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Barrier tissue immune responses are regulated in part by nociceptors. Nociceptor ablation alters local immune responses at peripheral sites and within draining lymph nodes (LNs). The mechanisms and significance of nociceptor-dependent modulation of LN function are unknown. Using high-resolution imaging, viral tracing, single-cell transcriptomics, and optogenetics, we identified and functionally tested a sensory neuro-immune circuit that is responsive to lymph-borne inflammatory signals. Transcriptomics profiling revealed that multiple sensory neuron subsets, predominantly peptidergic nociceptors, innervate LNs, distinct from those innervating surrounding skin. To uncover LN-resident cells that may interact with LN-innervating sensory neurons, we generated a LN single-cell transcriptomics atlas and nominated nociceptor target populations and interaction modalities. Optogenetic stimulation of LN-innervating sensory fibers triggered rapid transcriptional changes in the predicted interacting cell types, particularly endothelium, stromal cells, and innate leukocytes. Thus, a unique population of sensory neurons monitors peripheral LNs and may locally regulate gene expression.
Learn More >The skin covering the human palm and other specialized tactile organs contains a high density of mechanosensory corpuscles tuned to detect transient pressure and vibration. These corpuscles comprise a sensory afferent neuron surrounded by lamellar cells. The neuronal afferent is thought to be the mechanical sensor, whereas the function of lamellar cells is unknown. We show that lamellar cells within Meissner and Pacinian corpuscles detect tactile stimuli. We develop a preparation of bill skin from tactile-specialist ducks that permits electrophysiological recordings from lamellar cells and demonstrate that they contain mechanically gated ion channels. We show that lamellar cells from Meissner corpuscles generate mechanically evoked action potentials using R-type voltage-gated calcium channels. These findings provide the first evidence for R-type channel-dependent action potentials in non-neuronal cells and demonstrate that lamellar cells actively detect touch. We propose that Meissner and Pacinian corpuscles use neuronal and non-neuronal mechanoreception to detect mechanical signals.
Learn More >Dyspareunia, also known as vaginal hyperalgesia, is a prevalent and debilitating symptom of gynaecological disorders such as endometriosis and vulvodynia. Despite this, the sensory pathways transmitting nociceptive information from female reproductive organs remain poorly characterised. As such, the development of specific treatments for pain associated with dyspareunia is currently lacking. Here, we examined, for the first time, (1) the mechanosensory properties of pelvic afferent nerves innervating the mouse vagina; (2) the expression profile of voltage-gated sodium (NaV) channels within these afferents; and (3) how pharmacological modulation of these channels alters vaginal nociceptive signalling ex vivo, in vitro, and in vivo. We developed a novel afferent recording preparation and characterised responses of pelvic afferents innervating the mouse vagina to different mechanical stimuli. Single-cell reverse transcription-polymerase chain reaction determined mRNA expression of NaV channels within vagina-innervating dorsal root ganglia neurons. Vagina-innervating dorsal root ganglia neuroexcitability was measured using whole-cell patch-clamp electrophysiology. Nociception evoked by vaginal distension was assessed by dorsal horn neuron activation within the spinal cord and quantification of visceromotor responses. We found that pelvic afferents innervating the vagina are tuned to detect various mechanical stimuli, with NaV channels abundantly expressed within these neurons. Pharmacological modulation of NaV channels (with veratridine or tetrodotoxin) correspondingly alters the excitability and mechanosensitivity of vagina-innervating afferents, as well as dorsal horn neuron activation and visceromotor responses evoked by vaginal distension. This study identifies potential molecular targets that can be used to modulate vaginal nociceptive signalling and aid in the development of approaches to manage endometriosis and vulvodynia-related dyspareunia.
Learn More >Nociceptor sensory neurons innervate barrier tissues that are constantly exposed to microbial stimuli. During infection, pathogenic microorganisms can breach barrier surfaces and produce pain by directly activating nociceptors. Microorganisms that live in symbiotic relationships with their hosts, commensals and mutualists, have also been associated with pain, but the molecular mechanisms of how symbionts act on nociceptor neurons to modulate pain remain largely unknown. In this review, we will discuss the known molecular mechanisms of how microbes directly interact with sensory afferent neurons affecting nociception in the gut, skin and lungs. We will touch on how bacterial, viral and fungal pathogens signal to the host to inflict or suppress pain. We will also discuss recent studies examining how gut symbionts affect pain. Specifically, we will discuss how gut symbionts may interact with sensory afferent neurons either directly, through secretion of metabolites or neurotransmitters, or indirectly,through first signaling to epithelial cells or immune cells, to regulate visceral, neuropathic and inflammatory pain. While this area of research is still in its infancy, more mechanistic studies to examine microbial-sensory neuron crosstalk in nociception may allow us to develop new therapies for the treatment of acute and chronic pain.
Learn More >Rimegepant is a calcitonin gene-related peptide receptor antagonist that has shown efficacy and safety in the acute treatment of migraine. We aimed to compare the efficacy of rimegepant with placebo for preventive treatment of migraine.
Learn More >Prominent clinical problems related to the skin-nerve interface include barrier dysfunction and erythema but it is the symptoms of pain and itch that lead patients to seek medical treatment. Tissue-engineered innervated skin models provide an excellent solution for studying the mechanisms underlying neuro-cutaneous disorders for drug screening, and cutaneous device development. Innervated skin substitutes provide solutions to the traditional monolayer cultures and have advantages that make them preferable to animal studies for certain applications, such as measuring somatosensation. The tissue-engineered innervated skin models replicate the complex stratified epidermis that provides barrier function in native skin, a feature that is lacking in monolayer co-cultures, while allowing for measurement of nerve function that cannot be achieved in animal models. In this review, the advantages and disadvantages of different cell sources and scaffold materials will be discussed and a presentation of the current state of the field is reviewed.
Learn More >The mu opioid receptor-selective agonist, SR-17018, preferentially activates GTPγS binding over βarrestin2 recruitment in cellular assays, thereby demonstrating signaling bias. In mice, SR-17018 stimulates GTPγS binding in brainstem and produces antinociception with potencies similar to morphine. However, it produces much less respiratory suppression and mice do not develop antinociceptive tolerance in the hot plate assay upon repeated dosing. Herein we evaluate the effects of acute and repeated dosing of SR-17018, oxycodone and morphine in additional models of pain-related behaviors. In the mouse warm water tail immersion assay, an assessment of spinal reflex to thermal nociception, repeated administration of SR-17018 produces tolerance as does morphine and oxycodone. SR-17018 retains efficacy in a formalin-induced inflammatory pain model upon repeated dosing, while oxycodone does not. In a chemotherapeutic-induced neuropathy pain model SR-17018 is more potent and efficacious than morphine or oxycodone, moreover, this efficacy is retained upon repeated dosing of SR-17018. These findings demonstrate that, with the exception of the tail flick test, SR-17018 retains efficacy upon chronic treatment across several pain models.
Learn More >Evidence suggests altered pronociceptive and antinociceptive mechanisms in many chronic pain conditions. Knowledge about these mechanisms in nonspecific chronic neck pain (NSNP) would improve understanding of the causes and the design of more effective treatments. Pressure pain threshold (PPT) is often used to assess presence of altered nociceptive processing in NSNP; however, its usefulness to detect this is yet to be established. The purpose of this study was to determine the functional status of temporal summation of second pain (TSSP) and conditioned pain modulation (CPM) in NSNP and to characterize the association of both measures with PPT and clinical features of NSNP.
Learn More >To characterize the distribution and severity of sensory neuropathy using a portable quantitative sensory testing (QST) device in diabetic patients (DM) hospitalized with severe COVID-19 infection.
Learn More >To assess the effectiveness, safety, and tolerability of erenumab in a real-life migraine population, while trying to identify responsiveness predictors.
Learn More >Accurate, up-to-date estimates of the burden of migraine and severe headache are important for evidence-based decision-making about workforce needs and the distribution of health resources. We used data from US government health surveys to report the prevalence, trends, and impact of this condition by age, sex, and poverty status.
Learn More >Of painful conditions, somatic pain of acute nociceptive origin can be effectively managed clinically, while neuropathic pain of chronic neuropathy origin is difficult to control. For molecules involved in pain sensation, substance P (SP) is algesic, exacerbating painful sensation, while its amino-terminal fragment, heptapeptide SP, confers biological activities different from its full-length parent neuropeptide precursor. We previously demonstrated SP interaction with pain processing to alleviate chronic pain. Here we evaluated SP and its C-terminal amidated analogue SPamide, together with SP and opioid agonist DAMGO. We tested mouse behaviors of both acute somatic pain in tail-flick latency assay, and neuropathic pain in sciatic nerve injury model of chronic constriction injury (CCI). DAMGO produced dose-dependent analgesia for somatic pain as expected, so did both SP and its analogue SPamide, while SP yielded the opposite effect of algesia, in a phenomenon we termed 'contrintus', meaning 'opposite from within' to denote that two peptides of the same origin (SP and its metabolic fragment SP) produced opposite effects. In CCI model, DAMGO showed a general reduction in allodynia sensitivity for both nerve-injured and normal paws, without selective effect for neuropathic pain, consistent with clinical observation that opioids are less effective for chronic neuropathic pain. On the other hand, both SP and SPamide displayed dose-dependent anti-allodynia effect that is selective for neuropathic pain. These findings suggest that SP and its analogue may be useful for developing pharmaceuticals to treat neuropathic pain.
Learn More >In the context of neuropathic pain, the contribution of regeneration to the development of positive symptoms is not completely understood. Several efforts have been done to described changes in axotomized neurons, however, there is scarce data on changes occurring in intact neurons, despite experimental evidence of functional changes. To address this issue, we analyzed by immunohistochemistry the presence of phosphorylated signal transducer and activator of transcription 3 (pSTAT3), an accepted marker of regeneration, within DRGs where axotomized neurons were retrogradely labeled following peripheral nerve injury. Likewise, we have characterized abnormal electrophysiological properties in intact fibers after partial nerve injury.
Learn More >To ensure an adequate pain therapy with high patient adherence, it is necessary to know and consider patient preferences. A discrete choice experiment (DCE) was used to obtain patients' preferences regarding treatment with systemic or topical pain medication. Patients with peripheral neuropathic pain (pNP) were recruited in two pain-focused practices in Germany. To identify relevant attributes of topical or systemic pain medication, a literature review and face-to-face interviews with experts for pain treatment were conducted. The attributes used in the choice scenarios were noticeable onset of effect, time spent in medical office, risk of systemic and local side effects, impairment of daily life with regards to sleep quality and sexuality. The model was estimated with a mixed multinomial logit regression model. The study included 153 participants suffering from moderate to severe pNP. Most important attributes from patient's perspective was noticeable onset of effect (Odds Ratio 2.141 [95%-Confidence Interval 1.837 – 2.494]), followed by risk of systemic side effects (2.038 [1.731 – 2.400]), risk of sexual dysfunction (1.839 [1.580 – 2.140]), while risk of local side effects regarding skin ranked fourth (1.612 [1.321 – 1.966]).The impairment of sleep quality was also significant but less important (1.556 [1.346 – 1.798]). Local side effects were more likely to be accepted than systemic side effects. The risks of sexual dysfunction as a side effect of treatment are very important for patients, although it has received little attention in the literature.
Learn More >Postoperative cognitive dysfunction (POCD) is the collection of cognitive impairments, lasting days to months, experienced by individuals following surgery. Persistent POCD is most commonly experienced by older individuals and is associated with a greater vulnerability to developing Alzheimer's disease, but the underlying mechanisms are not known. It is known that laparotomy (exploratory abdominal surgery) in aged rats produces memory impairments for 4 days. Here we report that postsurgical treatment with morphine extends this deficit to at least 2 months while having no effects in the absence of surgery. Indeed, hippocampal-dependent long-term memory was impaired 2, 4, and 8 weeks postsurgery only in aged, morphine-treated rats. Short-term memory remained intact. Morphine is known to have analgesic effects via μ-opioid receptor activation and neuroinflammatory effects through Toll-like receptor 4 activation. Here we demonstrate that persistent memory deficits were mediated independently of the μ-opioid receptor, suggesting that they were evoked through a neuroinflammatory mechanism and unrelated to pain modulation. In support of this, aged, laparotomized, and morphine-treated rats exhibited increased gene expression of various proinflammatory markers (IL-1β, IL-6, TNFα, NLRP3, HMGB1, TLR2, and TLR4) in the hippocampus at the 2-week time point. Furthermore, central blockade of IL-1β signaling with the specific IL-1 receptor antagonist (IL-1RA), at the time of surgery, completely prevented the memory impairment. Finally, synaptophysin and PSD95 gene expression were significantly dysregulated in the hippocampus of aged, laparotomized, morphine-treated rats, suggesting that impaired synaptic structure and/or function may play a key role in this persistent deficit. This instance of long-term memory impairment following surgery closely mirrors the timeline of persistent POCD in humans and may be useful for future treatment discoveries.
Learn More >To determine the pain intensity of cluster headache through a large survey by comparing it to other painful disorders. Furthermore, to investigate the relationship between maximal pain, autonomic, and other clinical symptoms, as well as demographic attributes of cluster headache.
Learn More >Despite appropriate treatment, many patients who sustain distal radius fractures (DRFs) report persistent wrist pain. Chronic musculoskeletal pain is among the leading health problems in the elderly population associated with significant personal and societal burden.
Learn More >Chronic low back pain (LBP) is a very common health problem worldwide and a major cause of disability. Yet, the lack of quantifiable metrics on which to base clinical decisions leads to imprecise treatments, unnecessary surgery and reduced patient outcomes. Although, the focus of LBP has largely focused on the spine, the literature demonstrates a robust reorganization of the human brain in the setting of LBP. Brain neuroimaging holds promise for the discovery of biomarkers that will improve the treatment of chronic LBP. In this study, we report on morphological changes in cerebral cortical thickness (CT) and resting-state functional connectivity (rsFC) measures as potential brain biomarkers for LBP. Structural MRI scans, resting state functional MRI scans and self-reported clinical scores were collected from 24 LBP patients and 27 age-matched healthy controls (HC). The results suggest widespread differences in CT in LBP patients relative to HC. These differences in CT are correlated with self-reported clinical summary scores, the Physical Component Summary and Mental Component Summary scores. The primary visual, secondary visual and default mode networks showed significant age-corrected increases in connectivity with multiple networks in LBP patients. Cortical regions classified as hubs based on their eigenvector centrality (EC) showed differences in their topology within motor and visual processing regions. Finally, a support vector machine trained using CT to classify LBP subjects from HC achieved an average classification accuracy of 74.51%, AUC = 0.787 (95% CI: 0.66-0.91). The findings from this study suggest widespread changes in CT and rsFC in patients with LBP while a machine learning algorithm trained using CT can predict patient group. Taken together, these findings suggest that CT and rsFC may act as potential biomarkers for LBP to guide therapy.
Learn More >To evaluate evidence from randomised controlled trials and non-randomised controlled trials on the effectiveness of hospital clowns for a range of symptom clusters in children and adolescents admitted to hospital with acute and chronic conditions.
Learn More >Central sensitization is one of the important pathological mechanisms of chronic migraine (CM). Metabolic glutamate receptor 5 (mGluR5) mediates pain by activating various intracellular pathways. However, whether mGluR5 contributes to central sensitization in CM and the exact mechanism remains unclear. Male rats were used to establish a CM model by repeated infusions of inflammatory soup (IS) for 7 days to stimulate the activation of the dural nociceptor. The mechanical and thermal thresholds were used to evaluate allodynia, and central sensitization was assessed by measuring calcitonin gene-related peptide (CGRP) and substance P (SP). Microtubule associated protein 1 light chain 3 (LC3) and p62/SQSTM1 were used to assess autophagy. We found that the expression of mGluR5 in the trigeminal nucleus caudalis (TNC) of CM rats was significantly increased. In addition, the downregulation of mGluR5 activated autophagy by inhibiting the mTOR pathway. Moreover, the activation of autophagy alleviated allodynia and central sensitization in CM rats. This study identified a novel strategy for the treatment of CM; the downregulation of mGluR5 in a rat model of CM decreased the expression of the inflammatory factor interleukin-1 beta (IL-1β) and the central sensitization-associated proteins CGRP and SP by activating autophagy via inhibiting the mTOR pathway.
Learn More >To evaluate the association of routine exercise with headache frequency, intensity, and duration among adults with episodic migraine (EM).
Learn More >To determine whether pollen triggers urologic chronic pelvic pain syndrome (UCPPS) flares.
Learn More >Smokers have a higher incidence of chronic pain than non-smokers, but the neural mechanism is not yet fully understood. Nicotine is the main component of tobacco and acts as an agonist for nicotinic cholinergic receptors (nAChRs) in the nervous system. This study was approved by the IACUC of UM. The effects of chronic nicotine administration on mechanical sensitivity were studied using a rat model. The changes in the expression levels of the α7 isoform of nAChR (α7-nAChR), inflammatory cytokines TNFα and COX-2, as well as the density of neuro-immune cells (astrocytes and microglia) were measured concurrently. The results indicate that long-term nicotine administration induces hypersensitivity to mechanical stimuli, as demonstrated by a significant reduction in the pain perception threshold. In response to nicotine, the expression levels of α7-nAChR increased in the periaqueductal gray matter (PAG) and decreased in the spinal cord. Acute administration of the selective α7-nAChR agonist CDP-Choline reversed this hypersensitivity. Chronic nicotine administration led to an increase of microglial cells in the dorsal horn of the spinal cord and increased expression levels of the cytokines TNFα and COX-2. This study suggests that decreased α7-nAChR expression in the spinal cord, as a result of long-term exposure to nicotine, may be causatively linked to chronic pain. Simultaneously, the increase of neuro-immune factors in the spinal cord is also a potential factor leading to chronic pain.
Learn More >Pain is a core symptom of hidradenitis suppurativa (HS) and is of complex, multifactorial origin. HS patients frequently report typical neuropathic pain qualities, but its prevalence has been poorly described.
Learn More >To create a descriptive profile of chronic pain severity in men with lifetime cumulative violence histories, as a target and/or a perpetrator, and investigate how chronic pain severity is associated with and predicted by lifetime cumulative violence severity and known determinants of chronic pain.
Learn More >Persistent pain during pregnancy is a significant health issue, which could be correlated with psychological distress resulting from inadequate social support. This study aims to investigate whether the relationship between poor social support and antenatal pain is mediated by psychological distress. We also aimed to examine whether social cohesion moderates the influence of psychological distress on the relationship between social support and antenatal pain.
Learn More >To conduct a systematic review of the available literature for primary research articles identifying potential gene mutations, polymorphisms and other molecular regulatory mechanisms related to trigeminal neuralgia in order to identify the genetic and molecular models of primary trigeminal neuralgia currently being investigated.
Learn More >: Erenumab has recently been approved as a pharmacological treatment for the prevention of migraine. However, the incidence estimates of adverse drug reactions (ADRs) were not consistent among studies. Consequently, pooled measures of the incidences of ADRs that accounts for inter-study heterogeneity are desirable. In addition, little is known on the factors leading to such heterogeneity. : Clinical trials evaluating the occurrence of ADRs related to erenumab in migraine patients were searched with Ovid MEDLINE until April 2020. Random intercept models were used to estimate the pooled incidence of the ADRs reported at least in 5 different study populations. To examine whether specific factors correlated with the pooled incidence, we performed random-effects meta-regression. : Of 138 retrieved references, 8 clinical trials were included in the meta-analysis. We observed a significant heterogeneity of the incidence estimates of back pain, influenza, nasopharyngitis, and upper respiratory tract infection (URTI). Most of the observed heterogeneity is ascribed to treatment duration for back pain ( = 0.045), influenza ( < 0.001) and URTI ( < 0.001), and significantly attributed to Body Mass Index (BMI) for nasopharyngitis ( < 0.001). : Back pain, influenza, nasopharyngitis and URTI showed a significant heterogeneity of incidence estimates.
Learn More >Chemotherapy-induced peripheral neuropathy (CIPN) is a dose-limiting adverse event associated with treatment with paclitaxel and other chemotherapeutic agents. The prevention and treatment of CIPN are limited by a lack of understanding of the molecular mechanisms underlying this toxicity. In the current study, a human induced pluripotent stem cell-derived sensory neuron (iPSC-SN) model was developed for the study of chemotherapy-induced neurotoxicity. The iPSC-SNs express proteins characteristic of nociceptor, mechanoreceptor, and proprioceptor sensory neurons and show Ca influx in response to capsaicin, α,β-meATP, and glutamate. The iPSC-SNs are relatively resistant to the cytotoxic effects of paclitaxel, with half-maximal inhibitory concentration (IC ) values of 38.1 µM (95% confidence interval (CI) 22.9-70.9 µM) for 48-hour exposure and 9.3 µM (95% CI 5.7-16.5 µM) for 72-hour treatment. Paclitaxel causes dose-dependent and time-dependent changes in neurite network complexity detected by βIII-tubulin staining and high content imaging. The IC for paclitaxel reduction of neurite area was 1.4 µM (95% CI 0.3-16.9 µM) for 48-hour exposure and 0.6 µM (95% CI 0.09-9.9 µM) for 72-hour exposure. Decreased mitochondrial membrane potential, slower movement of mitochondria down the neurites, and changes in glutamate-induced neuronal excitability were also observed with paclitaxel exposure. The iPSC-SNs were also sensitive to docetaxel, vincristine, and bortezomib. Collectively, these data support the use of iPSC-SNs for detailed mechanistic investigations of genes and pathways implicated in chemotherapy-induced neurotoxicity and the identification of novel therapeutic approaches for its prevention and treatment.
Learn More >Psoriasis is a chronic, immune-mediated dermatologic disorder with a prevalence among children estimated at 0.1%-0.45%, and a median age of onset at approximately 7-10 years. Pediatric psoriasis is known to have negative impacts on health-related quality of life. Among the most bothersome symptoms, itch has been measured using the Itch Numeric Rating Scale (NRS). This study explored the symptom and impacts of itch with pediatric psoriasis patients and evaluated the content validity of the Itch NRS in children.
Learn More >Conditioned pain modulation (CPM) is a centrally processed measure of the net effect of the descending pain pathway. This comprises both the facilitatory as well as the inhibitory effect. In the past, CPM or similar effects have been previously described using different terminologies such as diffuse noxious inhibitory control (DNIC), heterotopic noxious conditioning stimulation (HNCS) or endogenous analgesia (EA). A variety of patient-related factors such as age, gender, hormones, race, genetic and psychological factors have been thought to influence the CPM paradigms. CPM paradigms have also been associated with a wide range of methodological variables including the mode of application of the 'test' as well as the 'conditioning' stimuli. Despite all these variabilities, CPM seems to reliably lend itself to the pain modulation profile concept and could in future become one of the phenotypic biomarkers for pain and also a guide for mechanism-based treatment in chronic pain. Future research should focus on establishing consistent methodologies for measuring CPM and thereby enhancing the robustness of this emerging biomarker for pain.
Learn More >No studies have prospectively investigated headache at onset of first-ever ischemic stroke, along with a large concurrent control group. Our aims were to answer two important questions: 1) are headaches at stroke onset causally related to the stroke and what are their typical clinical characteristics? 2) what aetiology of stroke is associated with these headaches?
Learn More >Prospective cohort study.
Learn More >There is an ongoing established need to develop engaging pain assessment strategies to provide more effective individualized care to pediatric patients with serious illnesses. This study explores the acceptability of wireless devices as one option. To evaluate the ability of wrist-wearable technology to collect physiological data from children with serious illnesses. Single-site prospective observational study conducted between September 2017 and September 2018 at Rady Children's Hospital, San Diego, California, inpatient wards. Pediatric patients with diagnoses of cancer and sickle cell disease admitted to the hospital for acute-on-chronic pain and taking opioid pain medications were asked to complete two 24-hour continuous monitoring periods with the Empatica E4 wristband. Data collected from the device correlated with manually obtained vital signs. Children responded favorably to wearing the device. Participants with reported subjective pain versus no pain had average heart rate increased by 16.4 bpm, skin temperature decreased by 3.5°C, and electrodermal activity decreased by 0.27. This study shows the possibility of collecting continuous biophysical data in a nonobtrusive manner in seriously ill children experiencing acute-on-chronic pain using wearable devices. It provides the framework for larger studies to explore the utility of such data in relation to metrics of pain and suffering in this patient population.
Learn More >Migraine is a common disabling neurological disorder. Current acute treatments for migraine in adolescents are mostly pharmacological and may have limited effectiveness, can cause side effects, and may lead to medication overuse. There is an unmet need for effective and well-tolerated treatments. Remote electrical neuromodulation (REN) is a novel acute treatment of migraine that stimulates upper arm peripheral nerves to induce conditioned pain modulation (CPM)-an endogenous analgesic mechanism. The REN device (Nerivio , Theranica Bio-Electronics Ltd., Israel) is a FDA-authorized device for acute treatment of migraine in adults. This study assessed the efficacy and safety of REN in adolescents with migraine.
Learn More >Chronic nonmalignant pain, sleep disturbances and sleep disorders are highly prevalent conditions among U.S. military veterans. Evidence summaries highlight the influence of sleep on pain outcomes in the general adult population but not for the military veteran population. This is a significant gap as U.S. military veterans are an exceedingly high-risk population for both chronic pain and sleep disturbances and/or disorders. We aimed to review the influence of sleep disturbances and sleep disorders on pain outcomes among veterans with chronic nonmalignant pain. A systematic scoping review was conducted using PubMed/Medline, EMBASE, Scopus, CINAHL, and PsycINFO. Twenty-six out of 1450 studies from initial search were included in this review resulting in a combined sample size of N = 923,434 participants. Sleep disturbances and sleep disorders were associated with worse pain outcomes among veterans with chronic pain. Treatment-induced sleep improvements ameliorated pain outcomes in veterans with sleep disorders and sleep disturbances. Research is indicated to address an overlooked pain treatment opportunity – that of sleep disturbance and sleep disorder management.
Learn More >Orofacial pain features may negatively influence a person's well-being and vice versa. Some aspects of well-being can be measured with axis II instruments that assess patients' psychosocial and behavioral status. The aim of this study was to investigate associations between pain features and psychosocial variables as indicators of well-being. Seven hundred ninety-nine anonymized datasets collected using the Web-based Interdisciplinary Symptom Evaluation (WISE) of patients reporting to the Interdisciplinary Orofacial Pain Unit, University of Zurich, between March 19, 2017 and May 19, 2019, were analyzed. Pain features including intensity, number of locations, impact, and duration were evaluated. Psychometric measures assessed pain-related catastrophizing and disability, illness perception, distress, anxiety, depression, injustice experience, dysmorphic concerns, and insomnia. Most patients were between 30 and 59 years old (58.3%), female (69.8%), working (66.0%), and experienced pain for more than 6 months (68.5%). Pain intensities were higher in women than men and higher in disabled than working patients. Scores indicating elevated stress and depression were also observed in disabled patients. The sample prevalence rates of clinically relevant axis II instrument scores were as follows: Graded Chronic Pain Scale for the Head (GCPS-H), 27%; Patient Health Questionnaire 4 (PHQ4), 21%; PHQ9, 21%; Pain Catastrophizing Scale (PCS), 20%; General Anxiety Disorder 7 (GAD7), 15%; Insomnia Severity Index (ISI), 15%; Injustice Experience Questionnaire (IEQ), 14%; GCPS for the Body (GCPS-B), 13%; PHQ for Stress (PHQstr), 6%; and Dysmorphic Concern Questionnaire (DCQ), 2%. Noteworthy results of correlation analysis of the clinically relevant axis II scores and pain measures were as follows: the PHQstr had moderate associations (0.34-0.43) with the sum of pain intensity at rest and during function, number of pain locations, and typical pain intensity. The IEQ scores were moderately associated with typical pain intensity at 0.39. The DCQ scores were moderately associated with pain extension at 0.41. Moderate correlations of certain pain and well-being measures were found in patients reporting clinically relevant stress, injustice experience, and dysmorphic concern, all of which reflect impaired well-being. PHQ4 is suitable for routine distress screening in the clinical setting.
Learn More >The antinociceptive effect of methadone in the morphine-resistant inflammatory pain state was described in the paw-withdrawal test using the complete Freund's adjuvant (CFA)-induced mouse inflammatory pain model. After intraplantar (i.pl.) injection of CFA, thermal hyperalgesia was observed in the ipsilateral paw. The antinociceptive effects of subcutaneous (s.c.) injection of morphine, fentanyl, and oxycodone against thermal hyperalgesia in the inflammatory pain state were reduced in the ipsilateral paw 7 days after CFA pretreatment. On the contrary, the antinociceptive effect of s.c. injection of methadone was maintained in the ipsilateral paw 7 days after CFA pretreatment. The suppressed morphine antinociception in the CFA model mice was bilaterally restored following s.c. treatment with methadone 20 min prior to or 3 days after CFA pretreatment. The suppressed morphine antinociception was also bilaterally restored by intraperitoneal treatment with MK-801 30 min prior to CFA pretreatment; however, the s.c. injection of morphine 30 min prior to CFA pretreatment failed to restore the suppressed morphine antinociception in the CFA model mice. The expression level of mRNA for µ-opioid receptors 7 days after i.pl. pretreatment was not significantly changed by i.pl. pretreatment with CFA or s.c. pretreatment with methadone. In conclusion, methadone is extremely effective against thermal hyperalgesia in the morphine-resistant inflammatory pain state, and restores suppressed morphine antinociception in the inflammatory pain state without altering the expression level of mRNA for µ-opioid receptors.
Learn More >The ongoing opioid overdose crisis is driven largely by exposure to illicitly-manufactured fentanyl. Preliminary observational and experimental research suggests that cannabis could potentially play a role in reducing use of prescription opioids among individuals with chronic pain. However, there is limited data on the effects of cannabis on illicit opioid consumption, particularly fentanyl, especially among individuals on opioid agonist therapy (OAT). We sought to assess the longitudinal association between cannabis use and exposure to fentanyl among people on OAT.
Learn More >Rodent models of human disease can be valuable for understanding the mechanisms of a disease and for identifying novel therapies. However, it is critical that these models be vetted prior to committing resources to developing novel therapeutics. Failure to confirm the model can lead to significant losses in time and resources. One model used for migraine headache is to administer nitroglycerin to rodents. Nitroglycerin is known to produce migraine-like pain in humans and is presumed to do the same in rodents. It is not known, however, if the mechanism for nitroglycerin headaches involves the same pathological processes as migraine. In the absence of known mechanisms, it becomes imperative that the model not only translates into successful clinical trials but also successfully reverse translates by demonstrating efficacy of current therapeutics. In this study female rats were given nitroglycerin and nociception was evaluated in OPADs. Estrous was not monitored. Based on the ED of nitroglycerin a dose of 10 mg/kg was used for experiments. Sumatriptan, caffeine, buprenorphine and morphine were administered to evaluate the reverse translatability of the model. We found that nitroglycerin did not produce mechanical allodynia in the face of the rats, which is reported to be a consequence of migraine in humans. Nitroglycerin reduced the animals' participation in the assay. The reduced activity was verified using an assay to measure exploratory behavior. Furthermore, the effects of nitroglycerin were not reversed or prevented by agents that are effective acute therapies for migraine. Two interesting findings from this study, however, were that morphine and nitroglycerin interact to increase the rats' tolerance of mechanical stimuli on their faces, and they work in concert to slow down the central motor pattern generator for licking on the reward bottle. These interactions suggest that nitroglycerin generated nitric oxide and mu opioid receptors interact with the same neuronal circuits in an additive manner. The interaction of nitroglycerin and morphine on sensory and motor circuits deserves additional examination. In conclusion, based on the results of this study the use of nitroglycerin at these doses in naïve female rats is not recommended as a model for migraine headaches.
Learn More >The Central Sensitization Inventory (CSI) is often used in clinical settings to screen for the presence of central sensitization. However, various cutoff scores have been reported for this tool, and scores have not been consistently associated with widespread pain sensitivity as measured with quantitative sensory testing (QST). The purpose of this study was to compare QST profiles among asymptomatic controls and participants with chronic musculoskeletal pain (CMP), and to determine the association between self-report questionnaires and QST in participants with CMP.
Learn More >Pain is a common symptom in endodontic conditions, but differential diagnostic procedures are often needed to exclude other pain origins. General dentists and endodontists thus need to be aware of alternative painful orofacial conditions, and be able to identify them. The new International Classification of Orofacial Pain (ICOP, 2020) is the first comprehensive classification that uniquely deals with orofacial pain. The ICOP is a hierarchical classification, modelled on the International Classification of Headache Disorders (ICHD-3) and covers pain in dentoalveolar and anatomically related tissues, muscle pain, temporomandibular joint (TMJ) pain, neuropathic pain affecting cranial nerves, pain resembling primary headaches, and idiopathic pain in the orofacial region. A description of each condition is given, and structured diagnostic criteria for each condition are proposed based on research data when available. This narrative review aims to (i) give an overview and brief explanation of the ICOP system, (ii) describe and give examples of how it can be of use to general dentists and endodontists with special attention to differential diagnosis of tooth pain, and (iii) highlight how endodontic research can contribute to validation and improvement of the classification. A comparison to other classification and diagnostic systems is also included.
Learn More >Dorsal root ganglion stimulation (DRGS) is a promising neurostimulation modality in the treatment of painful polyneuropathy. The aim of this prospective pilot study was to investigate the effect of DRGS on pain intensity in patients with intractable painful polyneuropathy.
Learn More >Although interstitial cystitis/bladder pain syndrome (IC/BPS) is a chronic condition causing bladder pain and urinary symptoms, effective treatments have not been established. The aim of this study was to adapt a chronic cystitis model in rats using lipopolysaccharide (LPS), which reflects IC/BPS pathology, and characterize the model's histological and behavioral effects. Furthermore, we investigated the effect of an α δ subunit ligand, gabapentin (GBP), on bladder hypersensitivity of rats with chronic cystitis. Cystitis models were created by repeated intravesical injections of LPS. In the histological examination, the LPS-injected group had greater inflammatory response, fibrosis, and abnormally thick re-epithelialization. In the LPS-injected group, LPS prompted hyperalgesia in both the lower abdomen and hind paw regions after day 1 of the first injection compared with the saline-injected controls, without any recovery for 21 days at least. During cystometry, the LPS-injected group showed bladder hyperactivity at all times. Systemic administration of GBP reduced cystitis-related pain due to chronic inflammation and reduced the increased frequency of voiding in the LPS-injected group. These results suggest that repeated intravesical injections of LPS induce long-lasting bladder inflammation, pain, and overactivity in rats, while GBP is effective in the management of those symptoms in this chronic cystitis model. The current study identifies a relatively simple method to develop an animal model for chronic cystitis and provides evidence that GBP may be an effective treatment option for patients with IC/BPS.
Learn More >Spinal infections represent a therapeutic challenge. The often protracted course of the disease is accompanied by pain, which can lead to a chronic pain experience even after the infectious disease has been treated successfully. The aim of this study was to investigate possible risk factors of pain chronification.
Learn More >Ankylosing spondylitis (AS) mainly affects the axial skeleton and is an important factor leading to chronic lower back pain in young individuals. However, few studies have explored alterations of brain gray matter volume in AS patients. The purpose of the present study was to describe brain gray matter abnormalities associated with AS pain. A total of 61 AS patients and 52 healthy controls (HCs) were included in this study. Using voxel-based morphometrics, we detected abnormal gray matter volume in AS patients. Based on the voxel-wise analysis, the gray matter volume in the left putamen of the AS group was increased significantly compared with that of the HC group. In addition, we found that the gray matter volume of the left putamen was positively correlated with the duration of AS and total back pain scores, whereas it was not significantly correlated with Bath Ankylosing Spondylitis Disease Activity Index scores, C-reactive protein, or erythrocyte sedimentation rate in AS patients. Taken together, our findings improve our understanding of the neural substrates of pain in AS and provide evidence of AS-related neurological impairment. Hence, further investigation of the pathophysiology of the left putamen in AS is warranted.
Learn More >Spinal manipulative therapy (SMT) helps to reduce chronic low back pain (cLBP). However, the underlying mechanism of pain relief and the neurological response to SMT remains unclear. We utilized brain functional magnetic resonance imaging (fMRI) upon the application of a real-time spot pressure mechanical stimulus to assess the effects of SMT on patients with cLBP. Patients with cLBP (Group 1, = 14) and age-matched healthy controls without cLBP (Group 2, = 20) were prospectively enrolled. Brain fMRI was performed for Group 1 at three time points: before SMT (TP1), after the first SMT session (TP2), and after the sixth SMT session (TP3). The healthy controls (Group 2) did not receive SMT and underwent only one fMRI scan. During fMRI scanning, a real-time spot pressure mechanical stimulus was applied to the low back area of all participants. Participants in Group 1 completed clinical questionnaires assessing pain and quality of life using a visual analog scale (VAS) and the Chinese Short Form Oswestry Disability Index (C-SFODI), respectively. Before SMT (TP1), there were no significant differences in brain activity between Group 1 and Group 2. After the first SMT session (TP2), Group 1 showed significantly greater brain activity in the right parahippocampal gyrus, right dorsolateral prefrontal cortex, and left precuneus compared to Group 2 ( < 0.05). After the sixth SMT session (TP3), Group 1 showed significantly greater brain activity in the posterior cingulate gyrus and right inferior frontal gyrus compared to Group 2 ( < 0.05). After both the first and sixth SMT sessions (TP2 and TP3), Group 1 had significantly lower VAS pain scores and C-SFODI scores than at TP1 ( < 0.001). We observed alterations in brain activity in regions of the default mode network in patients with cLBP after SMT. These findings suggest the potential utility of the default mode network as a neuroimaging biomarker for pain management in patients with cLBP. Chinese Clinical Trial Registry, identifier ChiCTR1800015620.
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