabolism and signal transduction. Potential applications of our results include the identification and characterization of signaling pathways involved in EA treatment and further exploration of the role of selected identified proteins in the animal model.     

A multistudy analysis reveals that evoked pain intensity representation is distributed across brain systems

Information is coded in the brain at multiple anatomical scales: locally, distributed across regions and networks, and globally. For pain, the scale of representation has not been formally tested, and quantitative comparisons of pain representations across regions and networks are lacking. In this multistudy analysis of 376 participants across 11 studies, we compared multivariate predictive models to investigate the spatial scale and location of evoked heat pain intensity representation. We compared models based on (a) a single most pain-predictive region or resting-state network; (b) pain-associated cortical–subcortical systems developed from prior literature (“multisystem models”); and (c) a model spanning the full brain. We estimated model accuracy using leave-one-study-out cross-validation (CV; 7 studies) and subsequently validated in 4 independent holdout studies. All spatial scales conveyed information about pain intensity, but distributed, multisystem models predicted pain 20% more accurately than any individual region or network and were more generalizable to multimodal pain (thermal, visceral, and mechanical) and specific to pain. Full brain models showed no predictive advantage over multisystem models. These findings show that multiple cortical and subcortical systems are needed to decode pain intensity, especially heat pain, and that representation of pain experience may not be circumscribed by any elementary region or canonical network. Finally, the learner generalization methods we employ provide a blueprint for evaluating the spatial scale of information in other domains.

Is pain represented by a single brain area or network, spanning multiple systems or distributed throughout the brain? fMRI brain decoding in a large multi-study dataset shows that multiple cortical and subcortical systems are needed to decode pain intensity; the approach is novel and can characterize scale of representation across diverse brain processes.     

反复电针对慢性痛的累加治疗作用及其机制研究

本研究从基础和临床两方面观察了反复电针对慢性痛的累加治疗作用,并结合疼痛患者及慢性痛动物模型中几种神经肽的放射免疫测定及相应受体拮抗剂的药理学研究结果,探讨了产生累加效应的可能机制。结果表明,在临床脊髓损伤性痉挛患者,１００Ｈｚ穴位体表电刺激有效地缓解痉挛并有累加效应;在临床慢性痛患者,２／１５Ｈｚ变频ＴＥＮＳ刺激有效地治疗疼痛并具有累加效应。在关节炎模型大鼠,电针刺激能产生明显的镇痛并具有累加效     

Rhythmic changes in pain sensitivity in teeth

In 136 healthy men, circadian variations in pain threshold have been observed in healthy front teeth, the pain being elicited by a cold stimulus, alterations in threshold then being inferred from changes in the minimum cold application time. The pain threshold is maximal in the early afternoon and at a minimum in the early morning. In previous experiments using an electrical current as the pain stimulus, a similar diurnal variation of sensitivity was also observed. These results conform with clinical experience of the time of onset of toothache, and are also in accord with known diurnal variations of pain sensitivity in other organs. Further studies were carried out on one subject. The minimum cold application time test was performed over more than 3 years on a healthy front tooth. The results suggest a circannual rhythm of the pain threshold, with a maximum in October/November and a minimum in May.     

疼痛的性别差异

目前已有许多临床流行病学研究和实验研究证实了人类的疼痛存在性别差异。临床迹象表明疼痛存在性别差异,许多慢性疼痛疾病（偏头痛、颞下颌关节痛、纤维肌痛、风湿痛等）的发生率女性明显高于男性。女性对一些实验性疼痛（机械刺激痛、电刺激痛、热刺激痛等）更加敏感,痛阈和对疼痛的耐受性比男性低,而且女性月经周期与疼痛有关。啮齿动物实验研究也发现存在疼痛的性别差异。但是在不同动物研究或不同实验性疼痛刺激下雌雄性别的反应不完全相同,这些差异可能是由很多影响因素所导致的。目前许多研究对疼痛存在性别差异的解释也有所不同,机制尚不清楚,可能的因素包括：生物因素（性激素、内源性镇痛、基因等）、社会心理因素以及两者的相互作用等。     

Postoperative analgesics in South African Clawed frogs (Xenopus laevis) after surgical harvest of oocytes

Heightened awareness for the welfare of earlier-evolved laboratory species has prompted increasing inquiries by institutional animal care committees, investigators, and laboratory animal veterinarians regarding the need for post-surgical analgesics in laboratory Xenopus. Basic research into the mechanisms and regulation of pain in Rana pipiens has demonstrated the clinical potential of opioid, alpha2-adrenergic, and non-opioid analgesic agents in amphibians. However, clinical studies using objectively established indices of amphibian pain, or pharmacological studies in either Rana pipiens or laboratory Xenopus have not been conducted. As discussed above, comparison of limited lethality data suggests that the safety index for these agents is quite narrow in Rana pipiens. Analgesic use in laboratory Xenopus has the added risk of drowning due to over sedation. Drug doses extrapolated from such studies and intended to provide pain relief in Xenopus should therefore be considered very carefully. An additional concern for laboratory Xenopus is that the effects of these agents on amphibian oogenesis, oocyte quality, and embryogenesis are unknown. As the numbers of laboratory Xenopus used in basic and biomedical research continues to increase, clinical studies that address all of these issues cannot come too soon.     

Internal radiotherapy of painful bone metastases

Internal radiotherapy is effective in the treatment of metastatic bone pain and can improve quality of life. A number of controlled studies using various agents have shown a mean response rate in pain relief of 70–80% of treated patients. Some investigators prefer radionuclides which emit low beta particles for the treatment of bone pain, because the assumption of lower bone marrow toxicity of this agents. However, neither dosimetric data for radiation absorbed dose to the bone marrow nor clinical blood count depression have shown any significant differences between these agents. Other researchers suggest enhanced antitumoral effects using high-energy beta emitters and propose aggressive first-line treatment in the early disease stage instead of using these radiopharmaceuticals only in end-stage patients suffering intractable bone pain. Another approach consists of including other treatment modalities such as autologous stem cell rescue or in combination with chemo or bisphosphonate therapy to a radionuclide treatment scheme. Future research should focus more on the curative effects of combination with radiosensitizer, for example, chemotherapy, or repeated treatments with bone seeking agents.     

Prevalencia y etiopatogenia del dolor oncológico neuropático en el anciano

The prevalence of neuropathic pain is difficult to estimate as most studies evaluating chronic pain do not differentiate neuropathic from nociceptive pain. There are only a few studies of neuropathic pain in the elderly, specifically in the oncology population. This article is a non-systematic review of the relevant evidence on the prevalence and aetiopathogenesis of neuropathic cancer pain in the elderly.     

Synergistic interactions between cannabinoid and opioid analgesics

Cannabinoids and opioids both produce analgesia through a G-protein-coupled mechanism that blocks the release of pain-propagating neurotransmitters in the brain and spinal cord. However, high doses of these drugs, which may be required to treat chronic, severe pain, are accompanied by undesirable side effects. Thus, a search for a better analgesic strategy led to the discovery that delta 9-tetrahydrocannabinol (THC), the major psychoactive constituent of marijuana, enhances the potency of opioids such as morphine in animal models. In addition, studies have determined that the analgesic effect of THC is, at least in part, mediated through delta and kappa opioid receptors, indicating an intimate connection between cannabinoid and opioid signaling pathways in the modulation of pain perception. A host of behavioral and molecular experiments have been performed to elucidate the role of opioid receptors in cannabinoid-induced analgesia, and some of these findings are presented below. The aim of such studies is to develop a novel analgesic regimen using low dose combinations of cannabinoids and opioids to effectively treat acute and chronic pain, especially pain that may be resistant to opioids alone.     

Attention modulates spinal cord responses to pain

Reduced pain perception while being distracted from pain is an everyday example of how cognitive processes can interfere with pain perception. Previous neuroimaging studies showed distraction-related modulations of pain-driven activations in various cortical and subcortical brain regions, but the precise neuronal mechanism underlying this phenomenon is unclear. Using high-resolution functional magnetic resonance imaging of the human cervical spinal cord in combination with thermal pain stimulation and a well-established working memory task, we demonstrate that this phenomenon relies on an inhibition of incoming pain signals in the spinal cord. Neuronal responses to painful stimulation in the dorsal horn of the corresponding spinal segment were significantly reduced under high working memory load compared to low working memory load. At the individual level, reductions of neuronal responses in the spinal cord predicted behavioral pain reductions. In a subsequent behavioral experiment, using the opioid antagonist naloxone in a double-blind crossover design with the same paradigm, we demonstrate a substantial contribution of endogenous opioids to this mechanism. Taken together, our results show that the reduced pain experience during mental distraction is related to a spinal process and involves opioid neurotransmission.     

Increased daily physical activity and fatigue symptoms in chronic fatigue syndrome

Individuals with chronic fatigue syndrome (CFS) have been shown to have reduced activity levels associated with heightened feelings of fatigue. Previous research has demonstrated that exercise training has beneficial effects on fatigue-related symptoms in individuals with CFS. PURPOSE: The aim of this study was to sustain an increase in daily physical activity in CFS patients for 4 weeks and assess the effects on fatigue, muscle pain and overall mood. METHODS: Six CFS and seven sedentary controls were studied. Daily activity was assessed by a CSA accelerometer. Following a two week baseline period, CFS subjects were asked to increase their daily physical activity by 30% over baseline by walking a prescribed amount each day for a period of four weeks. Fatigue, muscle pain and overall mood were reported daily using a 0 to 100 visual analog scale and weekly using the Profile of Mood States (Bipolar) questionnaire. RESULTS: CFS patients had significantly lower daily activity counts than controls (162.5 +/- 51.7 x 103 counts/day vs. 267.2 +/- 79.5 x 103 counts/day) during a 2-week baseline period. At baseline, the CFS patients reported significantly (P < 0.01) higher fatigue and muscle pain intensity compared to controls but the groups did not differ in overall mood. CFS subjects increased their daily activity by 28 +/- 19.7% over a 4 week period. Overall mood and muscle pain worsened in the CFS patients with increased activity. CONCLUSION: CFS patients were able to increase their daily physical activity for a period of four weeks. In contrast to previous studies fatigue, muscle pain, and overall mood did not improve with increased activity. Increased activity was not presented as a treatment which may account for the differential findings between this and previous studies. The results suggest that a daily "activity limit" may exist in this population. Future studies on the impact of physical activity on the symptoms of CFS patients are needed.