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Opioids are a mainstay of treatment for pain worldwide. Pruritus, a common side effect of opioids, is a patient dissatisfier that limits their use in many clinical settings. Both parenteral and neuraxial administration of opioids frequently evoke pruritus. The ability of opioids to suppress pain while causing itch continues to perplex clinicians and researchers alike. Several mechanisms have been proposed to explain how opioids can give rise to pruritus, but specific knowledge gaps perpetuate debate. This review summarizes the clinical burden of opioid-induced pruritus and emphasizes recent discoveries of peripheral and central mechanisms for opioid-induced pruritus, particularly with respect to scientific and conceptual advances in spinal cord circuitry and mast cell biology. The mechanisms and effectiveness of existing medications used for clinical management of pruritus will be evaluated, and we will highlight the emerging preclinical utility of selective κ-opioid receptor agonists, such as nalfurafine, for the management of opioid-induced pruritus.
Learn More >Pain is an immense clinical and societal challenge, and the key to understanding and treating it is variability. Robust interindividual differences are consistently observed in pain sensitivity, susceptibility to developing painful disorders, and response to analgesic manipulations. This review examines the causes of this variability, including both organismic and environmental sources. Chronic pain development is a textbook example of a gene-environment interaction, requiring both chance initiating events (e.g., trauma, infection) and more immutable risk factors. The focus is on genetic factors, since twin studies have determined that a plurality of the variance likely derives from inherited genetic variants, but sex, age, ethnicity, personality variables, and environmental factors are also considered.
Learn More >A remarkable molecular and functional heterogeneity of the primary sensory neurons and dorsal horn interneurons transmits pain- and or itch-relevant information, but the molecular signature of the projection neurons that convey the messages to the brain is unclear. Here, using retro-TRAP (translating ribosome affinity purification) and RNA sequencing, we reveal extensive molecular diversity of spino- and trigeminoparabrachial projection neurons. Among the many genes identified, we highlight distinct subsets of -, -, -, and -expressing projection neurons. By combining in situ hybridization of retrogradely labeled neurons with Fos-based assays, we also demonstrate significant functional heterogeneity, including both convergence and segregation of pain- and itch-provoking inputs into molecularly diverse subsets of NK1R- and non-NK1R-expressing projection neurons.
Learn More >Painful diabetic neuropathy (PDN) is an intractable complication affecting 25% of diabetic patients. PDN is characterized by neuropathic pain accompanied by dorsal root ganglion (DRG) nociceptor hyperexcitability, resulting in calcium overload, axonal degeneration, and loss of cutaneous innervation. The molecular pathways underlying these effects are unknown. Using high-throughput and deep-proteome profiling, we found that mitochondrial fission proteins were elevated in DRG neurons from mice with PDN induced by a high-fat diet (HFD). In vivo calcium imaging revealed increased calcium signaling in DRG nociceptors from mice with PDN. Furthermore, using electron microscopy, we showed that mitochondria in DRG nociceptors had fragmented morphology as early as two weeks after starting HFD, preceding the onset of mechanical allodynia and small-fiber degeneration. Moreover, preventing calcium entry into the mitochondria, by selectively deleting the mitochondrial calcium uniporter (MCU) from these neurons restored normal mitochondrial morphology, prevented axonal degeneration, and reversed mechanical allodynia in the HFD mouse model of PDN. These studies suggest a molecular cascade linking neuropathic pain to axonal degeneration in PDN. In particular, nociceptor hyperexcitability and the associated increased intracellular calcium concentrations could lead to excessive calcium entry into mitochondria mediated by the MCU, resulting in increased calcium-dependent mitochondrial fission and ultimately contributing to small-fiber degeneration and neuropathic pain in PDN. Hence, we propose that targeting calcium entry into nociceptor mitochondria may represent a promising effective and disease-modifying therapeutic approach for this currently intractable and widespread affliction. Moreover, these results are likely to inform studies of other neurodegenerative disease involving similar underlying events.
Learn More >Recent studies have brought to light the necessity to discern sex-specific differences in various pain states and different cell-types that mediate these differences. These studies have uncovered the role of neuroimmune interactions to mediate pain states in a sex-specific fashion. While investigating immune function in pain development, we discovered that females utilize immune components of sensory neurons to mediate neuropathic pain development. We utilized two novel transgenic mouse models that eitherrestore expression of toll-like receptor (TLR) 4 inNa1.8 nociceptors on a TLR4-null background (TLR4) or remove TLR4 specifically from Na1.8 nociceptors (TLR4). After spared nerve injury (SNI), a model of neuropathic injury, we observed a robust female-specific onset of mechanical hypersensitivity in our transgenic animals. Female Na1.8-TLR4 knockout animals were less mechanically sensitive than cre-negative TLR4 littermates. Conversely, female Na1.8-TLR4 reactivated animals were as mechanically sensitive as their wild-type counterparts. These sex and cell-specific effects were not recapitulated in male animals of either strain. Additionally, we find the danger associated molecular pattern, high mobility group box-1 (HGMB1), a potent TLR4 agonist, localization and ATF3 expression in females is dependent on TLR4 expression in dorsal root ganglia (DRG) populations following SNI. These experiments provide novel evidence toward sensory neuron specific modulation of pain in a sex-dependent manner.
Learn More >Chronic postsurgical pain can severely impair patient health and quality of life. This systematic review update evaluated the effectiveness of systemic drugs to prevent chronic postsurgical pain.
Learn More >Pain and other somatosensory sensations, such as itch, can be effectively decreased by placebo effects and increased by nocebo effects. There are indications that placebo effects on pain generalize to other sensations and that nocebo effects generalize within itch modalities. However, it has not yet been investigated whether learned effects can generalize within pain stimulus modalities or from pain to itch. Our aims were to test whether placebo and nocebo effects can generalize within pain modalities, i.e., from heat pain to pressure pain, and across somatosensory sensations with psychophysiological similarities, i.e., from heat pain to cowhage-evoked itch. For this purpose, sixty-five healthy participants were randomized to either a placebo or nocebo group. All participants firstly underwent a conditioning and verbal suggestion procedure with heat pain stimuli. Subsequently, responses to heat pain, pressure pain, and cowhage-evoked itch stimuli were tested. Results showed that altered levels of heat and pressure pain with the conditioned cue in both placebo and nocebo groups in the expected directions, but no significant difference in itch in both groups. In conclusion, placebo and nocebo effects on pain may generalize within but not across stimulus modalities. This study provides a novel perspective on the role that response generalization plays in physical symptoms.
Learn More >Knowledge of etiological mechanisms underlying whiplash-associated disorders (WAD) is incomplete. Localisation and quantification of peripheral musculoskeletal injury and inflammation in WAD would facilitate diagnosis, strengthen patients' subjective pain reports and aid clinical decisions, all of which could lead to improved treatment. In this longitudinal observational study we evaluated combined [11C]D-deprenyl positron emission tomography and computed tomography (PET-CT)) after acute whiplash injury and at 6 month follow-up. Sixteen adult patients (mean age 33 years) with whiplash injury grade II were recruited at the emergency department. [11C]D-deprenyl PET-CT, subjective pain levels, self-rated neck disability and active cervical range of motion were recorded within seven days after injury, and again at six month follow up. Imaging results showed possible tissue injuries after acute whiplash with an altered [11C]D-deprenyl uptake in the cervical bone structures and facet joints, associated with subjective pain locale and levels, as well as self-rated disability. At follow up, some patients had recovered, and some showed persistent symptoms, and reductions in [11C]D-deprenyl uptake correlated to reductions in pain levels. These findings help identify affected peripheral structures in whiplash injury and strengthen the idea that PET/CT detectable organic lesions in peripheral tissue are relevant for the development of persistent pain and disability in whiplash injury.
Learn More >Clinical evidence indicates dorsal root ganglion (DRG) stimulation effectively reduces pain without the need to evoke paresthesia. This paresthesia-free anesthesia by DRG stimulation can be promising to treat pain from the viscera, where paresthesia usually cannot be produced. Here, we explored the mechanisms and parameters for DRG stimulation using an ex vivo preparation with mouse distal colon and rectum (colorectum), pelvic nerve, L6 DRG, and dorsal root in continuity. We conducted single-fiber recordings from split dorsal root and assessed the effect of DRG stimulation on afferent neural transmission. We determined the optimal stimulus pulse width by measuring the chronaxies of DRG stimulation to be below 216 µsec, indicating spike initiation likely at attached axons rather than somata. Sub-kilohertz DRG stimulation significantly attenuates colorectal afferent transmission (10, 50, 100, 500 and 1000 Hz), of which 50 and 100 Hz show superior blocking effects. Synchronized spinal nerve and DRG stimulation reveals a progressive increase in conduction delay by DRG stimulation, suggesting activity-dependent slowing in blocked fibers. Afferents blocked by DRG stimulation show a greater increase in conduction delay than unblocked counterparts. Mid-range frequencies (50-500 Hz) are more efficient at blocking transmission than lower or higher frequencies. In addition, DRG stimulation at 50 and 100 Hz significantly attenuates in vivo visceromotor responses to noxious colorectal balloon distension. This reversible conduction block in C- and Aδ-type afferents by sub-kilohertz DRG stimulation likely underlies the paresthesia-free anesthesia by DRG stimulation, thereby offering a promising new approach for managing chronic visceral pain.
Learn More >Clinically significant new or worsening pain (CSNWP) is a common, yet often overlooked, sequelae of sexual assault. Little is known regarding factors influencing the development of CSNWP in sexual assault survivors. The current study used data from a recently completed prospective study to evaluate whether posttraumatic alterations in arousal and reactivity in the early aftermath of sexual assault influence the transition from acute to clinically significant new or worsening persistent pain. Women ≥ 18 years of age (n = 706) presenting for emergency care after sexual assault to 13 emergency care sites were enrolled in the study. Women completed assessments at the time of presentation as well as at 1 week (n = 706, 100%) and 6 weeks (n = 630, 91%). Nearly 70% of women reported CSNWP at the time of emergency care (n = 475, 69%), which persisted to 6 weeks in approximately 2 in 5 survivors (n = 248, 41%). A structural equation model adjusted for age, race, past trauma exposure, and preassault pain levels suggested that posttraumatic alterations in arousal/reactivity symptoms 1 week after assault partially mediated the transition from acute to persistent CSNWP. A significant portion (41%) of women sexual assault survivors develop CSNWP 6 weeks postassault. Posttraumatic arousal/reactivity symptoms in the early aftermath of assault contribute to CSNWP development; such symptoms are potential targets for secondary preventive interventions to reduce chronic postassault pain.
Learn More >Exercise is the most common treatment recommended by health care providers for treatment of musculoskeletal pain. We examined whether voluntary running wheel exercise improves pain and bone remodeling in rats with monosodium iodoacetate (MIA)-induced unilateral knee joint pain. During acquisition of wheel running prior to OA treatment, rats separated into two groups characterized by either high or low levels of voluntary wheel running as indicated by distance and peak speed. Following induction of knee joint OA, all rats showed diminished voluntary wheel running throughout the study. Voluntary wheel running failed to alter evoked nociceptive responses evaluated as weight asymmetry or hindpaw tactile thresholds at any time-point of the study. In contrast, relief of ongoing pain was demonstrated by conditioned place preference produced by lidocaine injection into the MIA-treated knee in high but not low running rats. Both high and low voluntary runners showed diminished trabecular bone loss compared to sedentary controls. These observations indicate that both high and low intensity exercise is beneficial in protecting against bone remodeling in advanced OA. The data suggest that similar to clinical observation, bone remodeling does not correlate with pain. Additionally, these results suggest that higher intensity exercise may relieve persistent ongoing OA pain while maintaining movement-evoked nociception. The relief of ongoing pain can potentially offer significant improvement in quality of life while preservation of responses to movement-evoked pain may be especially important in protecting the joint from damage due to overuse.
Learn More >The role that inflammation plays in human nerve injury and neuropathic pain is incompletely understood. Previous studies highlight the role of inflammation in the generation and maintenance of neuropathic pain, but the emerging evidence from the preclinical literature for its role in the resolution of neuropathic pain remains to be explored in humans. Here, we use carpal tunnel syndrome (CTS) as a human model system of nerve injury and neuropathic pain to determine changes in serum cytokine protein levels and gene expression levels before (active stage of disease) and after carpal tunnel decompression surgery (recovery). Fifty-five CTS patients were studied and 21 healthy age and gender matched participants served as controls. In the active stage of the disease (CTS before surgery vs healthy controls), PTGES2 mRNA was decreased in patients (adjusted p=0.013), while TGF-β and CCL5 protein levels were increased (adjusted p=0.016 and p=0.047 respectively). In the resolution phase (CTS before surgery vs after surgery), IL-9 mRNA was increased after surgery (adjusted p=0.014) and expression of IL-6 mRNA and IL-4 protein levels were increased before surgery (adjusted p=0.034 and p=0.002 respectively). IL-9 mRNA expression negatively correlated with several (neuropathic) pain scores. In contrast, protein levels of IL-4 positively correlated with pain scores. In conclusion, we demonstrate specific dysregulation of systemic cytokine expression both in the active and resolution phases of nerve injury and neuropathic pain. IL-9 represents an interesting candidate associated with resolution of nerve injury and neuropathic pain.
Learn More >Quantitative Sensory Testing (QST) can be useful to identify high-risk patients for the development of chronic postsurgical pain (CPSP). This systematic review aims to assess if presurgical sensory sensitivity measured using QST is associated with acute and CPSP after total joint arthroplasty.A systematic search was performed in Sep/2020 in PubMed, EMBASE, Web of Science and Scopus, using terms related to total joint arthroplasty and QST. Prospective studies were included if they reported an association between presurgical QST and postsurgical pain in adults with osteoarthritis undergoing primary unilateral total joint arthroplasty.From 2994 identified studies, 18 met the inclusion criteria (1869 patients). Total knee arthroplasty was the most common surgery (16 studies) and pressure pain threshold (PPT) was the most common test (11 studies), followed by dynamic measures (9 studies). Postsurgical pain was assessed at acute (5 studies), subacute (2 studies) and chronic (13 studies) time points. Risk of bias was assessed using the Quality in Prognosis Studies Tool, and evaluated as low-to-moderate in most domains. Fourteen studies reported at least one statistically significant association between QST and pain (acute: 4 studies, subacute: 1 study, chronic: 9 studies). PPT was associated with postsurgical pain in 6 studies (out of 11, 55%), heat pain threshold in 2 (out of 6, 33%), conditioned pain modulation in 1 (out of 6, 17%) and temporal summation of pain in 5 (out of 8, 63%). The predictive role of presurgical QST for post-arthroplasty pain remains unclear, mainly due to heterogeneous methodologies and inconsistent results.
Learn More >The interchange of information from one cell to another relies on the release of hundreds of different molecules including small peptides, amino acids, nucleotides, RNA, steroids, retinoids, or fatty acid metabolites. Many of them are released to the extracellular matrix as free molecules and others can be part of the cargo of cellular vesicles. Small extracellular vesicles (30-150 nm), also known as exosomes, are a known mechanism of cell-to-cell communication in the nervous system. Exosomes participate in the pathogenesis of several neurological conditions including Alzheimer's and Parkinson's disease. However, exciting emerging evidence demonstrates that exosomes also regulate mechanisms of the sensory process including nociception. The goal of this review is to summarize the literature on exosome biogenesis, methods of small vesicle isolation and purification, and their role in nociception. We also provide insights on the potential applications of exosomes as pain biomarkers or as novel therapeutics.
Learn More >A multi-cohort, case-control rodent study.
Learn More >Moderate to severe pain is often treated with opioids, but central mechanisms underlying opioid analgesia are poorly understood. Findings thus far have been contradictory and none could infer opioid specific effects. This placebo-controlled, randomized, two-way cross-over, double-blinded study aimed to explore opioid specific effects on central processing of external stimuli. Twenty healthy male volunteers were included and three sets of assessments were done at each of the two visits: 1) baseline, 2) during continuous morphine or placebo intravenous infusion and 3) during simultaneous morphine + naloxone or placebo infusion. Opioid antagonist naloxone was introduced in order to investigate opioid specific effects by observing which morphine effects are reversed by this intervention. Quantitative sensory testing (QST), spinal nociceptive withdrawal reflexes (NWR), spinal electroencephalography (EEG), cortical EEG responses to external stimuli and resting EEG were measured and analyzed. Longer lasting pain (cold-pressor test – hand in 2° water for two minutes, tetanic electrical), deeper structure pain (bone pressure) and strong nociceptive (NWR) stimulations were the most sensitive QST measures of opioid analgesia. In line with this, the principal opioid specific central changes were seen in NWRs, EEG responses to NWRs and cold-pressor EEG. The magnitude of NWRs together with amplitudes and insular source strengths of the corresponding EEG responses were attenuated. The decreases in EEG activity were correlated to subjective unpleasantness scores. Brain activity underlying slow cold-pressor EEG (1-4Hz) was decreased, whereas the brain activity underlying faster EEG (8-12Hz) was increased. These changes were strongly correlated to subjective pain relief. This study points to evidence of opioid specific effects on perception of external stimuli and the underlying central responses. The analgesic response to opioids is likely a synergy of opioids acting at both spinal and supra-spinal levels of the central nervous system. Due to the strong correlations with pain relief, the changes in EEG signals during cold-pressor test have the potential to serve as biomarkers of opioid analgesia. Perspective: This exploratory study presents evidence of opioid specific effects on the pain system at peripheral and central levels. The findings give insights into which measures are the most sensitive for assessing opioid-specific effects.
Learn More >Patient Reported Outcomes (PROs) are utilized in clinical registries and trials, necessitating development of benchmarks to enhance interpretability. This study aimed to 1) examine if PROMIS measures administered via computer adaptive testing (CAT) were responsive to change, and 2) highlight one method of assessing clinically significant change for youth seen in a tertiary pain clinic. Clinically significant change was achieved if patients had significantly reliable pre-to-post-changes greater than Reliable Change Index (RCI) value and reported decreased symptoms by at least one severity level (e.g., moderate to mild). Participants were 328 youth (8-17 years old) seen in a tertiary pediatric pain management clinic. Small to moderate effect sizes were noted across PROMIS measures (except Peer Relations). Reliable magnitudes of change were estimated for this sample as approximately 6-point reduction for Pain Interference and Mobility, 9 for Fatigue, and 11 for Anxiety and Depression. Depending on the measure, 10-24% were categorized as improved, 3-6% as deteriorated, and 68-81% were either not clinically elevated at baseline or remained unchanged at 3-months. Overall, PROMIS CAT measures demonstrated responsiveness to change over time. Estimation of clinically significant change offers preliminary yet rigorous benchmarks for evaluating treatment response and sets the stage for understanding treatment effects. Perspective This study assesses responsiveness of CAT administered PROMIS measures and highlights one methodological approach of presenting clinical significance for assessing treatment outcomes in pediatric chronic pain. These benchmarks will allow clinicians and researchers to evaluate treatment response utilizing PROs while allowing for a deeper understanding of treatment effects.
Learn More >Posttraumatic stress (PTS), depressive symptoms (DS), and musculoskeletal pain (MSP) are common sequelae of trauma exposure. Although these adverse posttraumatic neuropsychiatric sequelae (APNS) are often studied separately, clinical comorbidity is high. In a cohort of European American motor vehicle collision (MVC) trauma survivors (n = 781), substantial PTS (≥33, IES-R), DS (≥26, CES-D), and MSP (≥4, 0-10 NRS) were identified via a 6-month survey. Genetic risk was estimated using polygenic risk scores (PRSs) calculated from the largest available GWAS datasets of PTSD, MDD, and back pain. We then assessed comorbidity and genetic risk influence for developing chronic PTS, DS, and MSP after MVC. Secondary analyses explored whether common social determinants of health ameliorate genetic vulnerability. We found that 6 months after MVC, nearly half 357/781 (46%) of the participants had substantial PTS, DS, and/or MSP, and overlap was common (PTS + MSP (23%), DS + MSP (18%), PTS + DS (12%)). Genetic risk predicted post-MVC outcomes. PTSD-PRSs predicted PTS and DS (R = 2.21% and 2.77%, p < 0.01), MDD-PRSs predicted DS and MSP (R = 1.89%, p < 0.01) and 0.79%, p < 0.05), and back pain-PRS predicted MSP (R = 1.49%, p < 0.01). Individuals in the highest quintile of PTSD-PRSs had 2.8 and 3.5 times the odds of developing PTS and DS vs. the lowest quintile (95% CI = 1.39-5.75 and 1.58-7.76). Among these high-risk individuals, those living in non-disadvantaged neighborhoods and with college education had 47% (p = 0.048) and 52% (p = 0.04) less risk of developing PTS, and those with high social support had 60% (p = 0.008) less risk of developing DS. Overall, genetic factors influence the risk of APNS after MVC, genetic risk of distinct APNS are overlapping, and specific social determinants greatly augment genetic risk of APNS development after MVC.
Learn More >Lysophosphatidic acid (LPA) plays a critical role in developing and maintaining chronic pain in various animal models. Previous studies have reported that cytosolic and calcium-independent phospholipase A (PLA) is involved in the LPA receptor-mediated amplification of LPA production in the spinal dorsal horn (SDH) after nerve injury, while the involvement of secreted PLA (sPLA) remains unclear. The present study revealed that only sPLA -III among 11 species of PLA showed a significant upregulation of gene expression in the SDH. Intraspinal injection of adeno-associated virus-miRNA targeting sPLA-III prevented hyperalgesia and unique hypoalgesia in mice treated with partial sciatic nerve ligation. In addition, intrathecal treatment with antisense oligodeoxynucleotide or siRNA targeting sPLA-III significantly reversed the established thermal hyperalgesia. In the high-throughput screening of sPLA-III inhibitors from the chemical library, we identified two hit compounds. Through in vitro characterization of PLA inhibitor profiles and in vivo assessment of the anti-hyperalgesic effects of known PLA inhibitors as well as hit compounds, sPLA-III was found to be a novel therapeutic target molecule for the treatment of Neuropathic pain.
Learn More >Myofascial pain syndrome (MPS) affects most patients with chronic shoulder pain. Dry needling (DN) is a common treatment for MPS, but its temporal pattern and sensory effects remain unknown.
Learn More >Major advances in therapies to optimize recovery after surgery have been limited by the lack of an animal model that can mimic major domains of postoperative sickness behavior in humans. We hypothesized that the integration of commonly impaired domains of quality of recovery in humans could be reproduced in a rat model.
Learn More >Slow brushing over the skin activates C-tactile nerve fibers that transmit pleasant tactile experiences in healthy subjects, leading to an inverted U-shaped velocity dependence of ratings: C-tactile optimal stroking stimulations are rated as more pleasant than slower or faster stimulations. Chronic pain diseases such as postherpetic neuralgia (PHN) and complex regional pain syndrome show altered C-fiber innervation density, sensory loss, and pain sensitization.
Learn More >Migraine affects roughly 10% of youth aged 5-15 years, however the underlying mechanisms of migraine in youth are poorly understood. Multiple structural and functional alterations have been shown in the brains of adult migraine sufferers. This study aims to investigate the effects of migraine on resting-state functional connectivity during the period of transition from childhood to adolescence, a critical period of brain development and the time when rates of pediatric chronic pain spikes.
Learn More >Frequent nightly arousals typical for sleep disorders cause daytime fatigue and present health risks. As such arousals are often short, partial, or occur locally within the brain, reliable characterization in rodent models of sleep disorders and in human patients is challenging. We found that the EEG spectral composition of non-rapid-eye-movement sleep (NREMS) in healthy mice shows an infraslow (~50 s) interval over which microarousals appear preferentially. NREMS could hence be vulnerable to abnormal arousals on this time scale. Chronic pain is well-known to disrupt sleep. In the spared-nerve-injury (SNI) mouse model of chronic neuropathic pain, we found more numerous local cortical arousals accompanied by heart rate increases in hindlimb primary somatosensory, but not in prelimbic, cortices, although sleep macroarchitecture appeared unaltered. Closed-loop mechanovibrational stimulation further revealed higher sensory arousability. Chronic pain thus preserved conventional sleep measures but resulted in elevated spontaneous and evoked arousability. We develop a novel moment-to-moment probing of NREMS vulnerability and propose that chronic pain-induced sleep complaints arise from perturbed arousability.
Learn More >Pain is a universal experience and the most common reason for seeking healthcare. Inadequate pain management negatively impacts numerous aspects of patient health. Multidisciplinary treatment programmes, including psychosocial interventions, are more useful for pain management than purely biomedical treatment alone. Recently, researchers showed increasing interest in understanding the role of spirituality/religiosity and spiritual/religious practices on pain experience, with engagement in religious practices, such as prayer, showing to positively impact pain experience in religious individuals. This systematic review will seek to summarise and integrate the existing findings from randomised controlled trials assessing the effects of prayer and prayer-based interventions on pain experience.
Learn More >Dermatitis encompasses a spectrum of inflammatory skin disorders with aberrant immune responses classified as type 1, type 2, and/or type 3. Major advances in the understanding of the pathogenesis of atopic dermatitis (AD) have shed new light on how innate immune responses critically regulate type 2 inflammation and itch. This article highlights the diverse ways by which type 2 immune cells regulate diseases beyond AD. The discovery of human Mas-related G protein-coupled receptor X2 on mast cells has revealed novel T cell-independent and immunoglobulin E-independent mechanisms of allergic contact dermatitis-associated and urticarial itch, respectively.
Learn More >This journal recently published a paper by Rong et al., entitled "Persistent moderate to severe pain and long-term cognitive decline." (Rong et al., 2021). The authors demonstrate that, to a small but statistically significant degree, older adults with persistent moderate-to-severe pain (an approximation for chronic pain) experience a faster rate of late-life cognitive decline than older adults without pain. Given these findings, should clinicians be alert for accelerated cognitive decline in older adults with chronic pain? Rong and colleagues argue yes. But, interestingly, using the same data source, an earlier study by Veronese and colleagues concluded that there was no evidence for an effect (Veronese et al., 2018). What are we to make of this?
Learn More >Fibromyalgia (FM) is characterized by chronic widespread pain and both physical and emotional alterations, which in turn may affect the individual's quality of life. Thus, interventions aimed at treating such symptoms, without increasing fatigue, are needed. The aim of this study was to explore the effect of high-frequency transcranial magnetic stimulation (HF-TMS) and physical exercise (PE) on pain, impact of FM, physical conditioning, and emotional status in people with FM.
Learn More >TREK-1 channels are expressed in small nociceptive dorsal root ganglion (DRG) neurons where they participate in acute inflammatory and neuropathic pain. However, the role of TREK-1 in persistent pain is not well understood. The aim of this study was to investigate the local peripheral and spinal participation of TREK-1 in formalin-induced acute and long-lasting nociceptive hypersensitivity. Local peripheral or intrathecal pre-treatment with spadin, selective blocker of TREK-1, increased acute flinching behavior and secondary mechanical allodynia and hyperalgesia behavior observed 6 days after formalin injection. Local peripheral or intrathecal pre-treatment with BL-1249, selective opener of TREK-1, decreased long-lasting secondary mechanical allodynia and hyperalgesia induced by formalin. Pre-treatment with BL-1249 prevented the pro-nociceptive effect of spadin on acute nociception and long-lasting mechanical allodynia and hyperalgesia in rats. Pre-treatment with two recombinant channels that produce a high TREK-1 current, S300A and S333A (non-phosphorylated state of TREK-1), reduced formalin-induced acute pain and long-lasting mechanical allodynia and hyperalgesia. Besides, post-treatment with S300A, S333A or BL-1249 reversed long-lasting mechanical allodynia and hyperalgesia induced by formalin. Formalin increased TREK-1 expression at 1 and 6 days in DRG and dorsal spinal cord in rats, whereas that it increased c-fos expression at the DRG. Intrathecal repeated transfection of rats with S300A and S333A or injection with BL-1249 reduced formalin-induced enhanced c-fos expression. Data suggest that TREK-1 activity at peripheral and spinal sites reduces neuronal excitability in the process of acute and long-lasting nociception induced by formalin in rats.
Learn More >Sensitivity to pain traumatization (SPT) is defined as the propensity to develop responses to pain that resemble a traumatic stress reaction. To date, SPT has been assessed in adults with a self-report measure (Sensitivity to Pain Traumatization Scale (SPTS-12)). SPT may also be relevant in the context of parenting a child with chronic pain, as many of these parents report clinically elevated posttraumatic stress symptoms (PTSS). This study aimed to develop and validate a measure of parent SPT by adapting the SPTS-12 and evaluating its psychometric properties in a sample of parents whose children have chronic pain. In total, 170 parents (90.6% female) and children (aged 10-18 years, 71.2% female) were recruited from a tertiary chronic pain program. Parents completed the parent version of the SPTS-12 (SPTS-P) and measures of PTSS, depression, and parenting behaviors. Youth completed measures of pain. Consistent with the SPTS-12, the SPTS-P demonstrated a one-factor structure that accounted for 45% of the variance, adequate to good reliability and moderate construct validity. Parent SPT was positively related to their protective and monitoring behaviors but was unrelated to youth pain intensity, unpleasantness, and interference. These results provide preliminary evidence for the psychometric properties of the SPTS-P and highlight the interaction between parent distress about child pain and parent responses to child pain.
Learn More >HIV-associated distal sensory polyneuropathy (HIV-DSP) affects about one third of people with HIV and is characterized by distal degeneration of axons. The pathogenesis of HIV-DSP is not known and there is currently no FDA-approved treatment. HIV trans-activator of transcription (TAT) is associated with mitochondrial dysfunction and neurotoxicity in the brain and may play a role in the pathogenesis of HIV-DSP. In the present study, we measured indices of peripheral neuropathy in the doxycycline (DOX)-inducible HIV-TAT (iTAT) transgenic mouse and investigated the therapeutic efficacy of a selective muscarinic subtype-1 receptor (MR) antagonist, pirenzepine (PZ). PZ was selected as we have previously shown that it prevents and/or reverses indices of peripheral neuropathy in multiple disease models. DOX alone induced weight loss, tactile allodynia and paw thermal hypoalgesia in normal C57Bl/6J mice. Conduction velocity of large motor fibers, density of small sensory nerve fibers in the cornea and expression of mitochondria-associated proteins in sciatic nerve were unaffected by DOX in normal mice, whereas these parameters were disrupted when DOX was given to iTAT mice to induce TAT expression. Daily injection of PZ (10 mg/kg s.c.) prevented all of the disorders associated with TAT expression. These studies demonstrate that TAT expression disrupts mitochondria and induces indices of sensory and motor peripheral neuropathy and that MR antagonism may be a viable treatment for HIV-DSP. However, some indices of neuropathy in the DOX-inducible TAT transgenic mouse model can be ascribed to DOX treatment rather than TAT expression and data obtained from animal models in which gene expression is modified by DOX should be accompanied by appropriate controls and treated with due caution.
Learn More >Diminished inhibitory control of spinal nociception is one of the major culprits of chronic pain states. Restoring proper synaptic inhibition is a well-established rational therapeutic approach explored by several pharmaceutical companies. A particular challenge arises from the need for site-specific intervention to avoid deleterious side effects such as sedation, addiction, or impaired motor control, which would arise from wide-range facilitation of inhibition. Specific targeting of glycinergic inhibition, which dominates in the spinal cord and parts of the hindbrain, may help reduce these side effects. Selective targeting of the α3 subtype of glycine receptors (GlyRs), which is highly enriched in the superficial layers of the spinal dorsal horn, a key site of nociceptive processing, may help to further narrow down pharmacological intervention on the nociceptive system and increase tolerability. This review provides an update on the physiological properties and functions of α3 subtype GlyRs and on the present state of related drug discovery programs.
Learn More >A decarboxylated form of L-arginine, agmatine, preferentially antagonizes NMDArs containing Glun2B subunits within the spinal cord and lacks motor side effects commonly associated with non-subunit-selective NMDAr antagonism, namely sedation and motor impairment. Spinally delivered agmatine has been previously shown to reduce the development of tactile hypersensitivity arising from spinal nerve ligation. The present study interrogated the dependence of agmatine's alleviation of neuropathic pain (spared nerve injury (SNI) model) on GluN2B-containing NMDArs. SNI-induced hypersensitivity was induced in mice with significant reduction of levels of spinal GluN2B subunit of the NMDAr and their floxed controls. Agmatine reduced development of SNI-induced tactile hypersensitivity in controls but had no effect in subjects with reduced levels of GluN2B subunits. Ifenprodil, a known GluN2B-subunit-selective antagonist, similarly reduced tactile hypersensitivity in controls but not in the GluN2B-deficient mice. In contrast, MK-801, an NMDA receptor channel blocker, reduced hypersensitivity in both control and GluN2B-deficient mice, consistent with a pharmacological pattern expected from a NMDAr antagonist that does not have preference for GluN2B subtypes. Additionally, we observed that spinally delivered agmatine, ifenprodil and MK-801 inhibited nociceptive behaviors following intrathecal delivery of NMDA in control mice. By contrast, in GluN2B-deficient mice, MK-801 reduced NMDA-evoked nociceptive behaviors, but agmatine had a blunted effect and ifenprodil had no effect. These results demonstrate that agmatine requires the GluN2B subunit of the NMDA receptor for inhibitory pharmacological actions in pre-clinical models of NMDA receptor-dependent hypersensitivity.
Learn More >This article is a systematic review of data from 2018 to 2020 regarding information from publications on epidemiologic, diagnostic, and therapeutic advancements in human immunodeficiency virus-associated peripheral neuropathy.
Learn More >To determine whether erenumab is effective and safe in refractory chronic migraine with medication overuse headache.
Learn More >The search for an ideal biomarker for migraine has persisted for a long time. There is plentiful evidence of potential biomarkers for migraine found in cerebrospinal fluid, blood and saliva.
Learn More >Slow, deep breathing (SDB) is a common pain self-management technique. Stimulation of the arterial baroreceptors and vagal modulation are suggested, among others, as potential mechanisms underlying the hypoalgesic effects of SDB. We tested whether adding an inspiratory load to SDB, which results in a stronger baroreceptor stimulation and vagal modulation, enhances its hypoalgesic effects. Healthy volunteers performed SDB (controlled at 0.1 Hz) with and without an inspiratory threshold load. Controlled breathing (CB) at a normal frequency (0.23 Hz) was used as an active control. Each condition lasted 90 s, included an electrical pain stimulation on the hand, and was repeated four times in a randomized order. Pain intensity, self-reported emotional responses (arousal, valence, dominance), and cardiovascular parameters (including vagally-mediated heart rate variability) were measured per trial. A cover story was used to limit the potential effect of outcome expectancy. Pain intensity was slightly lower during SDB with load compared with normal-frequency CB, but the effect was negligible (Cohens d < 0.2), and there was no other difference in pain intensity between the conditions. Heart rate variability was higher during SDB with/without load compared with normal-frequency CB. Using load during SDB was associated with higher heart rate variability, but less favorable emotional responses. These findings do not support the role of baroreceptor stimulation or vagal modulation in the hypoalgesic effects of SDB. Other mechanisms, such as attentional modulation, warrant further investigation.
Learn More >The current opioid crisis highlights the urgent need to develop safe and effective pain medications. Thus, neurotensin (NT) compounds represent a promising approach, as the antinociceptive effects of NT are mediated by activation of the two G protein-coupled receptor subtypes (i.e., NTS1 and NTS2) and produce potent opioid-independent analgesia. Here, we describe the synthesis and pharmacodynamic and pharmacokinetic properties of the first constrained NTS2 macrocyclic NT(8-13) analog. The Tyr residue of NT(8-13) was replaced with a Trp residue to achieve NTS2 selectivity, and a rationally designed side-chain to side-chain macrocyclization reaction was applied between Lys and Trp to constrain the peptide in an active binding conformation and limit its recognition by proteolytic enzymes. The resulting macrocyclic peptide, CR-01-64, exhibited high-affinity for NTS2 (K 7.0 nM), with a more than 125-fold selectivity over NTS1, as well as an improved plasma stability profile (t > 24 h) compared with NT (t ~ 2 min). Following intrathecal administration, CR-01-64 exerted dose-dependent and long-lasting analgesic effects in acute (ED = 4.6 µg/kg) and tonic (ED = 7.1 µg/kg) pain models as well as strong mechanical anti-allodynic effects in the CFA-induced chronic inflammatory pain model. Of particular importance, this constrained NTS2 analog exerted potent nonopioid antinociceptive effects and potentiated opioid-induced analgesia when combined with morphine. At high doses, CR-01-64 did not cause hypothermia or ileum relaxation, although it did induce mild and short-term hypotension, all of which are physiological effects associated with NTS1 activation. Overall, these results demonstrate the strong therapeutic potential of NTS2-selective analogs for the management of pain.
Learn More >The study aimed to assess the feasibility of recording electrically evoked compound action potentials (ECAPs) from the rat spinal cord. To achieve this, we characterized electrophysiological responses of dorsal column (DC) axons from electrical stimulation and quantified the relationship between ECAP and motor thresholds (ECAPTs and MTs).
Learn More >Herpes zoster, the result of varicella-zoster virus (VZV) reactivation, is frequently complicated by difficult-to-treat chronic pain states termed postherpetic neuralgia (PHN). While there are no animal models of VZV-induced pain following viral reactivation, subcutaneous VZV inoculation of the rat causes long-term nocifensive behaviors indicative of mechanical and thermal hypersensitivity. Previous studies using UV-inactivated VZV in the rat model suggest viral gene expression is required for the development of pain behaviors. However, it remains unclear if complete infection processes are needed for VZV to induce hypersensitivity in this host. To further assess how gene expression and replication contribute, we developed and characterized three replication-conditional VZV using a protein degron system to achieve drug-dependent stability of essential viral proteins. Each virus was then assessed for induction of hypersensitivity in rats under replication permissive and nonpermissive conditions. VZV with a degron fused to ORF9p, a late structural protein that is required for virion assembly, induced nocifensive behaviors under both replication permissive and nonpermissive conditions, indicating that complete VZV replication is dispensable for the induction of hypersensitivity. This conclusion was confirmed by showing that a genetic deletion recombinant VZV lacking DNA packaging protein ORF54p still induced prolonged hypersensitivities in the rat. In contrast, VZV with a degron fused to the essential IE4 or IE63 proteins, which are involved in early gene regulation of expression, induced nocifensive behaviors only under replication permissive conditions, indicating importance of early gene expression events for induction of hypersensitivity. These data establish that while early viral gene expression is required for the development of nocifensive behaviors in the rat, complete replication is dispensable. We postulate this model reflects events leading to clinical PHN, in which a population of ganglionic neurons become abortively infected with VZV during reactivation and survive, but host signaling becomes altered in order to transmit ongoing pain.
Learn More >Stress contributes to major depressive disorder (MDD) and chronic pain, which affect a significant portion of the global population, but researchers have not clearly determined how these conditions are initiated or amplified by stress. The chronic social defeat stress (CSDS) model is a mouse model of psychosocial stress that exhibits depressive-like behavior and chronic pain. We hypothesized that metabotropic glutamate receptor 5 (mGluR5) expressed in the nucleus accumbens (NAc) normalizes the depressive-like behaviors and pain following CSDS. Here, we show that CSDS induced both pain and social avoidance and that the level of mGluR5 decreased in susceptible mice. Overexpression of mGluR5 in the NAc shell and core prevented the development of depressive-like behaviors and pain in susceptible mice, respectively. Conversely, depression-like behaviors and pain were exacerbated in mice with mGluR5 knockdown in the NAc shell and core, respectively, compared to control mice subjected to 3 days of social defeat stress. Furthermore, (RS)-2-chloro-5-hydroxyphenylglycine (CHPG), an mGluR5 agonist, reversed the reduction in the level of the endocannabinoid (eCB) 2-arachidonoylglycerol (2-AG) in the NAc of susceptible mice, an effect that was blocked by 3-((2-methyl-1, 3-thiazol-4-yl) ethynyl) pyridine hydrochloride (MTEP), an mGluR5 antagonist. In addition, the injection of CHPG into the NAc shell and core normalized depressive-like behaviors and pain, respectively, and these effects were inhibited by AM251, a cannabinoid type 1 receptor (CB1R) antagonist. Based on these results, mGluR5-mediated eCB production in the NAc relieves stress-induced depressive-like behaviors and pain.
Learn More >Acute pain management in patients with opioid use disorder who are maintained on methadone presents unique challenges due to high levels of opioid tolerance in this population. This randomized controlled study assessed the analgesic and abuse liability effects of escalating doses of acute intravenous (IV) hydromorphone versus placebo utilizing a validated experimental pain paradigm, quantitative sensory testing (QST).
Learn More >The bed nucleus of the stria terminalis (BNST) is a compact but neurophenotypically complex structure in the ventral forebrain that is structurally and functionally linked to other limbic structures, including the amygdala nuclear complex, hypothalamic nuclei, hippocampus, and related midbrain structures, to participate in a wide range of functions, especially emotion, emotional learning, stress-related responses, and sexual behaviors. From a variety of sensory inputs, the BNST acts as a node for signal integration and coordination for information relay to downstream central neuroendocrine and autonomic centers for appropriate homeostatic physiological and behavioral responses. In contrast to the role of the amygdala in fear, the BNST has gained wide interest from work suggesting that it has main roles in mediating sustained responses to diffuse, unpredictable and/or long-duration threats that are typically associated with anxiety-related responses. Further, some BNST subregions are highly sexually dimorphic which appear contributory to the differential stress and social interactive behaviors, including reproductive responses, between males and females. Notably, maladaptive BNST neuroplasticity and function have been implicated in chronic pain, depression, anxiety-related abnormalities, and other psychopathologies including posttraumatic stress disorders. The BNST circuits are predominantly GABAergic-the glutaminergic neurons represent a minor population-but the complexity of the system results from an overlay of diverse neuropeptide coexpression in these neurons. More than a dozen neuropeptides may be differentially coexpressed in BNST neurons, and from variable G protein-coupled receptor signaling, may inhibit or activate downstream circuit activities. The mechanisms and roles of these peptides in modulating intrinsic BNST neurocircuit signaling and BNST long-distance target cell projections are still not well understood. Nevertheless, an understanding of some of the principal players may allow assembly of the circuit interactions.
Learn More >Communication pathways of the hypothalamus with other brain regions and the periphery are critical to successfully control key physiological and psychological processes. With advanced functional magnetic resonance imaging (fMRI) techniques, it is possible to target hypothalamic function and infer discrete hypothalamus networks. Resting-state functional connectivity (RSFC) is a promising tool to study the functional organization of the brain and may act as a marker of individual differences and dysfunctions. Based on recent fMRI findings, the hypothalamus is mostly connected to parts of the striatum, midbrain, thalamus, insula, frontal, cingulate, and temporal cortices and the cerebellum. There is a strong interplay of the hypothalamus with these regions in response to different metabolic, hormonal, and nutritional states. In a state of hunger, hypothalamus RSFC increases with a strong shift to reward-related brain regions, especially in person with excessive weight. Nutrient signals and hormones, as insulin, act on these same connections conveying reward and internal signals to regulate homeostatic control. Moreover, dysfunctional hypothalamus communication has been documented in persons with neurological and psychiatric diseases. The results implicate that patients with depression, epilepsy, and neurodegenerative diseases show mostly a reduction in hypothalamus RSFC, whereas patients with migraine and headache display predominantly increased hypothalamus RSFC. The extent of these changes and regions affected depend on the disorder and symptom severity. Whether hypothalamus RSFC can serve as a marker for disease states or is a prodromal neurobiological feature still needs to be investigated.
Learn More >Central sensitization is a condition that represents a cascade of neurological adaptations, resulting in an amplification of nociceptive responses from noxious and non-noxious stimuli. However, whether this abnormality translates into motor output and more specifically, ventral horn abnormalities, needs to be further explored. Twenty healthy participants aged 20-70 were randomly allocated to topical capsaicin or a placebo topical cream which was applied onto their left upper back to induce a transient state of sensitization. Visual analogue scale (VAS) ratings of pain intensity and brush allodynia score (BAS) were used to determine the presence of pain and secondary allodynia. Surface electromyography (sEMG) and intramuscular electromyography (iEMG) were used to record motor unit activity from the upper trapezius and infraspinatus muscles before and twenty minutes after application of capsaicin/placebo. Motor unit recruitment and variability were analyzed in the sEMG and iEMG, respectively. An independent t-test and Kruskal-Wallis H test were performed on the data. The sEMG results demonstrated a shift in the motor unit recruitment pattern in the upper trapezius muscle, while the iEMG showed a change in motor unit variability after application of capsaicin. These results suggest that capsaicin-induced central sensitization may cause changes in ventral horn excitability outside of the targeted spinal cord segment, affecting efferent pathway outputs. This preclinical evidence may provide some explanation for the influence of central sensitization on changes in movement patterns that occur in patients who have pain encouraging of further clinical investigation.Clinical Trials registration number: NCT04361149; date of registration: 24-Apr-2020.
Learn More >The fear-avoidance model provides an explanation for the development of chronic pain, including the role of perception (i.e. pain catastrophism) as an explanatory variable. Recent research has shown that the relationship between pain catastrophism and avoidance is influenced in turn by different psychological and contextual variables, highlighting the affective-motivational ones. From this perspective, the Goal Pursuit Questionnaire (GPQ) was developed to measure the preference for hedonic goals (mood-management or pain-avoidance goals) over achievement goals in musculoskeletal pain patients. Recently, the Spanish version of the GPQ in fibromyalgia patients has been validated. Our aim has been to adapt the Spanish version of GPQ from pain to fatigue symptoms and to validate this new questionnaire (GPQ-F) in fibromyalgia. Despite the recognition of fibromyalgia as a complex disorder and the need for a differential study of its symptoms, fatigue, despite its high prevalence and limiting nature, remains the forgotten symptom. We conducted a cross-sectional study with 231 women with fibromyalgia. Previously, we adapted the Spanish GPQ for fatigue symptoms with three sub-studies (group structured interview, self-administration questionnaire and thinking-aloud; n = 15-27 patients). We explored the GPQ structure and performed path analyses to test conditional mediation relationships. Exploratory factor analysis showed two factors: 'Fatigue-avoidance goal' and 'Mood-management goal' (39.3% and 13.9% of explained variance, respectively). The activity avoidance pattern fully mediated the relation between both catastrophizing and fatigue-avoidance goals with fatigue. The study shows initial findings about the usefulness of the GPQ-F as a tool to analyze goal preferences related to fatigue in fibromyalgia. The results supported the mediational role of activity avoidance patterns in the relationship between preference for fatigue-avoidance goals and fatigue.
Learn More >To develop and implement criteria for description of post COVID syndrome based on analysis of patients presenting for evaluation at Mayo Clinic Rochester between November 2019 and August 2020.
Learn More >Recurrent acute pancreatitis (RAP) and chronic pancreatitis (CP) are progressive inflammatory syndromes with variable features. Pain is the primary feature that contributes to low physical and mental quality of life with a third of patients reporting severe pain. Pain experience is worsened by depression. Here, we tested the hypothesis that genetic risk of the psychiatric conditions of anxiety and post-traumatic stress disorder (PTSD) is associated with pain in CP and RAP + CP subjects.
Learn More >A new series of propionamide derivatives was developed as dual μ-opioid receptor agonists and σ receptor antagonists. Modification of a high-throughput screening hit originated a series of piperazinylcycloalkylmethyl propionamides, which were explored to overcome the challenge of achieving balanced dual activity and convenient drug-like properties. The lead compound identified, , showed good analgesic effects in several animal models of both acute (paw pressure) and chronic (partial sciatic nerve ligation) pain, with reduced gastrointestinal effects in comparison with oxycodone.
Learn More >Diabetic peripheral neuropathic pain (DPNP), a symptom of diabetic polyneuropathy (DPN), is underdiagnosed in people with diabetes. To date, no studies have determined the relationship between diagnosis of DPN and satisfaction with treatment for pain. Additionally, the factors that influence satisfaction with treatment for pain remain unknown. This questionnaire study was conducted to understand satisfaction with treatment for pain among participants with diabetes who experienced bilateral pain or numbness in their feet.
Learn More >Neurophysiological investigation of nociceptive pathway has so far been limited to late cortical responses. We sought to detect early components of the cortical evoked potentials possibly reflecting primary sensory activity.
Learn More >Association of temporomandibular disorders (TMD)-related pain with severe headaches (migraine and tension-type headaches [TTH]) was studied over a follow-up period of 11 years.
Learn More >Indigenous peoples are vulnerable populations that live in remote areas of the Amazon forest with limited access to health-care services. Underreporting and undertreatment of pain is a common event in the general population but little is known about these issues in indigenous peoples. The aim of this study was to investigate the characteristics and cultural aspects of pain management in five ethnicities of the Brazilian Amazon.
Learn More >Chemotherapy-induced peripheral neuropathy ((CI)PN) becomes chronic in 30% of cancer patients. Knowledge of predictors of chronic (CI)PN and related impairments in health-related quality of life (HRQoL) is lacking. We examined the role of optimism in chronic (CI)PN severity and associated HRQoL in colorectal cancer (CRC) patients up to two years after diagnosis.
Learn More >AIMS: To investigate characteristics of emerging adults accessing a specialized chronic non-cancer pain clinic and describe interventions offered and utilized by this group.
Learn More >Oxaliplatin is an effective anti-cancer platinum-based chemotherapy drug which can cause severe chronic neuropathy, but the molecular mechanism underlying this adverse effect is still unclear. Opa interacting protein 5 (OIP5) is a member of the cancer/testis antigen (CTA) family and is involved in a variety of cancers. Studies have shown that Raf1, which is a serine/threonine-protein kinase, can directly combine with OIP5 to promote its expression. Whether Raf1 and OIP5 can participate in oxaliplatin-induced neuropathic pain has not been reported.
Learn More >Yoga is a meditative movement therapy focused on mind-body awareness. The impact of yoga on health-related quality of life (HRQOL) outcomes in patients with chemotherapy-induced peripheral neuropathy (CIPN) is unclear.
Learn More >The neurophysiological mechanisms underlying NGF-induced masseter muscle sensitization and sex-related differences in its effect are not well understood in humans. Therefore, this longitudinal cohort study aimed to investigate the effect of NGF injection on the density and expression of substance P, NMDA-receptors and NGF by the nerve fibers in the human masseter muscle, to correlate expression with pain characteristics, and to determine any possible sex-related differences in these effects of NGF. The magnitude of NGF-induced mechanical sensitization and pain during oral function was significantly greater in women than in men (P < 0.050). Significant positive correlations were found between nerve fiber expression of NMDA-receptors and peak pain intensity (r = 0.620, P = 0.048), and expression of NMDA-receptors by putative nociceptors and change in temporal summation pain after glutamate injection (r = 0.561, P = 0.003). In women, there was a significant inverse relationship between the degree of NGF-induced mechanical sensitization and the change in nerve fiber expression of NMDA-receptors alone (r = - 0.659, P = 0.013), and in combination with NGF (r = - 0.764, P = 0.001). In conclusion, women displayed a greater magnitude of NGF-induced mechanical sensitization that also was associated with nerve fibers expression of NMDA-receptors, when compared to men. The present findings suggest that, in women, increased peripheral NMDA-receptor expression could be associated with masseter muscle pain sensitivity.
Learn More >This study examined the prevalence of suicidality and associations with pain characteristics (i.e., presence of usual pain/discomfort, pain intensity) among those with chronic pain conditions (i.e., arthritis, migraine, back pain).
Learn More >Preclinical studies demonstrate that cannabidiol (CBD) elicits an antinociceptive response in animal models of neuropathic pain; in humans, limited data are available to support such analgesic effects. Few studies have examined CBD's analgesic effects when administered without other compounds, and little is known regarding dose-dependent effects in non-cannabis users.
Learn More >Localized provoked vulvodynia (LPV) causes dyspareunia among reproductive aged women. We review the pathogenesis of LPV and suggest that LPV is an inflammatory pain syndrome of the vestibular mucosa triggered by microbial antigens in a susceptible host. Tissue inflammation and hyperinnervation are characteristic findings which explain symptoms and clinical signs. Education of health care providers of LPV is important since this condition is common, often unrecognized, and patients often become frustrated users of health care. Research is needed on the antigen triggers of the syndrome. Randomized clinical trials are needed to evaluate treatment modalities.
Learn More >High-frequency repetitive transcranial magnetic stimulation (rTMS) has been shown to reduce neuropathic pain, but intermittent "theta-burst" stimulation (iTBS) could be a better alternative because of shorter duration and greater ability to induce cortical plasticity. Here we compared head-to-head the pain-relieving efficacy of the two modalities when applied daily for 5 days to patients with neuropathic pain.
Learn More >Although total knee arthroplasty (TKA) is an effective treatment for severe knee osteoarthritis (OA), a subset of patients experience significant postoperative pain and dissatisfaction. Several clinical trials support the analgesic benefits of genicular nerve radiofrequency ablation (GN-RFA) for non-operative knee OA, but only one prior trial has examined the effects of this intervention given preoperatively on postoperative outcomes following TKA, showing no analgesic benefit of cooled GN-RFA. The current study evaluated whether conventional thermal GN-RFA performed preoperatively resulted in significant improvements in pain and function following TKA.
Learn More >Exercise and physical activity are an evidence-based practice for chronic pain. Health professionals need instruments to assess self-efficacy for this practice taking into account the specific barriers of patients with these health problems.
Learn More >Globally, medical cannabis legalization has increased in recent years and medical cannabis is commonly used to treat chronic pain. However, there are few randomized control trials studying medical cannabis indicating expert guidance on how to dose and administer medical cannabis safely and effectively is needed.
Learn More >With millions of people using cannabinoids to treat a host of medical conditions, clinicians want guidance on how to utilize cannabinoids as pharmacotherapy in their practices. The Delphi method is a systematic, interactive forecasting method that aims to develop consensus best practices where guidelines are not available. BODY: A multidisciplinary group of global cannabinoid experts utilized a modified Delphi process to develop three protocols for the dosing and administration of cannabinoids to treat chronic pain. Two protocols recommend cannabidiol (CBD), for which there is limited evidence as an analgesic, starting well below doses required for other indications. Guidance on prescribing CBD for pain may demonstrate consensus recommendations based upon suboptimal evidence.
Learn More >Neuroimaging and neuropsychological investigations have indicated that migraineurs exhibit frontal lobe-related cognitive impairment. We investigated whether orbitofrontal and dorsolateral functioning differed between individuals with episodic migraine (EM) and chronic migraine (CM), focusing on orbitofrontal dysfunction because it is implicated in migraine chronification and medication overuse headache (MOH) in migraineurs. This cross-sectional study recruited women with CM with/without MOH (CM + MOH, CM – MOH), EM, and control participants who were matched in terms of age and education. We conducted neuropsychological assessments of frontal lobe function via the Trail Making Test (TMT) A and B, the Wisconsin Card Sorting Test (WCST), and the Iowa Gambling Task (IGT). We enrolled 36 CM (19 CM + MOH, 17 CM – MOH), 30 EM, and 30 control participants. The CM patients performed significantly ( < 0.01) worse on the TMT A and B than the EM patients and the control participants. The WCST also revealed significant differences, with poorer performance in the CM patients versus the EM patients and the control participants. However, the net scores on the IGT did not significantly differ among the three groups. Our findings suggest that the CM patients exhibited frontal lobe dysfunction, and, particularly, dorsolateral dysfunction. However, we found no differences in frontal lobe function according to the presence or absence of MOH.
Learn More >The neuropeptide calcitonin gene-related peptide (CGRP) is known to play a central role in the underlying pathophysiology of migraine. In comparison to the effective triptan class of antimigraine treatments, the CGRP antagonists possess a comparable efficacy but a superior cardiovascular safety profile in patients. This paper describes the development of selective and potent peptidic CGRP antagonist, FE 205030, that has a fast onset of action and an optimal half-life (subcutaneous T ∼ 60 min, and t ∼ 4.4h in 80 kg pigs, respectively), which is key to prevention of the progression of debilitating migraine symptoms. The in vivo efficacy of this agent has been established a translational pharmacodynamic model (inhibition of capsaicin-induced increase in skin blood flow) in cynomolgus monkeys and shows maximal inhibitory activity at circulating concentrations of 30-100 nM. Antagonist activity of FE 205030 was characterized on CGRP-induced vasodilation in isolated human mesenteric resistance arteries in an ex vivo isometric myograph study, and FE 205030 effectively blocked CGRP-induced vasodilation with a pA of 9.3 ± 0.1, mean ± standard error. Multispecies allometric scaling and modeling of subcutaneous (SC) effective concentrations indicates that a dose of 10-30 mg/day is sufficient to achieve a drug exposure/target coverage of 8h, which is useful to prevent migraine recurrence in patients. The molecule also possesses appropriate physicochemical properties that allows for a convenient dosing form factor of 1 ml injection volume with a sufficient solubility and acceptable short-term stability, optimal for treatment of acute migraine episodes in patients. Hence, FE 205030 may provide an important fast-acting injectable option for patients suffering from frequent acute migraine episodes, complementary to preventative monoclonal antibodies and oral small molecule CGRP-R antagonist therapies.
Learn More >To review the pharmacokinetics of major classes of migraine preventives and the clinical implications of drug-drug interactions (DDIs) with the use of these therapies in migraine management.
Learn More >The objective of this prospective, multicenter study is to characterize responses to percutaneous medial branch peripheral nerve stimulation (PNS) to determine if results from earlier, smaller single-center studies and reports were generalizable when performed at a larger number and wider variety of centers in patients recalcitrant to non-surgical treatments. Participants with chronic axial low back pain were implanted with percutaneous PNS leads targeting the lumbar medial branch nerves for up to 60 days, after which the leads were removed. Participants were followed long-term for 12 months after the 2-month PNS treatment. Data collection is complete for visits through end of treatment with PNS (Primary Endpoint) and 6 months after lead removal (8 months after start of treatment), with some participant follow-up visits thereafter in progress. Clinically and statistically significant reductions in pain intensity, disability, and pain interference were reported by a majority of participants. Seventy-three percent of participants were successes for the Primary Endpoint, reporting clinically significant (≥30%) reductions in back pain intensity after the 2-month percutaneous PNS treatment (n=54/74). While prospective follow up is ongoing, among those who had already completed the long-term follow up visits (n=51), reductions in pain intensity, disability, and pain interference were sustained in a majority of participants through 14 months after the start of treatment. Given the minimally invasive, non-destructive nature of percutaneous PNS and the significant benefits experienced by participants who were recalcitrant to non-surgical treatments, percutaneous PNS may provide a promising first-line neurostimulation treatment option for patients with chronic axial back pain.
Learn More >To identify how frequently the neck pain associated with migraine presents with a pattern of cervical musculoskeletal dysfunction akin to cervical musculoskeletal disorders, and to determine if pain hypersensitivity impacts on cervical musculoskeletal function in persons with migraine.
Learn More >This narrative review aims to update the reader on the new classification of trigeminal neuralgia (TN), clinical signs, pathophysiologic evidence, and their implications on management. This review is based on the authors' collective experience and knowledge of the literature in addition to a literature search.
Learn More >Cisplatin, which is a chemotherapy drug listed on the World Health Organisation's List of Essential Medicines, commonly induces dose-limiting side effects including chemotherapy-induced peripheral neuropathy (CIPN) that has a major negative impact on quality of life in cancer survivors. Although adjuvant drugs including anticonvulsants and antidepressants are used for the relief of CIPN, analgesia is often unsatisfactory. Herein, we used a rat model of CIPN (cisplatin) to assess the effect of a glycine transporter 2 (GlyT2) inhibitor, relative to pregabalin, duloxetine, indomethacin and vehicle. Male Sprague-Dawley rats with cisplatin-induced mechanical allodynia and mechanical hyperalgesia in the bilateral hindpaws received oral bolus doses of the GlyT2 inhibitor (3-30 mg/kg), pregabalin (3-100 mg/kg), duloxetine (3-100 mg/kg), indomethacin (1-10 mg/kg) or vehicle. The GlyT2 inhibitor alleviated both mechanical allodynia and hyperalgesia in the bilateral hindpaws at a dose of 10 mg/kg, but not at higher or lower doses. Pregabalin and indomethacin induced dose-dependent relief of mechanical allodynia but duloxetine lacked efficacy. Pregabalin and duloxetine alleviated mechanical hyperalgesia in the bilateral hindpaws while indomethacin lacked efficacy. The mechanism underpinning pain relief induced by the GlyT2 inhibitor at 10 mg/kg is likely due to increased glycinergic inhibition in the lumbar spinal cord, although the bell-shaped dose-response curve warrants further translational considerations.
Learn More >In our efforts to discover new drugs to treat pain, we identified molleamines A-E (-) as major neuroactive components of the sea slug, , and their prey, , tunicates. The chemical structures of molleamines were elucidated by spectroscopy and confirmed by the total synthesis of molleamines A () and C (). Synthetic completely blocked acetylcholine-induced calcium flux in peptidergic nociceptors (PNs) in the somatosensory nervous system. Compound affected neither the α7 nAChR nor the muscarinic acetylcholine receptors in calcium flux assays. In addition to nociceptors, partially blocked the acetylcholine-induced calcium flux in the sympathetic nervous system, including neurons from the superior cervical ganglion. Electrophysiology revealed a block of α3β4 (mouse) and α6/α3β4 (rat) nicotinic acetylcholine receptors (nAChRs), with IC values of 1.4 and 3.1 μM, respectively. Molleamine C () is a partial antagonist, reaching a maximum block of 76-82% of the acetylcholine signal and showing no partial agonist response. Molleamine C () may thus provide a lead compound for the development of neuroactive compounds with unique biological properties.
Learn More >The treatment of neuropathic and central pain still remains a major challenge. Thalamic deep brain stimulation (DBS) involving various target structures is a therapeutic option which has received increased re-interest. Beneficial results have been reported in several more recent smaller studies, however, there is a lack of prospective studies on larger series providing long term outcomes. Forty patients with refractory neuropathic and central pain syndromes underwent stereotactic bifocal implantation of DBS electrodes in the centromedian-parafascicular (CM-Pf) and the ventroposterolateral (VPL) or ventroposteromedial (VPM) nucleus contralateral to the side of pain. Electrodes were externalized for test stimulation for several days. Outcome was assessed with five specific VAS pain scores (maximum, minimum, average pain, pain at presentation, allodynia). The mean age at surgery was 53.5 years, and the mean duration of pain was 8.2 years. During test stimulation significant reductions of all five pain scores was achieved with either CM-Pf or VPL/VPM stimulation. Pacemakers were implanted in 33/40 patients for chronic stimulation for whom a mean follow-up of 62.8 months (range 3-180 months) was available. Of these, 18 patients had a follow-up beyond four years. Hardware related complications requiring secondary surgeries occurred in 11/33 patients. The VAS maximum pain score was improved by ≥50% in 8/18, and by ≥30% in 11/18 on long term follow-up beyond four years, and the VAS average pain score by ≥50% in 10/18, and by ≥30% in 16/18. On a group level, changes in pain scores remained statistically significant over time, however, there was no difference when comparing the efficacy of CM-Pf versus VPL/VPM stimulation. The best results were achieved in patients with facial pain, poststroke/central pain (except thalamic pain), or brachial plexus injury, while patients with thalamic lesions had the least benefit. Thalamic DBS is a useful treatment option in selected patients with severe and medically refractory pain.
Learn More >The growth differentiation factor 5 (GDF5) gene regulates the growth of neuronal axons and dendrites and plays a role in the inflammatory response and tissue damage. The gene may also be associated with chronic postsurgical pain. This study aimed to reveal the relationship between SNPs in the GDF5 gene and orthopedic chronic postsurgical pain in Han Chinese population based on a case-control study.
Learn More >This study aimed to develop culturally sensitive pain neuroscience education (PNE) materials for Hausa speaking patients with chronic spinal pain (CSP). PNE is a program of teaching patients about pain that has gained considerable attention in research and is increasingly used during physical therapy for patients with chronic pain. It helps in decreasing pain, disability, fear-avoidance, pain catastrophization, movement restriction, and health care utilization among patients with chronic pain. However, existing PNE materials and their application are limited to few languages and cultural inclinations. Due to the variations in pain perceptions, beliefs, and related outcomes among different population groups, culture-sensitive PNE materials addressing these outcomes are warranted. A focus-group discussion comprising 4 experts was used to adapt and develop preliminary PNE materials. Thereafter, an internet-based 3-round modified Delphi-study involving 22 experts ensued. Experts' consensus/recommendations concerning the content were used in modifying the PNE materials. Consensus was predefined as ≥75% level of (dis)agreement. Eighteen experts completed the Delphi rounds. Nineteen, 18 and 18 experts participated in rounds 1, 2 and 3 respectively, representing 86%, 94% and 100% participation rate respectively. Consensus agreement was reached in every round and content of the materials, including drawings, examples, figures and metaphors were adapted following the experts' suggestions. We therefore concluded that, culture-sensitive PNE materials for Hausa speaking patients with CSP were successfully produced. The present study also provides a direction for further research whereby the effects of culturally-sensitive PNE materials can be piloted among Hausa speaking patients with CSP.
Learn More >The efficacy of onabotulinumtoxinA (OnaB-A) as a preventative treatment for chronic migraine, emerging fortuitously from clinical observation is now supported by class one evidence and over two decades of real-world clinical data. There is still limited ability to predict a clinically meaningful response to OnaB-A for individual patients, however. This review summarises briefly the proposed mechanism of OnaB-A in chronic migraine, the literature of predictors of clinical response, and recent developments in the field.
Learn More >