Papers: 29 Jan 2022 - 4 Feb 2022

Peripheral nerve injury (PNI) is a public health concern that results in sensory and motor disorders as well as neuropathic pain and secondary lesions. Currently, effective treatments for PNI are still limited. For example, while nerve growth factor (NGF) is widely used in the treatment of PNI to promote nerve regeneration, it also induces pain. Maresin 1 (MaR1) is an anti-inflammatory and proresolving mediator that has the potential to regenerate tissue. We determined whether MaR1 is able to promote nerve regeneration as well as alleviating neuropathic pain, and to be considered as a putative therapeutic agent for treating PNI.

Contrary to pre-attack symptoms before an individual cluster headache attack, little is known about the pre-cluster symptoms before the onset of cluster bouts. We previously described pre-attack symptoms before cluster headache attacks. The aim of this study was to investigate characteristics of pre-cluster symptoms in patients with episodic cluster headache.

Thalamic reticular nucleus (TRN) is known to be crucial for dynamically modulating sensory processing. Recently, the functional role of TRN in itch and pain sensation processing has drawn much attention. We found that ventrobasal thalamus (VB) neurons exhibited scratching behavior-related and nociceptive behavior-related neuronal activity changes, and most of VB neurons responsive to pruritic stimulus were also activated by nociceptive stimulus. Inhibition of VB could relieve itch-induced scratching behaviors and pathological pain without affecting basal nociceptive thresholds, and activation of VB could facilitate scratching behaviors. Tracing and electrophysiology recording results showed that VB mainly received inhibitory inputs from ventral TRN. Furthermore, optogenetic activation of TRN-VB projections suppressed scratching behaviors, and ablation of TRN enhanced scratching behaviors. In addition, activation of TRN-VB projections relieved the pathological pain without affecting basal nociceptive thresholds. Thus, our study indicates that TRN modulates itch and pain signals processing via TRN-VB inhibitory projections.

To develop a deep learning algorithm for detection of active inflammatory sacroiliitis in short tau inversion recovery (STIR) sequence magnetic resonance imaging (MRI).

: Functional near-infrared spectroscopy (fNIRS) has evaluated pain in awake and anesthetized states. : We evaluated fNIRS signals under general anesthesia in patients undergoing knee surgery for anterior cruciate ligament repair. : Patients were split into groups: those with regional nerve block (NB) and those without (non-NB). Continuous fNIRS measures came from three regions: the primary somatosensory cortex (S1), known to be involved in evaluation of nociception, the lateral prefrontal cortex (BA9), and the polar frontal cortex (BA10), both involved in higher cortical functions (such as cognition and emotion). : Our results show three significant differences in fNIRS signals to incision procedures between groups: (1) NB compared with non-NB was associated with a greater net positive hemodynamic response to pain procedures in S1; (2) dynamic correlation between the prefrontal cortex (PreFC) and S1 within 1 min of painful procedures are anticorrelated in NB while positively correlated in non-NB; and (3) hemodynamic measures of activation were similar at two separate time points during surgery (i.e., first and last incisions) in PreFC and S1 but showed significant differences in their overlap. Comparing pain levels immediately after surgery and during discharge from postoperative care revealed no significant differences in the pain levels between NB and non-NB. : Our data suggest multiple pain events that occur during surgery using devised algorithms could potentially give a measure of "pain load." This may allow for evaluation of central sensitization (i.e., a heightened state of the nervous system where noxious and non-noxious stimuli is perceived as painful) to postoperative pain levels and the resulting analgesic consumption. This evaluation could potentially predict postsurgical chronic neuropathic pain.

Neuropathic pain is a challenging clinical problem and remains difficult to treat. Altered gene expression in peripheral sensory nerves and neurons due to nerve injury is well documented and contributes critically to the synaptic plasticity in the spinal cord and the initiation and maintenance of chronic pain. However, our understanding of the epigenetic mechanisms regulating the transcription of pro-nociceptive (e.g., NMDA receptors and α2δ-1) and antinociceptive (e.g., potassium channels and opioid and cannabinoid receptors) genes are still limited. In this review, we summarize recent studies determining the roles of histone modifications (including methylation, acetylation, and ubiquitination), DNA methylation, and noncoding RNAs in neuropathic pain development. We review the epigenetic writer, reader, and eraser proteins that participate in the transcriptional control of the expression of key ion channels and neurotransmitter receptors in the dorsal root ganglion after traumatic nerve injury, which is commonly used as a preclinical model of neuropathic pain. A better understanding of epigenetic reprogramming involved in the transition from acute to chronic pain could lead to the development of new treatments for neuropathic pain.

Capsaicin, the compound in hot chili peppers responsible for their pungency and an agonist of the transient receptor potential cation channel, subfamily V, member 1 (TRPV1), has long been known to promote the desensitization of nociceptors at high concentrations. This has led to the utilization and implementation of topical capsaicin cream as an analgesic to treat acute and chronic pain. Critically, the application of capsaicin cream is limited due to capsaicin's high pungency, which is experienced prior to analgesia. To combat this issue, novel capsaicin analogues were developed to provide analgesia with reduced pungency. Analogues reported in this paper add to and show some differences from previous structure-activity relationship (SAR) studies of capsaicin-like molecules against TRPV1, including the necessity of phenol in the aromatic "A-region", the secondary amide in the "B-region", and modifications in the hydrophobic "C-region". This provided a new framework for small-molecule design using capsaicin as the starting point. In this study, we describe the synthesis of capsaicin analogues, their activity in Ca assays, and initial pungency and feasibility studies of capsaicin analogues YB-11 and YB-16 as analgesics. Our results demonstrate that male and female mice treated with YB capsaicin analogues showed diminished pain-associated behavior in the spontaneous formalin assay as well as reduced thermal sensitivity in the hotplate assay.

Migraine is the second most disabling disorder across all age groups worldwide. Since 2018, two classes of drugs that inhibit the actions of calcitonin gene-related peptide (CGRP), which is implicated in migraine pathophysiology, have become available: gepants (CGRP receptor antagonists) and monoclonal antibodies directed against CGRP or its receptor. Despite phase 3 clinical trials and some real world evidence, knowledge of the pharmacology and related clinical effects of these drugs is low, and trial data are not necessarily generalisable to all populations. Additionally, several pharmacodynamic processes affected by both gepants and monoclonal antibodies to CGRP and its receptor are not fully understood. Sex, body-mass index, age, ethnic background, and other characteristics, which are subject to considerable variation, might affect the pharmacokinetics of these therapies, especially gepants. If studies confirm this possibility, these characteristics could assist clinicians in choosing the optimal treatment for patients with migraine. The choice between a gepant or monoclonal antibody should be made carefully, taking into consideration a patient's comorbidities and preferences. As more becomes known about CGRP-targeted therapies, management based on the characteristics of patients could have a more prominent role in the treatment of migraine.

Chronic pain damages the balance between excitation and inhibition in the sensory cortex. It has been confirmed that the activity of cortical glutamatergic pyramidal cells increases after chronic pain. However, whether the activity of inhibitory interneurons synchronized changed remains obscure, especially in in vivo conditions. In the present study, we checked the firing rate of pyramidal cells and interneurons in the anterior cingulate cortex, a main cortical area for the regulation of nociceptive information in mice with spared nerve injury by using in vivo multi-channel recording system. We found that the firing rate of pyramidal cells but not interneurons increased in the ACC, which was further confirmed by the increased FOS expression in pyramidal cells but not interneurons, in mice with neuropathic pain. Selectively high frequency stimulation of the ACC nociceptive afferent fibers only potentiated the activity of pyramidal cells either. Our results thus suggest that the increased activity of pyramidal cells contributes to the damaged E/I balance in the ACC and is important for the pain hypersensitivity in mice with neuropathic pain.

The early identification of factors that increase risk of poor recovery from acute low back pain (LBP) is critical to prevent the transition to chronicity. Although most studies of risk factors for poor outcome in LBP tend to investigate the condition once it is already persistent, there is evidence to suggest that this differs from risk factors measured during the early-acute stage. This study aimed to identify early risk factors for poor outcome in the short- and long-term in individuals with acute LBP, and to compare this with factors identified at 3 months in the same cohort.

Pain is an integrative phenomenon coupled with dynamic interactions between sensory and contextual processes in the brain, often associated with detectable neurophysiological changes. Recent advances in brain activity recording tools and machine learning technologies have intrigued research and development of neurocomputing techniques for objective and neurophysiology-based pain detection. This paper proposes a pain detection framework based on Electroencephalogram (EEG) and deep convolutional neural networks (CNN). The feasibility of CNN is investigated for distinguishing induced pain state from resting state in the recruitment of 10 chronic back pain patients. The experimental study recorded EEG signals in two phases: 1. movement stimulation (MS), where induces back pain by executing predefined movement tasks; 2. video stimulation (VS), where induces back pain perception by watching a set of video clips. A multi-layer CNN classifies the EEG segments during the resting state and the pain state. The novel approach offers high and robust performance and hence is significant in building a powerful pain detection algorithm. The area under the receiver operating characteristic curve (AUC) of our approach is 0.83±0.09 and 0.81±0.15, in MS and VS, respectively, higher than the state-of-the-art approaches. The sub-brain-areas are also analyzed, to examine distinct brain topographies relevant for pain detection. The results indicate that MS-induced pain tends to evoke a generalized brain area, while the evoked area is relatively partial under VS-induced pain. This work may provide a new solution for researchers and clinical practitioners on pain detection.

The ability to sense pain signals is closely linked to the activity of ion channels expressed in nociceptors, the first neurons that transduce noxious stimuli into pain. Among these ion channel, TREK1, TREK2 and TRAAK from the TREK subfamily of the Two-Pore-Domain potassium (K) channels, are hyperpolarizing channels that render neurons hypoexcitable. They are regulated by diverse physical and chemical stimuli as well as neurotransmitters through G-protein coupled receptors activation. Here, we review the molecular mechanisms underlying these regulations and their functional relevance in pain and migraine induction.

Radiofrequency lesioning (RFL) is used to surgically manage trigeminal neuralgia (TN) secondary to multiple sclerosis (MS). However, the long-term outcome of RFL has not been established.

This review summarizes key findings from recent investigations of psychological interventions for pediatric headache disorders and discusses important avenues for future research.

Long-term opioid therapy (>12 months) is not effective for improving chronic non-cancer pain and function. Where patients are not experiencing pain relief with long-term opioids, the opioid should be tapered and discontinuation considered. Practitioners may find it challenging to tell patients experiencing pain that they are better off reducing or not taking medicines that do not help. This review aims to ascertain what is published about: (1) the interaction and (2) the nature of the relationship between practitioners and patients when prescribing opioids for chronic non-cancer pain in primary care.

Patients with early onset vascular pathology have been reported to manifest neovascular age-related macular degeneration (AMD). While the blood vessels involved in pathogenesis of migraine remains controversial, it is generally accepted that a major contributor is blood vessel pathology. This study aimed to examine the association between migraine and AMD using a nationwide population-based dataset. Retrospective claims data were collected from the Taiwan National Health Insurance Research Database. We identified 20,333 patients diagnosed with neovascular AMD (cases), and we selected 81,332 propensity score-matched controls from the remaining beneficiaries in Taiwan's National Health Insurance system. We used Chi-square tests to explore differences in the prevalence of migraine prior to the index date between cases and controls. We performed multiple logistic regressions to estimate the odds of prior migraine among neovascular AMD patients vs. controls after adjusting for age, sex, monthly income, geographic location, residential urbanization level, hyperlipidemia, diabetes, coronary heart disease, hypertension, and previous cataract surgery. A total of 5184 of sample patients (5.1%) had a migraine claim before the index date; 1215 (6.1%) among cases and 3969 (4.9%) among controls (p < 0.001), with an unadjusted OR of 1.239 (95% CI 1.160~1.324, p < 0.001) for prior migraine among cases relative to controls. Furthermore, the adjusted OR was 1.201 (95% CI 1.123~1.284; p < 0.001) for AMD cases relative to controls. The study offers population-based evidence that persons with migraine have 20% higher risk of subsequently being diagnosed with neovascular AMD.

Angiography headache (AH) is common but not negligible, and the criteria for AH have been based on only a few studies. The purpose of this study was to investigate the incidence, risk factors and possible mechanism of AH and reappraise the diagnostic criteria for AH in the International Classification of Headache Disorders 3 (ICHD-3).

Neuropathic pain (NP) is poorly managed, and in-depth mechanisms of gene transcriptome alterations in NP pathogenesis are not yet fully understood. To determine microRNA-related molecular mechanisms of NP and their transcriptional regulation in NP, PubMed, Embase, Web of Science and CINAHL Complete (EBSCO) were searched from inception to April 2021. Commonly dysregulated miRNAs in NP were assessed. The putative targets of these miRNAs were determined using TargetScan, Funrich, Cytoscape and String database. A total of 133 literatures containing miRNA profiles studies and experimentally verify studies were included. Venn analysis, target gene prediction analysis and functional enrichment analysis indicated several miRNAs (miR-200b-3p, miR-96, miR-182, miR-183, miR-30b, miR-155 and miR-145) and their target genes involved in known relevant pathways for NP. Targets on transient receptor potential channels, voltage-gated sodium channels and voltage-gated calcium channels may be harnessed for pain relief. A further delineation of signal processing and modulation in neuronal ensembles is key to achieving therapeutic success in future studies.

This study aims to investigate the effects of ankle joint mobilization (AJM) on mechanical hyperalgesia and peripheral and central inflammatory biomarkers after intraplantar (i.pl.) Complete Freund's Adjuvant (CFA)-induced inflammation.

In attempts to understand the migraine patients' overall brain functional architecture, blood oxygenation level-dependent (BOLD) signals in the white matter (WM) and gray matter (GM) were considered in the current study. Migraine, a severe and multiphasic brain condition, is characterized by recurrent attacks of headaches. BOLD fluctuations in a resting state exhibit similar temporal and spectral profiles in both WM and GM. It is feasible to explore the functional interactions between WM tracts and GM regions in migraine. Forty-eight migraineurs without aura (MWoA) and 48 healthy controls underwent resting-state functional magnetic resonance imaging. Pearson's correlations between the mean time courses of 48 white matter (WM) bundles and 82 gray matter (GM) regions were computed for each subject. Two-sample -tests were performed on the Pearson's correlation coefficients (CC) to compare the differences between the MWoA and healthy controls in the GM-averaged CC of each bundle and the WM-averaged CC of each GM region. The MWoAs exhibited an overall decreased average temporal CC between BOLD signals in 82 GM regions and 48 WM bundles compared with healthy controls, while little was increased. In particular, WM bundles such as left anterior corona radiata, left external capsule and bilateral superior longitudinal fasciculus had significantly decreased mean CCs with GM in MWoA. On the other hand, 16 GM regions had significantly decreased mean CCs with WM in MWoA, including some areas that are parts of the somatosensory regions, auditory cortex, temporal areas, frontal areas, cingulate cortex, and parietal cortex. Decreased functional connections between WM bundles and GM regions might contribute to disrupted functional connectivity between the parts of the pain processing pathway in MWoAs, which indicated that functional and connectivity abnormalities in cortical regions may not be limited to GM regions but are instead associated with functional abnormalities in WM tracts.

Since new roles of nucleotides as neurotransmitters were proposed by Geoffrey Burnstock, the roles of ATP and P2 receptors (P2Rs) have been extensively studied in pain signaling. Chronic pain is a debilitating condition that often occurs following peripheral tissue inflammation and nerve injury. Especially neuropathic pain is a significant clinical problem because there are few clinically effective drugs. This review summarizes the findings for the role of ATP signaling through P2X3Rs and P2X2/3Rs in primary afferent neurons and through P2X4Rs, P2X7Rs, and P2YR in spinal microglia in chronic pain to discuss the therapeutic potentials with considering active situation of drug development of P2R compounds.

Nitric oxide (NO) levels in brain nuclei, such as the hippocampus and brainstem, are involved in morphine analgesia, but the relationship between the dorsal hippocampus (dH) and the dorsolateral periaqueductal gray matter (dlPAG) needs to be clarified, which is our goal.

To date, pain relief in general continues to be the most prominent outcome measurement in daily routine care and clinical research. Nevertheless, the awareness of a shift toward more functional outcomes and/or emotional and cognitive outcomes has been raised. The interplay between bodily functions (such as pain intensity) and emotional or cognitive factors, however, has not yet been fully elucidated. The aim of this study was to systematically review the evidence for associations between bodily functions and cognitive and emotional factors in patients with chronic pain who are treated with neuromodulation.

Failed back surgery syndrome (FBSS) refers to new or persistent pain following spinal surgery for back or leg pain in a subset of patients. Spinal cord stimulation (SCS) is a neuromodulation technique that can be considered in patients with predominant leg pain refractory to conservative treatment. Patients with predominant low back pain benefit less from SCS. Another neuromodulation technique for treatment of chronic low back pain is subcutaneous stimulation or peripheral nerve field stimulation (PNFS). We investigated the effect of SCS with additional PNFS on pain and quality of life of patients with FBSS compared with that of SCS alone after 12 months.

Intrathecal drug delivery systems (IDDSs) are used for the treatment of pain and spasticity. A wide range of educational criteria exist for these devices. The North American Neuromodulation Society (NANS) Education Committee developed a comprehensive IDDS curriculum to function as a standard for physician graduate education and assessment through training and into practice.

Transcutaneous electrical nerve stimulation (TENS) is a noninvasive electrical stimulation therapy indicated for pain control that has been applied for the regeneration of nerves. This systematic review aimed to analyze the evidence on TENS effectiveness on nerve regeneration.

Mechanotransduction is a biological phenomenon where mechanical stimuli are converted to biochemical responses. A model system for studying mechanotransduction are the chondrocytes of articular cartilage. Breakdown of this tissue results in decreased mobility, increased pain, and reduced quality of life. Either disuse or overloading can disrupt cartilage homeostasis, but physiological cyclical loading promotes cartilage homeostasis. To model this, we exposed SW1353 cells to cyclical mechanical stimuli, shear and compression, for different durations of time (15 and 30 min). By utilizing liquid chromatography-mass spectroscopy (LC-MS), metabolomic profiles were generated detailing metabolite features and biological pathways that are altered in response to mechanical stimulation. In total, 1457 metabolite features were detected. Statistical analyses identified several pathways of interest. Taken together, differences between experimental groups were associated with inflammatory pathways, lipid metabolism, beta-oxidation, central energy metabolism, and amino acid production. These findings expand our understanding of chondrocyte mechanotransduction under varying loading conditions and time periods. This article has an associated First Person interview with the first author of the paper.

Narrative review.

Migraine is indeed a neurovascular disorder for which several genes have been identified in this era of Genome-Wide Association Studies (GWAS) and neuroimaging studies have already revealed structural changes and different mechanisms that cause migraine, but the exact cause of this debilitating and disabling neurovascular disorder remained unclear. Low neuronal hyperexcitability ("the migrainous brain") is set and hindered by genetic and environmental factors, respectively. Migraine is also found to be associated with different diseases (co-morbidity). There is still a subject of contention: is migraine a disease of evolution or disease of pathology? This research review seeks to provide a brief overview on the genetics of disorders, structural abnormalities in the brain, CSD-like symptoms, and faulty Trigeminovascular System activation for migraine pain phenotype. This review briefly covered here to provide some ideas that may also be utilized in migraine research and to serve as motivation for future research.

Modeling addictive behavior among individuals with, or at risk for, opioid use disorder (OUD) in a way that is accurate, ethical, and reproducible presents a pressing concern. OUD risk is elevated among people with chronic pain on long-term opioid therapy (LTOT).

Accumulated evidence garnered in the last few decades has highlighted the role of yoga in health and disease. The overwhelming mortality and morbidity mediated by noncommunicable epidemics such as heart disease and cancer have fostered a search for mechanisms to attenuate them. Despite overwhelming success in acute care, the efficacy of modern medicines has been limited on this front. Yoga is one of the integrative therapies that has come to light as having a substantial role in preventing and mitigating such disorders. It thus seems trite to analyze and discuss the research advancements in yoga for 2020. The present review attempts to distill recent research highlights from voluminous literature generated in 2020. This review was conducted on the articles published or assigned to an issue in 2020. The authors searched the PubMed database for clinical studies published in the English language, using yoga (including meditation) as the intervention, and having an adequate description of the intervention. Then, they extracted data from each study into a standardized Google sheet. A total of 1149 citations were retrieved in the initial search. Of these, 46 studies met eligibility criteria and were finally included. The studies were predominantly on mental health and neuropsychology, addressing various issues such as anxiety, postural balance, migraine, academic performance, and childhood neglect. Anxiety, stress, and depression were other common denominators. Eight studies were on cardiorespiratory systems, including exercise capacity, cardiac rehabilitation, myocardial infarction, and hypertension. Three studies were on diabetes, evaluating the effect of yoga. Five studies focused on cognition, health status, and autonomic regulation and few others included cancers, infertility, ulcerative colitis, urinary incontinence, restless leg syndrome, rheumatoid arthritis, chronic pain, and metabolic syndrome. Finally, most studies were on noncommunicable diseases with one exception, human immunodeficiency virus; two randomized controlled trials were dedicated to it. Yoga has been studied under a wide variety of clinicopathological conditions in the year 2020. This landscape review intends to provide an idea of the role of yoga in various clinical conditions and its future therapeutic implications.

Neuropathic pain is a common cause of chronic pain and is often accompanied by negative emotions, making it complex and difficult to treat. However, the neural circuit mechanisms underlying these symptoms remain unclear. Herein, we present a novel pathway associated with comorbid chronic pain and anxiety. Using chemogenetic methods, we found that activation of glutamatergic projections from the rostral anterior cingulate cortex (rACC ) to the ventrolateral periaqueductal gray (vlPAG) induced both hyperalgesia and anxiety-like behaviors in sham mice. Inhibition of the rACC -vlPAG pathway reduced anxiety-like behaviors and hyperalgesia in the spared nerve injury (SNI) mice model; moreover, electroacupuncture (EA) effectively alleviated these symptoms. Investigation of the related mechanisms revealed that the chemogenetic activation of the rACC -vlPAG circuit effectively blocked the analgesic effect of EA in the SNI mice model but did not affect the chronic pain-induced negative emotions. This study revealed a novel pathway, the rACC -vlPAG pathway, that mediates neuropathic pain and pain-induced anxiety.

Many patients experience positive symptoms after traumatic nerve injury. Despite the increasing number of experimental studies in models of peripheral neuropathy and the knowledge acquired, most of these patients lack an effective treatment for their chronic pain. One possible explanation might be that most of the preclinical studies focused on the development of mechanical or thermal allodynia/hyperalgesia, neglecting that most of the patients with peripheral neuropathies complain mostly about spontaneous forms of pains. Here, we summarize the aberrant electrophysiological behavior of peripheral nerve fibers recorded in experimental models, the underlying pathophysiological mechanisms, and their relationship with the symptoms reported by patients. Upon nerve section, axotomized but also intact fibers develop ectopic spontaneous activity. Most interestingly, a proportion of axotomized fibers might present receptive fields in the skin far beyond the site of damage, indicative of a functional cross talk between neuromatose and intact fibers. All these features can be linked with some of the symptoms that neuropathic patients experience. Furthermore, we spotlight the consequence of primary afferents with different patterns of spontaneous discharge on the neural code and its relationship with chronic pain states. With this article, readers will be able to understand the pathophysiological mechanisms that might underlie some of the symptoms that experience neuropathic patients, with a special focus on spontaneous pain.