Papers: 25 Jun 2022 - 1 Jul 2022

Migraine is a heterogeneous disorder with variable symptoms and responsiveness to therapy. Due to previous analytic shortcomings, variance in migraine symptoms has been inconsistently related to brain function. In the current analysis we used data from two sites (n=143, male and female humans), and performed Canonical Correlation Analysis (CCA), relating resting-state functional connectivity (RSFC) with a broad range of migraine symptoms ranging from headache characteristics to sleep abnormalities. This identified three dimensions of covariance between symptoms and RSFC. The first dimension related to headache intensity, headache frequency, pain catastrophizing, affect, sleep disturbances, and somatic abnormalities, and was associated with frontoparietal and dorsal attention network connectivity, both of which are major cognitive networks. Additionally, RSFC scores from this dimension – both the baseline value and the change from baseline to post-intervention – were associated with responsiveness to mind-body therapy. The second dimension was related to an inverse association between pain and anxiety, and to default mode network connectivity. The final dimension was related to pain catastrophizing, and salience, sensorimotor and default mode network connectivity. In addition to performing CCA, we evaluated the current clustering of migraine patients into episodic and chronic subtypes, and found no evidence to support this clustering. However, when using RSFC scores from the three significant dimensions, we identified a novel clustering of migraine patients into four biotypes with unique functional connectivity patterns. These findings provide new insight into individual variability in migraine, and could serve as the foundation for novel therapies that take advantage of migraine heterogeneity.Using a large multi-site dataset of migraine patients we identified three dimensions of multivariate association between symptoms and functional connectivity. This analysis revealed neural networks that relate to all measured symptoms, but also to specific symptom ensembles, such as patient propensity to catastrophize painful events. Using these three dimensions, we found four biotypes of migraine informed by clinical and neural variation together. Such findings pave the way for precision medicine therapy for migraine.

Obesity induces chronic inflammation resulting in insulin resistance and metabolic disorders. Cold exposure can improve insulin sensitivity in humans and rodents, but the mechanisms have not been fully elucidated. Here, we find that cold resolves obesity-induced inflammation and insulin resistance and improves glucose tolerance in diet-induced obese mice. The beneficial effects of cold exposure on improving obesity-induced inflammation and insulin resistance depend on brown adipose tissue (BAT) and liver. Using targeted liquid chromatography with tandem mass spectrometry, we discovered that cold and β3-adrenergic stimulation promote BAT to produce maresin 2 (MaR2), a member of the specialized pro-resolving mediators of bioactive lipids that play a role in the resolution of inflammation. Notably, MaR2 reduces inflammation in obesity in part by targeting macrophages in the liver. Thus, BAT-derived MaR2 could contribute to the beneficial effects of BAT activation in resolving obesity-induced inflammation and may inform therapeutic approaches to combat obesity and its complications.

A miniaturized, flexible cooling device can be used for precise analgesia.

EEG-based neurofeedback uses mental behaviours (MB) to enable voluntary self-modulation of brain activity, and has potential to relieve central neuropathic pain (CNP) after a spinal cord injury (SCI). This study aimed to understand neurofeedback learning and the relationship between MB and neurofeedback success. Twenty-five non-CNP participants and ten CNP participants received neurofeedback training (reinforcing 9-12 Hz; suppressing 4-8 Hz and 20-30 Hz) on four visits. Participants were interviewed about the MB they used after each visit. Questionnaires examined the following factors: self-efficacy, locus of control, motivation, and workload of neurofeedback. MB were grouped into mental strategies (a goal-directed mental action) and affect (emotional experience during neurofeedback). Successful non-CNP participants significantly used more imagination-related MS and reported more negative affect compared to successful CNP participants. However, no mental strategy was clearly associated with neurofeedback success. There was some association between the lack of success and negative affect. Self-efficacy was moderately correlated with neurofeedback success (r = < 0.587, p = < 0.020), whereas locus of control, motivation, and workload had low, non-significant correlations (r < 0.300, p > 0.05). Affect may be more important than mental strategies for a successful neurofeedback performance. Self-efficacy was associated with neurofeedback success, suggesting that increasing confidence in one's neurofeedback abilities may improve neurofeedback performance.

Pain acceptance and values-based action are relevant to treatment outcomes in those with chronic pain. It is unclear if patterns of responding in these two behavioral processes can be used to classify patients into distinct classes at treatment onset and used to predict treatment response. This observational cohort study had two distinct goals. First, it sought to classify patients at assessment based on pain acceptance and values-based action (N = 1746). Second, it sought to examine treatment outcomes based on class membership in a sub-set of patients completing an interdisciplinary pain rehabilitation program of Acceptance and Commitment Therapy for chronic pain (N = 343). Latent profile analysis was used in the larger sample to identify three distinct patient classes: low acceptance and values-based (AV) action (Low AV; n = 424), moderate acceptance and values-based action (Moderate AV; n = 983) and high acceptance and values-based action (High AV; n = 339). In the smaller treated sample, participants in the Low AV and Moderate AV class demonstrated improvements across all outcome variables, whereas those in the High AV class did not. These findings support the role of pain acceptance and values-based action in those with chronic pain.

For pediatric chronic pain patients, intensive interdisciplinary pain treatment (IIPT) is a well-established treatment. The treatment's short-term effectiveness can be improved by an additive psychosocial aftercare (PAC). However, neither the program's long-term effectiveness nor the patients in particular need have been investigated yet.

The effectiveness and long-term outcomes of Spinal Cord Stimulation (SCS) are not fully established, especially considering that data from patients who withdrew from the trial are rarely analyzed, which may lead to overestimation of SCS efficacy. We evaluated short and long-term effects of SCS on chronic pain and perceived health, beyond natural variability in these outcomes.

Attentional deficits in patients with chronic pain are common and well-studied. Yet, few studies have examined the effects of chronic pain on more complex cognitive abilities that rely on well-functioning attentional systems. With the current study, we aimed to investigate whether the impact of chronic pain on attention affects creative ideation as measured with an adaptation of the alternate uses task (AUT).

Spinal cord stimulation (SCS) can provide long-term pain relief for various chronic pain conditions, but some patients have no relief with trial stimulation or lose efficacy over time. To "salvage" relief in patients who do not respond or have lost efficacy, alternative stimulation paradigms or anatomical targets can be considered. Dorsal root ganglion stimulation (DRG-S) has a different mechanism of action and anatomical target than SCS.

Traditional medical neuroanatomy/neurobiology textbooks teach that pain is generated by several ascending pathways that course in the anterolateral quadrant of the spinal cord, including the spinothalamic, spinoreticular and spinoparabrachial tracts. The textbooks also teach, building upon the mid-19th century report of Brown-Séquard, that unilateral cordotomy, namely section of the anterolateral quadrant, leads to contralateral loss of pain (and temperature). In many respects, however, this simple relationship has not held up. Most importantly, pain almost always returns after cordotomy, indicating that activation of these so-called "pain" pathways may be sufficient to generate pain, but they are not necessary. Indeed, Brown-Séquard, based on his own studies, eventually came to the same conclusion. But his new view of "pain" pathways was largely ignored, and certainly did not forestall Spiller and Martin's 1912 introduction of cordotomy to treat patients. This manuscript reviews the history of "pain" pathways that followed from the first description of the Brown-Séquard Syndrome and concludes with a discussion of multisynaptic spinal cord ascending circuits. The latter, in addition to the traditional oligosynaptic "pain" pathways, may be critical to the transmission of "pain" messages, not only in the intact spinal cord but also particularly after injury.

The prevalence of peripheral neuropathy is high in diabetic and overweight populations. Chronic neuropathic pain, a symptom of peripheral neuropathy, is a major disabling symptom that leads to a poor quality of life. Glucose management for diabetic and prediabetic individuals often fail to reduce or improve pain symptoms, therefore, exploring other mechanisms is necessary to identify effective treatments. A large body of evidence suggest that lipid signaling may be a viable target for management of peripheral neuropathy in obese individuals. The nuclear transcription factors, Liver X Receptors (LXR), are known regulators of lipid homeostasis, phospholipid remodeling, and inflammation. Notably, the activation of LXR using the synthetic agonist GW3965, delayed western diet (WD)-induced allodynia in rodents. To further understand the neurobiology underlying the effect of LXR, we used translating ribosome affinity purification and evaluated translatomic changes in the sensory neurons of WD-fed mice treated with the LXR agonist GW3965. We also observed that GW3965 decreased prostaglandin levels and decreased free fatty acid content, while increasing lysophosphatidylcholine, phosphatidylcholine, and cholesterol ester species in the sensory neurons of the dorsal root ganglia (DRG). These data suggest novel downstream interplaying mechanisms that modifies DRG neuronal lipid following GW3965 treatment.

Chronic pain entails a large burden of disease and high social costs, but is seldom 'in the picture' and barely understood. Until recently, it was not systematically classified but instead viewed as a symptom or sign. In the new International Classification of Diseases, (ICD)-11, to be implemented in 2022, 'chronic' pain is now classified as a separate disease category and, to a certain extent, approached as a 'disease in its own right'. Reasons that have been given for this are not based so much on new scientific insights, but are rather of pragmatic nature. To explore the background of these recent changes in definition and classification of chronic pain, this paper provides a historical-philosophical analysis. By sketching a brief history of how pain experts have been working on the definition and taxonomy since the 1970s, we demonstrate the various social and practical functions that underlie the new ICD-11 classification of chronic pain. Building on this historical-empirical basis, we discuss philosophical issues regarding defining and classifying chronic pain, in particular performativity and pragmatism, and discuss their implications for the broader philosophical debate on health and disease.

Gut microbiota has been found involved in neuronal functions and neurological disorders. Whether and how gut microbiota impacts chronic somatic pain disorders remain elusive.

Digital therapeutics (DTx, mobile medical apps, software as a medical device) are rapidly emerging as clinically effective treatments for diverse chronic diseases. For example, the Food and Drug Administration (FDA) has recently authorized a prescription virtual reality (VR) app for treatment of moderate to severe low back pain. The FDA has also approved an adjunct digital therapy in conjunction with buprenorphine for opioid use disorder, further illustrating opportunities to integrate digital therapeutics with pharmacotherapies. There are ongoing needs to disseminate knowledge about advances in digital interventions among health care professionals, policymakers, and the public at large. This mini-review summarizes accumulating clinical evidence of digital interventions delivered virtual reality and mobile apps to improve opioid-based analgesia. We identified relevant randomized controlled trials (RCTs) using Embase and PubMed databases which reported pain scores with a validated pain scale (e.g., visual analog scales, graphic rating scale, numeric rating scale) and use of a digital intervention in conjunction with opiates. Among identified RCTs, the majority of studies reported improved pain scores in the digital intervention group, as compared to "treatment as usual" group. Our work suggests that VR and mobile apps can be used as adjunct digital therapies for pain management. We discuss these findings in the context of how digital health technologies can transform patient-centered pharmacy care.

The currently available drugs to treat neuropathic pain do not provide adequate pain management. As such, other treatments including stem cells, platelet-rich plasma and plasma-derived molecules such as alpha-2 macroglobulin (A2M) are being explored because they show promising potential for neuropathic pain. The various mechanisms and immunomodulatory effects could be a desirable approach in targeting neuropathic pain. This review indicates that A2M can be highly efficacious due to its conformational change during activation and specificity of action on various cytokines. Its ability to reduce neuropathic pain can further the future of neuropathic intervention. However, there is a lack of robust clinical studies and thus further research is needed to verify and expand the understanding of its therapeutic effects.

Descending pain modulatory systems (DPMS) that originate within the brain and act to modulate spinal nociceptive transmission are a major determinant of the acute and chronic pain experience. Investigations of these systems in basic scientific research is critical to the development of therapeutic strategies for the relief of pain. Despite our best efforts, something is lost in translation. This article will explore whether this is due in part to a primary focus on sensory modality leading to a failure to differentiate between descending control of A- vs. C-fiber mediated spinal nociception.

Spinal cord injury (SCI) is a complex syndrome that has profound effects on patient well-being, including the development of medically-resistant chronic pain. The mechanisms underlying SCI pain have been the subject of thorough investigation but remain poorly understood. While the majority of the research has focused on changes occurring within and surrounding the site of injury in the spinal cord, there is now a consensus that alterations within the peripheral nervous system, namely sensitization of nociceptors, contribute to the development and maintenance of chronic SCI pain. Using an skin/nerve/DRG/spinal cord preparation to characterize afferent response properties following SCI, we found that SCI increased mechanical and thermal responding, as well as the incidence of spontaneous activity (SA) and afterdischarge (AD), in below-level C-fiber nociceptors 24 hr following injury relative to naïve controls. Interestingly, the distribution of nociceptors that exhibit SA and AD are not identical, and the development of SA was observed more frequently in nociceptors with low heat thresholds, while AD was found more frequently in nociceptors with high heat thresholds. We also found that SCI resulted in hindpaw edema and elevated cutaneous calcitonin gene-related peptide (CGRP) concentration that were not observed in naïve mice. These results suggest that SCI causes a rapidly developing nociceptor sensitization and peripheral inflammation that may contribute to the early emergence and persistence of chronic SCI pain.

Chronic pain is a widespread disorder affecting millions of people and is insufficiently addressed by current classes of analgesics due to significant long-term or high dosage side effects. A promising approach that was recently proposed involves the systemic inhibition of the voltage-gated sodium channel Nav1.7, capable of cancelling pain perception completely. Notwithstanding numerous attempts, currently no drugs have been approved for the inhibition of Nav1.7. The task is complicated by the difficulty of creating a selective drug for Nav1.7, and avoiding binding to the many human paralogs performing fundamental physiological functions. In our work, we obtained a promising set of ligands with up to 5-40-fold selectivity and reaching 5.2 nanomolar binding affinity by employing a proper treatment of the problem and an innovative differential in silico screening procedure to discriminate for affinity and selectivity against the Nav paralogs. The absorption, distribution, metabolism, and excretion (ADME) properties of our top-scoring ligands were also evaluated, with good to excellent results. Additionally, our study revealed that the top-scoring ligand is a stereoisomer of an already-approved drug. These facts could reduce the time required to bring a new effective and selective Nav1.7 inhibitor to the market.

Pannexin 1 (Panx1) is involved in the spinal central sensitization process in rats with neuropathic pain, but its interaction with well-known, pain-related, ligand-dependent receptors, such as NMDA receptors (NMDAR) and P2X7 purinoceptors (P2X7R), remains largely unexplored. Here, we studied whether NMDAR- and P2X7R-dependent nociceptive signaling in neuropathic rats require the activation of Panx1 channels to generate spinal central sensitization, as assessed by behavioral (mechanical hyperalgesia) and electrophysiological (C-reflex wind-up potentiation) indexes. Administration of either a selective NMDAR agonist i.t. (NMDA, 2 mM) or a P2X7R agonist (BzATP, 150 μM) significantly increased both the mechanical hyperalgesia and the C-reflex wind-up potentiation, effects that were rapidly reversed (minutes) by i.t. administration of a selective pannexin 1 antagonist (10panx peptide, 300 μM), with the scores even reaching values of rats without neuropathy. Accordingly, 300 μM 10panx completely prevented the effects of NMDA and BzATP administered 1 h later, on mechanical hyperalgesia and C-reflex wind-up potentiation. Confocal immunofluorescence imaging revealed coexpression of Panx1 with NeuN protein in intrinsic dorsal horn neurons of neuropathic rats. The results indicate that both NMDAR- and P2X7R-mediated increases in mechanical hyperalgesia and C-reflex wind-up potentiation require neuronal Panx1 channel activation to initiate and maintain nociceptive signaling in neuropathic rats.

The purposes of this study were to (1) detect the intra- and inter-reliabilities of the lumbar erector spinae stiffness by MyotonPRO among participants with chronic lower back pain (CLBP); (2) compare the muscle stiffness between pain and non-pain sides during different positions; (3) explore the correlation between intensity of pain and muscle stiffness.

Fibromyalgia syndrome (FM) is a chronic widespread pain syndrome characterised by fatigue, sleep disturbances and many idiopathic pain symptoms. The aim of this review is to describe and summarise the most recent findings concerning the diagnosis, aetiopathogenesis and treatment of fibromyalgia syndrome published between January 2021 and January 2022 and appearing on PubMed database. In particular, last year's literature focused on the impact of COVID-19 pandemic on FM patients, on new aetiopathogenetic horizons and the last conclusions about pharmacological and non-pharmacological interventions.

Nociceptors are a type of sensory neuron that are integral to most forms of pain. Targeted disruption of nociceptor sensitization affords unique opportunities to prevent pain. An emerging model for nociceptors are sensory neurons derived from human stem cells. Here, we subjected five groups to high-throughput sequencing: human induced pluripotent stem cells (hiPSCs) prior to differentiation, mature hiPSC-derived sensory neurons, mature co-cultures containing hiPSC-derived astrocytes and sensory neurons, mouse dorsal root ganglion (DRG) tissues, and mouse DRG cultures. Co-culture of nociceptors and astrocytes promotes expression of transcripts enriched in DRG tissues. Comparisons of the hiPSC models to tissue samples reveal that many key transcripts linked to pain are present. Markers indicative of a range of neuronal subtypes present in the DRG were detected in mature hiPSCs. Intriguingly, translation factors were maintained at consistently high expression levels across species and culture systems. As a proof of concept for the utility of this resource, we validated expression of eukaryotic initiation factor 5A (eIF5A) in DRG tissues and hiPSC samples. eIF5A is subject to a unique posttranslational hypusine modification required for its activity. Inhibition of hypusine biosynthesis prevented hyperalgesic priming by inflammatory mediators in vivo and diminished hiPSC activity in vitro. Collectively, our results illuminate the transcriptomes of hiPSC sensory neuron models. We provide a demonstration for this resource through our investigation of eIF5A. Our findings reveal hypusine as a potential target for inflammation associated pain in males.

The International Association for the Study of Pain (IASP) has defined pain as an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage, which also comprises a subjective component […].

Chronic postsurgical pain (CPSP) is a common and disabling postoperative complication. Several risk factors for CPSP have been established, but it is unclear whether they are significant for any type of surgery. This systematic review aimed to assess the risk of CPSP related to three known preoperative risk factors "age, sex and preoperative pain" in the adult population after any type of elective non-obstetrical surgery.

Nucleus accumbens (NAcc) played an important role in pain mediation, and presents changes of neuronal plasticity and functional connectivity. However, less is known about altered perfusion of NAcc in chronic migraine (CM). The aim of this study is to investigate the altered perfusion of the NAcc in CM using a MR three-dimensional pseudo-continuous arterial spin labeling (3D PCASL) imaging.

Intervertebral disc degeneration (IDD), characterized by conversion of genotypic and phenotypic, is a major etiology of low back pain and disability. In general, this process starts with alteration of metabolic homeostasis leading to ongoing inflammatory process, extracellular matrix degradation and fibrosis, diminished tissue hydration, and impaired structural and mechanical functionality. During the past decades, extensive studies have focused on elucidating the molecular mechanisms of degeneration and shed light on the protective roles of various factors that may have the ability to halt and even reverse the IDD. Mutations of GDF-5 are associated with several human and animal diseases that are characterized by skeletal deformity such as short digits and short limbs. Growth and differentiation factor-5 (GDF-5) has been shown to be a promise biological therapy for IDD. Substantial literature has revealed that GDF-5 can decelerate the progression of IDD on the molecular, cellular, and organ level by altering prolonged imbalance between anabolism and catabolism. GDF family members are the central signaling moleculars in homeostasis of IVD and upregulation of their gene promotes the expression of healthy nucleus pulposus (NP) cell marker genes. In addition, GDF signaling is able to induce mesenchymal stem cells (MSCs) to differentiate into NPCs and mobilize resident cell populations as chemotactic signals. This review will discuss the promising critical role of GDF-5 in maintenance of structure and function of IVDs, and its therapeutic role in IDD endogenous repair.

Given the high volume of hysterectomies performed, the contribution of gynecologists to the opioid crisis is potentially significant. Following a hysterectomy, most patients are over-prescribed opioids, are vulnerable to developing new persistent opioid use, and can be the source of misuse, diversion, or accidental exposure. People who misuse opioids are at risk of an overdose related death, which is now one of the leading causes of death in the United States and is rising in other countries. It is the physician's responsibility to reduce opioid use by making impactful practice changes, such as 1) using pre-emptive opioid sparing strategies, 2) optimizing multimodal nonopioid pain management, 3) restricting postoperative opioid prescribing, and 4) educating patients on proper disposal of unused opioids. These changes can be implemented with an enhanced recovery after surgery protocol, shared decision-making, and patient education strategies related to opioids.

Chronic pain in the USA has presented with higher prevalence rates among women, older adults, those unemployed, living in poverty, living in rural environments, and adults with public health insurance. The COVID-19 pandemic has heavily played into the biopsychosocial model of pain. Consequently, greater impacts have affected patients with mood disorders, opioid abuse, and chronic pain. Concurrently, telemedicine has become a popular vehicle during the COVID-19 pandemic in continuing to provide quality patient care. The purpose of this article is to review the benefits and challenges related to the delivery of telemedicine for patients with chronic pain.

(1) AlphαSynuclein (αSyn) is a synaptic protein which is expressed in the nervous system and has been linked to neurodegenerative diseases, in particular Parkinson's disease (PD). Symptoms of PD are mainly due to overexpression and aggregation of αSyn and include pain. However, the interconnection of αSyn and pain has not been clarified so far. (2) We investigated the potential effects of a αSyn knock-out on the nociceptive behaviour in mouse models of acute, inflammatory and neuropathic pain. Furthermore, we assessed the impact of αSyn deletion on pain-related cellular and molecular mechanisms in the spinal cord in these models. (3) Our results showed a reduction of acute cold nociception in αSyn knock-out mice while responses to acute heat and mechanical noxious stimulation were similar in wild type and knock-out mice. Inflammatory nociception was not affected by αSyn knock-out which is also mirrored by unaltered inflammatory gene expression. In contrast, in the SNI model of neuropathic pain, αSyn knock-out mice showed decreased mechanical allodynia as compared to wild type mice. This effect was associated with reduced proinflammatory mechanisms and suppressed activation of MAP kinase signalling in the spinal cord while endogenous antinociceptive mechanisms are not inhibited. (4) Our data indicate that αSyn plays a role in neuropathy and its inhibition might be useful to ameliorate pain symptoms after nerve injury.