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Papers: 13 Aug 2022 - 19 Aug 2022

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TRPV1 drugs alter core body temperature via central projections of primary afferent sensory neurons.

TRPV1, a capsaicin- and heat-activated ion channel, is expressed by peripheral nociceptors and has been implicated in various inflammatory and neuropathic pain conditions. Although pharmacological modulation of TRPV1 has attracted therapeutic interest, many TRPV1 agonists and antagonists produce thermomodulatory side effects in animal models and human clinical trials, limiting their utility. These on-target effects may result from the perturbation of TRPV1 receptors on nociceptors, which transduce signals to central thermoregulatory circuits and release proinflammatory factors from their peripheral terminals, most notably the potent vasodilative neuropeptide, calcitonin gene-related peptide (CGRP). Alternatively, these body temperature effects may originate from the modulation of TRPV1 on vascular smooth muscle cells (vSMCs), where channel activation promotes arteriole constriction. Here, we ask which of these pathways is most responsible for the body temperature perturbations elicited by TRPV1 drugs in vivo. We address this question by selectively eliminating TRPV1 expression in sensory neurons or vSMCs and show that only the former abrogates agonist-induced hypothermia and antagonist-induced hyperthermia. Furthermore, lesioning the central projections of TRPV1-positive sensory nerve fibers also abrogates drug-mediated thermomodulation, whereas eliminating CGRP has no effect. Thus, TRPV1 drugs alter core body temperature by modulating sensory input to the central nervous system, rather than through peripheral actions on the vasculature. These findings suggest how mechanistically distinct TRPV1 antagonists may diminish inflammatory pain without affecting core body temperature.

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Empowering Physical Therapist Professional Education Programs to Deliver Modern Pain Content.

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The thermal grill illusion of pain in chronic pain patients: a clinical marker of central sensitization?

The thermal grill illusion of pain (TGIP) is a paradoxical burning pain sensation elicited by the simultaneous application of innocuous cutaneous warm and cold stimuli with a thermode ('thermal grill') consisting of interlaced heated and cooled bars. Its neurophysiological mechanisms are unclear, but TGIP may have some mechanisms in common with pathological pain, including central sensitization in particular, through the involvement of N-methyl-D-aspartate (NMDA) receptors. However, few studies have investigated TGIP in chronic pain patients and its clinical relevance is uncertain. We hypothesized that the TGIP would be increased in comparison with controls in patients with fibromyalgia or irritable bowel syndrome (IBS), which are regarded as typical "nociplastic" primary pain syndromes related to changes in central pain processing. We compared the sensations elicited by a large range of combinations of temperature differentials between the warm and cold bars of a thermal grill applied to the hand between patients with fibromyalgia (n = 30) or IBS (n= 30) and controls (n = 30). The percentage of TGIP responses, and the intensity and unpleasantness of TGIP were significantly greater in patients than controls. Furthermore, positive correlations were found between TGIP intensity and clinical pain intensity, and between TGIP intensity and the cold pain threshold measured on the hand. These results are consistent with our working hypothesis of shared mechanisms between TGIP and clinical pain mechanisms in patients with nociplastic chronic pain syndromes and suggest that TGIP might represent a clinical marker of central sensitization in these patients.

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Pronociceptive autoantibodies in the spinal cord mediate nociceptive sensitization, loss of function, and spontaneous pain in the lumbar disk puncture model of chronic back pain.

Previously, we observed that B cells and autoantibodies mediated chronic nociceptive sensitization in the mouse tibia fracture model of complex regional pain syndrome and that complex regional pain syndrome patient antibodies were pronociceptive in fracture mice lacking mature B cells and antibodies (muMT). The current study used a lumbar spinal disk puncture (DP) model of low back pain in wild-type (WT) and muMT mice to evaluate pronociceptive adaptive immune responses. Spinal disks and cords were collected 3 weeks after DP for polymerase chain reaction and immunohistochemistry analyses. Wild-type DP mice developed 24 weeks of hindpaw mechanical allodynia and hyperalgesia, grip weakness, and a conditioned place preference response indicative of spontaneous pain, but pain responses were attenuated or absent in muMT DP mice. Spinal cord expression of inflammatory cytokines, immune cell markers, and complement components were increased in WT DP mice and in muMT DP mice. Dorsal horn immunostaining in WT DP mice demonstrated glial activation and increased complement 5a receptor expressionin spinal neurons. Serum collected from WT DP mice and injected into muMT DP mice caused nociceptive sensitization, as did intrathecal injection of IgM collected from WT DP mice, and IgM immune complexes were observed in lumbar spinal disks and cord of WT DP mice. Serum from WT tibia fracture mice was not pronociceptive in muMT DP mice and vice versa, evidence that each type of tissue trauma chronically generates its own unique antibodies and targeted antigens. These data further support the pronociceptive autoimmunity hypothesis for the transition from tissue injury to chronic musculoskeletal pain state.

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Chronic primary musculoskeletal pain: a new concept of nonstructural regional pain.

The concept that a regional musculoskeletal pain may occur in the absence of identifiable tissue abnormality may be puzzling. Previously these regional complaints were generally categorized as myofascial pain syndromes, or prior to the formalization of the nociplastic pain concept, as musculoskeletal pain with a neuropathic component, and treatments were anatomically focussed. Chronic primary musculoskeletal pain is now identified under the chronic primary pain stem category with the mechanistic descriptor of nociplastic pain. It is possible that many patients previously diagnosed with myofascial pain do in fact suffer from chronic primary musculoskeletal pain, requiring a paradigm shift in management towards more centrally directed treatment strategies. Many questions remain, including validation of the proposed examination techniques, prevalence, ideal treatment, and uptake and acceptance by the healthcare community. This new classification should be welcomed as an explanation for regional pain conditions that previously responded poorly to physically focussed treatments.

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Reconsidering Fordyce’s classic article, “Pain and Suffering: what is the unit?” to help make our model of chronic pain truly biopsychosocial.

The biopsychosocial model (BPS) of chronic pain aspires to be comprehensive, incorporating psychological and social factors omitted from biomedical models. Although psychosocial factors are viewed as highly influential in understanding behavioral and psychological responses to pain, these factors are usually viewed as modifiers of biological causes of the experience of pain itself, rather than as equal contributors to pain. To further advance the BPS model, we re-examine a classic 1994 paper by Wilbert "Bill" Fordyce, "Pain and suffering: what is the unit?" In this paper, Fordyce suggested that pain-related disability and suffering should be viewed as "transdermal", as having causes both inside and outside the body. We consider Fordyce's paper theoretically important because this concept allows us to more fully break free of the medical model of chronic pain than customary formulations of the BPS model. It makes it possible to place psychological and social factors on an equal footing with biological ones in explaining pain itself and to remove distinctions between pain mechanisms and pain meanings. The brain's salience network now offers a platform on which diverse influences on pain experience-from nociception to multisensory indicators of safety or danger-can be integrated, bridging the gap between impersonal nociceptive mechanisms and personal meanings. We also argue that Fordyce's article is practically important because this concept expands the BPS model beyond the bounds of the clinical encounter, opening the door to the full range of social, psychological, and biological interventions, empowering patients and non-medical providers to tackle chronic pain.

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Patient Perceptions About Opioid Risk Communications Within the Context of a Randomized Clinical Trial.

Opioid overdose rates continue to increase, and extant literature suggests that many individuals who use heroin were first introduced to opioids through a medical prescription.

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Efficacy of Ubrogepant in the Acute Treatment of Migraine With Mild Pain Versus Moderate or Severe Pain.

To examine the efficacy of ubrogepant in the treatment of migraine with mild versus moderate or severe pain.

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Evidence-Based Clinical Practice Guidelines for Laser-Assisted Drug Delivery.

Laser-assisted drug delivery (LADD) is used for various medical and cosmetic applications. However, there is insufficient evidence-based guidance to assist clinicians performing LADD.

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Effect of Integrating Access to a Prescription Drug Monitoring Program Within the Electronic Health Record on the Frequency of Queries by Primary Care Clinicians: A Cluster Randomized Clinical Trial.

Tools that are directly integrated with the electronic health record (EHR) workflow can reduce the hassle cost of certain guideline-concordant practices, such as querying a prescription drug monitoring program (PDMP) before prescribing opioids.

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Association of Patient Race and Ethnicity With Differences in Opioid Prescribing by Primary Care Physicians for Older Adults With New Low Back Pain.

Substantial patient racial and ethnic differences in opioid prescribing have been documented, but how much of these differences were attributable to physicians prescribing opioids differently to patients of racial and ethnic minority groups is unknown, particularly during the first wave of the opioid epidemic when the dangers of opioid prescribing and use were not as well known.

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Gonadal hormone-dependent nociceptor sensitization maintains nociplastic pain state in female mice.

Nociplastic pain conditions develop predominantly in women. We recently established a murine nociplastic pain model by applying postinjury thermal (40°C) stimulation to an injured (capsaicin-injected) area, triggering a transition to a nociplastic pain state manifesting as persistent mechanical hypersensitivity outside of the previously injured area. The nociplastic pain state was centrally maintained by spinal microglia in males but peripherally by ongoing afferent activity at the previously injured area in females. Here, we investigated whether gonadal hormones are critical for the development of this peripherally maintained nociplastic pain state in females. Although the transition to a nociplastic pain state still occurred in ovariectomized females, the pain state was maintained neither by ongoing afferent activity at the previously injured area nor by spinal microglia. Estradiol reconstitution a week before the injury plus postinjury stimulation, but not after the transition had already occurred, restored the development of peripherally maintained nociplastic mechanical hypersensitivity in ovariectomized females. G protein-coupled estrogen receptor antagonism during the transition phase mimicked ovariectomy in gonad-intact females, whereas the receptor antagonism after the transition gradually alleviated the nociplastic mechanical hypersensitivity. At the previously injured area, afferents responsive to allyl isothiocyanate (AITC), a TRPA1 agonist, contributed to the maintenance of nociplastic mechanical hypersensitivity in gonad-intact females. In ex vivo skin-nerve preparations, only AITC-responsive afferents from the nociplastic pain model in gonad-intact females showed ongoing activities greater than control. These results suggest that gonadal hormones are critical for peripherally maintained nociplastic pain state in females by sensitizing AITC-responsive afferents to be persistently active.

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Content validity of patient-reported outcome measures for patients with chronic pain: considering the patient’s perspective.

Understanding chronic pain and disability requires a consideration of the lived experience of the patient. There is limited evaluation of the content validity of patient-reported outcome measures (PROMs) in chronic pain using a comprehensive biopsychosocial view of the patient's experience. To address this gap, this study aimed to evaluate the content validity of PROMs for patients with chronic pain. A literature review was performed to identify PROMs for patients with chronic pain. Concepts from PROMs were linked to the International Classification of Functioning, Disability, and Health (ICF); the ICF Core Set for Chronic Widespread Pain; and the International Classification of Diseases-11 Functioning Properties of Chronic Pain (FP). Concepts were compared with published "attributes'' of chronic pain. 62 PROMs (1336 items total) were identified and linked to 560 unique second-level ICF categories. The greatest number of items across PROMs were represented in the activities and participation category (44% of all total items), followed by body functions (41%), environmental factors (9%), personal factors (5%), and body structures (0.3%). There was a 41% to 78% match with the Core Set for Chronic Widespread Pain and the International Classification of Diseases-11 FP, respectively. 20% of items reflected the pain-experience attributes with the most items reflecting the concept of "control over pain." Content validity analysis suggests chronic widespread pain patient-reported outcome measures poorly address attributes of living with chronic pain that matter most to patients. Future development or refinement should consider a more comprehensive view of the patients' lived experience.

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Brain-specific genes contribute to chronic but not to acute back pain.

Back pain is the leading cause of disability worldwide. Although most back pain cases are acute, 20% of acute pain patients experience chronic back pain symptoms. It is unclear whether acute pain and chronic pain have similar or distinct underlying genetic mechanisms.

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Inhibition of itch by neurokinin 1 receptor (Tacr1) -expressing ON cells in the rostral ventromedial medulla in mice.

The rostral ventromedial medulla (RVM) is important in descending modulation of spinal nociceptive transmission, but it is unclear if the RVM also modulates spinal pruriceptive transmission. RVM ON cells are activated by noxious algesic and pruritic stimuli and are pronociceptive. Many RVM-spinal projection neurons express the neurokinin-1 receptor (Tacr1), and ON-cells are excited by local administration of substance P (SP). We hypothesized that Tacr1-expressing RVM ON cells exert an inhibitory effect on itch opposite to their pronociceptive action. Intramedullary microinjection of SP significantly potentiated RVM ON cells and reduced pruritogen-evoked scratching while producing mild mechanical sensitization. Chemogenetic activation of RVM Tacr1-expressing RVM neurons also reduced acute pruritogen-evoked scratching. Optotagging experiments confirmed RVM Tacr1-expressing neurons to be ON cells. We conclude that Tacr1-expressing ON cells in RVM play a significant role in the modulation of pruriceptive transmission.

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Impact of Spinal Cord Stimulation on Sick Leave and Disability Pension in Patients with Chronic Neuropathic Pain: A Real-world Evidence Study in Sweden.

Current research indicates that spinal cord stimulation (SCS) has a positive short-term impact on outcomes such as quality of life, pain, and productivity in patients with chronic neuropathic pain. However, there is a need for studies on larger population samples. This study utilized data from Swedish national registers to analyze change and predictors of sick leave and disability pension two years before and after SCS treatment. Patients with SCS implanted between 2006-2017, and a reference group consisting of 5 individuals matched to each SCS patient without replacement with respect to age, sex, and region of residence, were included. A difference-in-difference approach was used to compare the average change (two years after treatment versus two years before treatment) in net disability days and indirect cost related to disability days for the SCS group, compared to the average change for the reference group. The results showed that SCS treatment in Sweden is associated with a decrease of 21 disability days and consequent decrease in indirect cost of €3,372 in working age patients. Large work loss prior to index date was also demonstrated (average 214 days one year prior), indicating a significant burden on the patient, employers, and the society at large. The number of disability days varied considerably depending on age, sex, socioeconomic variables, and comorbidities, however, the effect of SCS appeared to have little association with patient characteristics. This economic benefit needs to be considered, as well as the clinical outcome, when evaluating the full societal value of SCS.

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Mirror peripheral neuropathy and unilateral chronic neuropathic pain: insights from asymmetric neurological patterns in leprosy.

Leprosy-related multiple mononeuropathy offers a pattern of impairment where neuropathy with and without neuropathic pain (NeP) are present in the same individual, thus allowing to investigate peripheral sensory and innervation in both conditions. This cross-sectional study collected data on clinical and neurological examination, pain-assessment questionnaires, quantitative sensory test, and intraepidermal nerve fiber density (IENFD) of patients with leprosy and divided the cohort into two groups: with (P+) and without NeP (P-). Further, we assessed mirror body areas in the same NeP individuals with bilateral neuropathy also presenting unilateral NeP. Pain-free patients having unilateral neuropathy were controls. A total of 37 P+ patients and 22 P- patients were evaluated. Limb areas with NeP had signs of C-fiber dysfunction and hyperesthesia on QST compared with limb areas having neuropathy without NeP. Skin denervation was found in all leprosy patients. Comparisons of limbs with and without neuropathy, and with and without NeP revealed that higher heat pain thresholds (HPT) were associated with neuropathic pain areas, whereas less altered HPT was correlated with higher fiber density. Furthermore, a relationship was found between time of leprosy treatment termination and more intense neuropathy, expressed by HPT increasing 0.03 °C each month. As expected, interindividual comparisons failed to show differences in IENFD and subepidermal plexus areas between patients P+ and P- (p=0.2980, p = 0.9044; respectively). Higher HPT and lower mechanical detection threshold were related to NeP. The present study pointed out the relevance of intra-individual comparisons including mirror areas when assessing local changes in peripheral NeP.

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Is pain contagious? Innocuous stimulation can be transformed into the pain experience by observational learning.

Studies indicate that classical and operant conditioning have potential to play a role in the formation of the allodynic effect. Only a few studies have examined the role of observational learning in pain induction. Due to some methodological challenges, evidence that the allodynic effect can be learned through observation is limited. In the present study, healthy participants (n = 88) received two series of innocuous electrocutaneous stimuli: at the beginning of the study and after observation of a model who rated all the stimuli as painful. Participants and the model rated all the stimuli alternately (real-time group), or the participant first observed the model and then rated the stimuli, while the model stayed in (post-hoc+ group) or left (post-hoc- group) the laboratory. There was no model in the control group. The study demonstrated that allodynia can be induced by observational learning. Furthermore, this effect was shown to be similar, regardless of whether stimuli were received during the observation of the model and rated immediately afterwards, or when the observation and stimuli reception were time-separated. The mere presence of the model during the stimuli reception also did not affect the magnitude of this effect. This research may contribute to our understanding of the mechanisms of chronic pain development and assist in the development of suitable treatment for it. Perspective. This article presents study results on the role of observational learning in allodynia induction without tissue injury. The results may contribute to our understanding of the mechanisms of chronic pain development and assist in the development of suitable treatment for it.

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Epigenetic age predictors in community-dwelling adults with high impact knee pain.

Gerontological research reveals considerable interindividual variability in aging phenotypes, and emerging evidence suggests that high impact chronic pain may be associated with various accelerated biological aging processes. In particular, epigenetic aging is a robust predictor of health-span and disability compared to chronological age alone. The current study aimed to determine whether several epigenetic aging biomarkers were associated with high impact chronic pain in middle to older age adults (44-78 years old). Participants ( = 213) underwent a blood draw, demographic, psychosocial, pain and functional assessments. We estimated five epigenetic clocks and calculated the difference between epigenetic age and chronological age, which has been previously reported to predict overall mortality risk, as well as included additional derived variables of epigenetic age previously associated with pain. There were significant differences across Pain Impact groups in three out of the five epigenetic clocks examined (DNAmAge, DNAmPhenoAge and DNAmGrimAge), indicating that pain-related disability during the past 6 months was associated with markers of epigenetic aging. Only DNAmPhenoAge and DNAmGrimAge were associated with higher knee pain intensity during the past 48 h. Finally, pain catastrophizing, depressive symptomatology and more neuropathic pain symptoms were significantly associated with an older epigenome in only one of the five epigenetic clocks (i.e. DNAmGrimAge) after correcting for multiple comparisons (corrected 's < 0.05). Given the scant literature in relation to epigenetic aging and the complex experience of pain, additional research is needed to understand whether epigenetic aging may help identify people with chronic pain at greater risk of functional decline and poorer health outcomes.

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P2Y receptor in trigeminal ganglion contributes to neuropathic pain in mice.

Trigeminal nerve injury is a common complication of various dental and oral procedures, which could induce trigeminal neuropathic pain but lack effective treatments. P2 purinergic receptors have emerged as novel therapeutic targets for such pain. Recent reports implied that the P2Y receptor (P2YR) was activated and promoted orofacial inflammatory pain and migraine. However, the role and mechanism of P2YR in trigeminal neuropathic pain remain unknown. We induced an orofacial neuropathic pain model by chronic constriction injury of the infraorbital nerve (CCI-ION). Von-Frey tests showed that CCI-ION induced orofacial mechanical hypersensitivity. The increased activating transcription factor 3 (ATF3) expression in the trigeminal ganglion (TG) measured by immunofluorescence confirmed trigeminal nerve injury. Immunofluorescence showed that P2YR was expressed in trigeminal ganglion neurons (TGNs) and satellite glial cells (SGCs). RT-qPCR and Western blot identified increased expression of P2YR in TG after CCI-ION. CCI-ION also upregulated interleukin-1β (IL-1β), interleukin-6 (IL-6), C-C motif chemokine ligand 2 (CCL2), and tumor necrosis factor-α (TNF-α) in TG. Notably, CCI-ION-induced mechanical hypersensitivity and pro-inflammatory cytokines production were decreased by a P2YR antagonist (PPTN). Trigeminal administration of P2YR agonist (UDP-glucose) evoked orofacial mechanical hypersensitivity and increased pro-inflammatory cytokines above in TG. Furthermore, CCI-ION induced activation of extracellular signal-regulated kinase 1/2 (ERK1/2) and p38 in TG, which also were reduced by PPTN. The inhibitors of ERK1/2 (U0126) and p38 (SB203580) decreased these upregulated pro-inflammatory cytokines after CCI-ION. Collectively, this study revealed that P2YR in TG contributed to trigeminal neuropathic pain via ERK- and p38-dependent neuroinflammation. Thus, P2YR may be a potential drug target against trigeminal neuropathic pain.

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Efficacy of lasmiditan for the acute treatment of perimenstrual migraine.

Perimenstrual migraine attacks in women with menstrual migraine is difficult to treat. This post-hoc analysis evaluated the efficacy of lasmiditan, a high affinity and selective 5-HT receptor agonist, for perimenstrual attacks.

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Pain relief after topical capsaicin: does it result from nociceptor degeneration or regeneration?

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Quantitative sensory testing in paediatric patients with chronic pain: a systematic review and meta-analysis.

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In the back of your mind: Cortical mapping of paraspinal afferent inputs.

Topographic organisation is a hallmark of vertebrate cortex architecture, characterised by ordered projections of the body's sensory surfaces onto brain systems. High-resolution functional magnetic resonance imaging (fMRI) has proven itself as a valuable tool to investigate the cortical landscape and its (mal-)adaptive plasticity with respect to various body part representations, in particular extremities such as the hand and fingers. Less is known, however, about the cortical representation of the human back. We therefore validated a novel, MRI-compatible method of mapping cortical representations of sensory afferents of the back, using vibrotactile stimulation at varying frequencies and paraspinal locations, in conjunction with fMRI. We expected high-frequency stimulation to be associated with differential neuronal activity in the primary somatosensory cortex (S1) compared with low-frequency stimulation and that somatosensory representations would differ across the thoracolumbar axis. We found significant differences between neural representations of high-frequency and low-frequency stimulation and between representations of thoracic and lumbar paraspinal locations, in several bilateral S1 sub-regions, and in regions of the primary motor cortex (M1). High-frequency stimulation preferentially activated Brodmann Area (BA) regions BA3a and BA4p, whereas low-frequency stimulation was more encoded in BA3b and BA4a. Moreover, we found clear topographic differences in S1 for representations of the upper and lower back during high-frequency stimulation. We present the first neurobiological validation of a method for establishing detailed cortical maps of the human back, which might serve as a novel tool to evaluate the pathological significance of neuroplastic changes in clinical conditions such as chronic low back pain.

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Unravelling the role of unmyelinated nerve fibres in trigeminal neuralgia with concomitant continuous pain.

In this clinical and neurophysiological study, we aimed to test trigeminal nerve fibre function in patients with trigeminal neuralgia, with and without concomitant continuous pain.

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Reduced postoperative pain in patients receiving nociception monitor guided analgesia during elective major abdominal surgery: a randomized, controlled trial.

The Nociception Level index (NOL™) is a multiparameter index, based on artificial intelligence for the monitoring of nociception during anesthesia. We studied the influence of NOL-guided analgesia on postoperative pain scores in patients undergoing major abdominal surgery during sevoflurane/fentanyl anesthesia. This study was designed as a single-center, prospective randomized, controlled study. After Institutional Review Board approval and written informed consent, 75 ASA 1-3 adult patients undergoing major abdominal surgery, were randomized to NOL-guided fentanyl dosing (NOL) or standard care (SOC) and completed the study. The sevoflurane target MAC range was 0.8-1.2. In the NOL-guided group (N = 36), when NOL values were > 25 for at least 1 min, a weight adjusted fentanyl bolus was administered. In the control group (N = 39) fentanyl administration was based on hemodynamic indices and clinician judgement. After surgery, pain, was evaluated using the Numerical Rating Scale (NRS) pain scale, ranging from 0 to 10, at 15 min intervals for 180 min or until patient discharge from the PACU. Median postoperative pain scores reported were 3.0 [interquartile range 0.0-5.0] and 5.0 [3.0-6.0] at 90 min in NOL-guided and control groups respectively (Bootstrap corrected actual difference 1.5, 95% confidence interval 0.4-2.6). There was no difference in postoperative morphine consumption or intraoperative fentanyl consumption. Postoperative pain scores were significantly improved in nociception level index-guided patients. We attribute this to more objective fentanyl dosing when timed to actual nociceptive stimuli during anesthesia, contributing to lower levels of sympathetic activation and surgical stress. Clinicaltrials.gov identifier: NCT03970291 date of registration May 31, 2019.

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Chemogenetic and Optogenetic Manipulations of Microglia in Chronic Pain.

Chronic pain relief remains an unmet medical need. Current research points to a substantial contribution of glia-neuron interaction in its pathogenesis. Particularly, microglia play a crucial role in the development of chronic pain. To better understand the microglial contribution to chronic pain, specific regional and temporal manipulations of microglia are necessary. Recently, two new approaches have emerged that meet these demands. Chemogenetic tools allow the expression of designer receptors exclusively activated by designer drugs (DREADDs) specifically in microglia. Similarly, optogenetic tools allow for microglial manipulation via the activation of artificially expressed, light-sensitive proteins. Chemo- and optogenetic manipulations of microglia in vivo are powerful in interrogating microglial function in chronic pain. This review summarizes these emerging tools in studying the role of microglia in chronic pain and highlights their potential applications in microglia-related neurological disorders.

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New trigeminal stimulation technique with dorsal root ganglion stimulation electrode and maxillary fixation: technique description.

Trigeminal neuralgia is considered the worst pain a human being can experience. Initial treatment utilizes anticonvulsant sodium channel blockers, which relieve pain in approximately 70% of patients. In refractory cases, it is possible to perform ablative treatments decompressive surgeries and neuromodulatory techniques. This report describes the treatment of a patient with refractory trigeminal neuralgia, remaining with a painful clinical picture after four surgical procedures and three ablative procedures. A dorsal root ganglion (DRG) stimulation electrode was implanted in the trigeminal ganglion, through intraoral puncture with maxillary fixation of the electrode, in order to minimize the chances of displacement. The test phase consisted of implanting a quadripolar electrode for DRG stimulation through puncture lateral to the buccal rim in a fluoroscopic coaxial view. The electrode was fixed to the skin and maintained for five days, during which the patient remained completely pain-free. After the test, the definitive implant was performed, now with intraoral puncture and maxillary electrode fixation. The patient presented with severe pain (verbal numerical scale between 9 and 10), manifesting an evident suicidal ideation. After a five-day test period, the definitive stimulation electrode was implanted through intraoral puncture. The patient remains pain-free in the three-month follow-up to the present, with no displacement of the electrode. The dorsal root ganglion electrode may be considered a therapeutic option in patients with severe trigeminal neuralgia. Controlled studies must be performed in order to determine the efficacy and safety of the method.

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Chronic musculoskeletal pain: traps and pitfalls in classification and management of a major global disease burden.

Mary-Ann Fitzcharles et al. propose to introduce "regional fibromyalgia" as a new diagnosis. This commentary summarizes why this term is misleading but nonetheless the article may pave the way towards useful concepts for myofascial pains.

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Clarifying “chronic primary musculoskeletal pain”? The waters remain murky.

: Fitzcharles M-A, Cohen SP, Clauw DJ, Littlejohn G, Usui C, Häuser W. Chronic primary musculoskeletal pain: a new concept of non-structural regional pain. PAIN Reports 2022;7:e1024. : Treede R-D. Chronic musculoskeletal pain: traps and pitfalls in classification and management of a major global disease burden. PAIN Reports 2022;7:e1023.

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Microstructure in patients with visual snow syndrome: an ultra-high field morphological and quantitative MRI study.

Visual snow syndrome is a neurological condition characterized by continuous visual disturbance and a range of non-visual symptoms, including tinnitus and migraine. Little is known about the pathological mechanisms underlying visual snow syndrome. Here, we assessed brain morphometry and microstructure in visual snow syndrome patients using high-resolution structural and quantitative MRI. Forty visual snow syndrome patients (22 with migraine) and 43 controls underwent 7-Tesla MRI (MP2RAGE, 0.75 mm isotropic resolution). Volumetric and quantitative T1 values were extracted for white and grey matter regions and compared between groups. Where regions were significantly different between groups (false discovery rate corrected for multiple comparisons), comparisons were examined between patients with and without migraine. For visual snow syndrome patients, significant MRI variables were correlated with clinical severity (number of visual symptoms, perceived visual snow intensity, disruptiveness, fatigue and quality of life) and psychiatric symptoms prevalent in visual snow syndrome (depression, anxiety and depersonalization). Finally, cortical regions and individual thalamic nuclei were studied. Compared with controls, visual snow syndrome patients demonstrated a trend towards larger brain and white matter volumes and significantly lower T1 values for the entire cortex ( < 0.001), thalamus ( = 0.001) and pallidum ( = 0.001). For the patient group, thalamic T1 correlated with number of visual symptoms ( = 0.019,  = 0.390) and perceived disruptiveness of visual snow ( = 0.010,  = 0.424). These correlations did not survive multiple comparison corrections. As for specificity in visual snow syndrome group, T1 changes were most evident in caudal regions (occipital cortices) followed by parietal, temporal and prefrontal cortices. T1 values differed between groups for most individual thalamic nuclei. No differences were revealed between patients with and without migraine. In visual snow syndrome patients, we observed no changes in morphometry, instead widespread changes in grey matter microstructure, which followed a caudal-rostral pattern and affected the occipital cortices most profoundly. Migraine did not appear to independently affect these changes. Lower T1 values may potentially result from higher neurite density, myelination or increased iron levels in the visual snow syndrome brain. Further investigation of these changes may enhance our understanding of the pathogenesis of visual snow syndrome, ultimately leading to new treatment strategies.

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Persistent inflammatory pain is linked with anxiety-like behaviors, increased blood corticosterone, and reduced global DNA methylation in the rat amygdala.

Chronic pain increases the risk of developing anxiety, with limbic areas being likely neurological substrates. Despite high clinical relevance, little is known about the precise behavioral, hormonal, and brain neuroplastic correlates of anxiety in the context of persistent pain. Previous studies have shown that decreased nociceptive thresholds in chronic pain models are paralleled by anxiety-like behavior in rats, but there are conflicting ideas regarding its effects on the stress response and circulating corticosterone levels. Even less is known about the molecular mechanisms through which the brain encodes pain-related anxiety. This study examines how persistent inflammatory pain in a rat model would impact anxiety-like behaviors and corticosterone release, and whether these changes would be reflected in levels of global DNA methylation in brain areas involved in stress regulation. Complete Freund's adjuvant (CFA) or saline was administered in the right hindpaw of adult male Wistar rats. Behavioral testing included the measurement of nociceptive thresholds (digital anesthesiometer), motor function (open field test), and anxiety-like behaviors (elevated plus maze and the dark-light box test). Corticosterone was measured via radioimmunoassay. Global DNA methylation (enzyme immunoassay) as well as DNMT3a levels (western blotting) were quantified in the amygdala, prefrontal cortex, and ventral hippocampus. CFA administration resulted in persistent reduction in nociceptive threshold in the absence of locomotor abnormalities. Increased anxiety-like behaviors were observed in the elevated plus maze and were accompanied by increased blood corticosterone levels 10 days after pain induction. Global DNA methylation was decreased in the amygdala, with no changes in DNMT3a abundance in any of the regions examined. Persistent inflammatory pain promotes anxiety -like behaviors, HPA axis activation, and epigenetic regulation through DNA methylation in the amygdala. These findings describe a molecular mechanism that links pain and stress in a well-characterized rodent model.

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Peripheral N-methyl-D-aspartate receptor activation contributes to monosodium glutamate-induced headache but not nausea behaviours in rats.

Monosodium glutamate induces behaviors thought to reflect headache and nausea in rats. We explored the effects of the N-methyl-D-aspartate receptor antagonist (2R)-amino-5-phosphonovaleric acid, the inotropic glutamate receptor antagonist kynurenic acid, and the CGRP receptor antagonist olcegepant, on monosodium glutamate-induced increases in nocifensive, headache-like and nausea behaviours. Effects of these antagonists on motor function were examined with a rotarod. The effect of the dopamine receptor antagonist metoclopramide and the serotonin 3 receptor antagonist ondansetron on nausea behaviour was also assessed. (2R)-amino-5-phosphonovaleric acid, and to a lesser extent, kynurenic acid and olcegepant, reduced nocifensive and headache-like behaviours evoked by monosodium glutamate. No alteration in motor function by (2R)-amino-5-phosphonovaleric acid, kynurenic acid or olcegepant was observed. No sex-related differences in the effectiveness of these agents were identified. Nausea behaviour was significantly more pronounced in male than in female rats. Olcegepant, ondansetron and metoclopramide ameliorated this nausea behaviour in male rats. Ondansetron and metoclopramide also reduced headache-like behaviour in male rats. These findings suggest that peripheral N-methyl-D-aspartate receptor activation underlies monosodium glutamate-induced headache-like behaviour but does not mediate the nausea behaviour in rats.

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Effects of remifentanil on brain responses to noxious stimuli during deep propofol sedation.

The safety of anaesthesia has improved as a result of better control of anaesthetic depth. However, conventional monitoring does not inform on the nature of nociceptive processes during unconsciousness. A means of inferring the quality of potentially painful experiences could derive from analysis of brain activity using neuroimaging. We have evaluated the dose effects of remifentanil on brain response to noxious stimuli during deep sedation and spontaneous breathing.

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Excess intracellular ATP causes neuropathic pain following spinal cord injury.

Intractable neuropathic pain following spinal cord injury (NP-SCI) reduces a patient's quality of life. Excessive release of ATP into the extracellular space evokes neuroinflammation via purinergic receptor. Neuroinflammation plays an important role in the initiation and maintenance of NP. However, little is known about whether or not extracellular ATP cause NP-SCI. We found in the present study that excess of intracellular ATP at the lesion site evokes at-level NP-SCI. No significant differences in the body weight, locomotor function, or motor behaviors were found in groups that were negative and positive for at-level allodynia. The intracellular ATP level at the lesion site was significantly higher in the allodynia-positive mice than in the allodynia-negative mice. A metabolome analysis revealed that there were no significant differences in the ATP production or degradation between allodynia-negative and allodynia-positive mice. Dorsal horn neurons in allodynia mice were found to be inactivated in the resting state, suggesting that decreased ATP consumption due to neural inactivity leads to a build-up of intracellular ATP. In contrast to the findings in the resting state, mechanical stimulation increased the neural activity of dorsal horn and extracellular ATP release at lesion site. The forced production of intracellular ATP at the lesion site in non-allodynia mice induced allodynia. The inhibition of P2X4 receptors in allodynia mice reduced allodynia. These results suggest that an excess buildup of intracellular ATP in the resting state causes at-level NP-SCI as a result of the extracellular release of ATP with mechanical stimulation.

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Chronic Pelvic Pain Profiles in Women Seeking Care in a Tertiary Pelvic Pain Clinic.

Female chronic pelvic pain (CPP) has multiple pain generators and significant psychosocial sequalae. Biopsychosocial-based phenotyping could help identify clinical heterogeneity that may inform tailored patient treatment. This study sought to identify distinct CPP profiles based on routinely collected clinical information and evaluate the validity of the profiles through associations with social histories and subsequent health care utilization.

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Soluplus®-based dissolving microarray patches loaded with colchicine: towards a minimally invasive treatment and management of gout.

Considered as one of the most common inflammatory arthritis, gout is characterised by a sudden onset of severe joint pain. As the first-line drug of choice used in treating acute gout, colchicine (CLC) is hindered by poor gastrointestinal permeability as well as unfavourable gastrointestinal side effects. Herein, we present, for the first time, the preparation of microarray array patches (MAPs) made of a polymeric solubiliser, Soluplus®, loaded with CLC for its systemic delivery. The fabricated MAPs displayed acceptable mechanical properties and were capable of being inserted into the skin to a depth of ≈500 μm in full thickness neonatal porcine skin, as evidenced by optical coherence tomography. dermatokinetic studies utilising full thickness neonatal porcine skin demonstrated that the CLC-loaded MAPs delivered CLC across all skin strata, resulting in a delivery efficiency of 73% after 24 hours. Furthermore, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) and cell proliferation assays along with LIVE/DEAD™ staining on the 3T3-L1 cell line showed that the MAP formulation displayed minimal toxicity, with acceptable biocompatibility. Lastly, the anti-inflammatory properties of the formulation were evaluated using a THP-1 macrophage cell line. It was shown that treatment of THP-1 macrophages that are exposed to lipopolysaccharide (LPS) with CLC-loaded MAPs caused a significant ( < 0.05) reduction of TNF-α production, a pro-inflammatory cytokine typically associated with the early onset of acute gout. Accordingly, CLC-loaded MAPs could represent a new minimally-invasive alternative strategy for management of acute gout.

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Short Report of Longitudinal CGRP-Measurements in Migraineurs During a Hypoxic Challenge.

Calcitonin gene related peptide (CGRP) plays a key role in the pathophysiology of migraine and is therefore considered a potential biomarker for primary headache disorders. The challenge remaining is establishing standardized protocols for its assessment in various extracellular compartments and identifying pathological situations associated with an increase in CGRP.

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Source localized infraslow neurofeedback training in people with chronic painful knee osteoarthritis: A randomized, double-blind, sham-controlled feasibility clinical trial.

Persistent pain is a key symptom in people living with knee osteoarthritis (KOA). Infra-slow Neurofeedback (ISF-NF) training is a recent development focusing on modulating cortical slow-wave activity to improve pain outcomes. A parallel, two-armed double-blinded, randomized sham-controlled, feasibility clinical trial aimed to determine the feasibility and safety of a novel electroencephalography-based infraslow fluctuation neurofeedback (EEG ISF-NF) training in people with KOA and determine the variability of clinical outcomes and EEG changes following NF training. Eligible participants attended nine 30-min ISF-NF training sessions involving three cortical regions linked to pain. Feasibility measures were monitored during the trial period. Pain and functional outcomes were measured at baseline, post-intervention, and follow-up after 2 weeks. Resting-state EEG was recorded at baseline and immediate post-intervention. Participants were middle-aged (61.7 ± 7.6 years), New Zealand European (90.5%), and mostly females (62%) with an average knee pain duration of 4 ± 3.4 years. The study achieved a retention rate of 91%, with 20/22 participants completing all the sessions. Participants rated high levels of acceptance and "moderate to high levels of perceived effectiveness of the training." No serious adverse events were reported during the trial. Mean difference (95% CI) for clinical pain and function measures are as follows for pain severity [active: 0.89 ± 1.7 (-0.27 to 2.0); sham: 0.98 ± 1.1 (0.22-1.7)], pain interference [active: 0.75 ± 2.3 (-0.82 to 2.3); Sham: 0.89 ± 2.1 (-0.60 to 2.4)], pain unpleasantness [active: 2.6 ± 3.7 (0.17-5.1); sham: 2.8 ± 3 (0.62-5.0)] and physical function [active: 6.2 ± 13 (-2.6 to 15); sham: 1.6 ± 12 (-6.8 to 10)]. EEG sources demonstrated frequency-specific neuronal activity, functional connectivity, and ISF ratio changes following NF training. The findings of the study indicated that the ISF-NF training is a feasible, safe, and acceptable intervention for pain management in people with KOA, with high levels of perceived effectiveness. The study also reports the variability in clinical, brain activity, and connectivity changes following training.

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NF-κB and AP-1 are required for the lipopolysaccharide-induced expression of MCP-1, CXCL1, and Cx43 in cultured rat dorsal spinal cord astrocytes.

TLR4 and Cx43 signaling in dorsal spinal cord has been shown to be involved in the development of neuropathic pain. However, it is not clear whether TLR4 signaling is associated with the expression of MCP-1, CXCL1, and Cx43 in LPS (lipopolysaccharide)-treated rat dorsal spinal cord astrocytes under condition. In the present study, we found that TLR4 antagonist TAK-242 significantly inhibited LPS-induced MCP-1, CXCL1, and Cx43 expression, suggesting the role of TLR4 in response to LPS in cultured dorsal spinal cord astrocytes. Application of TAK-242 significantly blocked LPS-induced NF-κB and AP-1 activity and the expression of MCP-1, CXCL1 and Cx43. Furthermore, NF-κB inhibitor PDTC and AP-1 inhibitor SR11302 significantly blocked LPS-induced MCP-1, CXCL1, and Cx43 expression. DNA-binding activity of NF-κB, its effect on MCP-1 expression was suppressed by PDTC and SR11302. On the other hand, DNA-binding activity of AP-1, its effect on CXCL1 or Cx43 expression was also suppressed by PDTC and SR11302. In addition, PDTC was found to inhibit the nuclear translocation of AP-1 and the expression of c-Jun induced by LPS, which suggested that NF-κBp65 is essential for the AP-1 activity. Similarly, SR11302 significantly blocked LPS-induced the nuclear translocation of NF-κBp65 and the expression of NF-κBp65 induced by LPS. Pretreatment with CBX, Gap26, or Gap19 (Cx43 blockers) significantly inhibited abnormal astrocytic hemichannel opening and chemokines (MCP-1 and CXCL1) release in LPS-stimulated astrocytes. In summary, cell culture experiments revealed that LPS stimulation could evoke TLR4 signaling with the subsequent activation of NF-κB and AP-1, resulting in the expression of MCP-1, CXCL1, and Cx43. TLR4 activation increased Cx43 hemichannel, but not gap-junction activities and induced the release of the MCP-1 and CXCL1 from astrocytes via Cx43 hemichannel. These findings may help us to understand the role of astrocytic signaling in inflammatory response within dorsal spinal cord tissue.

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Profiling of fatty acid metabolism in the dorsal root ganglion after peripheral nerve injury.

Peripheral nerve injury (PNI) induces neuronal hyperexcitability, which underlies neuropathic pain. The emergence of RNA sequencing technologies has enabled profiling of transcriptional changes in pathological conditions. However, these approaches do not provide information regarding metabolites such as lipids that are not directly encoded by genes. Fatty acids (FAs) are some of the essential lipids in mammalian organisms and are mainly stored as membrane phospholipids. In response to various biological stimuli, FAs are rapidly released and converted into several mediators, such as eicosanoids and docosanoids. FAs themselves or their metabolites play important roles in physiology and pathology. In this study, using a comprehensive lipidomic analysis of FA metabolites, 152 species were measured in the dorsal root ganglia of mice at multiple time points after PNI. We found that PNI increased the ω-6 FA metabolites produced by cyclooxygenases but not those produced by lipoxygenases or cytochrome P450 enzymes in the dorsal root ganglia. In contrast, ω-3 FA metabolites biosynthesized by any enzyme transiently increased after nerve injury. Overall, these findings provide a new resource and valuable insights into PNI pathologies, including pain and nerve regeneration.

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Long-Term Prophylactic Transcranial Direct Current Stimulation Ameliorates Allodynia and Improves Clinical Outcomes in Individuals With Migraine.

Migraine is a common and substantially debilitating disorder that may associate with allodynia, a marker of central sensitization in the pain circuits. Several unmet needs, like limited adherence to drugs due to adverse events and cost-effectivity, still occur in the prophylactic treatment of migraine. Transcranial direct current stimulation (tDCS) has recently been indicated to be beneficial in individuals with migraine with and without allodynia. However, to our knowledge, there are no studies evaluating the efficacy of six-month tDCS in migraine.

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Diagnosis of temporomandibular disorders using artificial intelligence technologies: A systematic review and meta-analysis.

Artificial intelligence (AI) algorithms have been applied to diagnose temporomandibular disorders (TMDs). However, studies have used different patient selection criteria, disease subtypes, input data, and outcome measures. Resultantly, the performance of the AI models varies.

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Efficacy and Safety of Erenumab, Galcanezumab, and Fremanezumab in the Treatment of Drug-Resistant Chronic Migraine: Experience in Real Clinical Practice.

Due to the recent introduction of new biologic drugs for chronic migraine, a global evaluation in real clinical practice is necessary.

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Acyloxyacyl hydrolase regulates microglia-mediated pelvic pain.

Chronic pelvic pain conditions such as interstitial cystitis/bladder pain syndrome (IC/BPS) remain clinical and mechanistic enigmas. Microglia are resident immune cells of the central nervous system (CNS) that respond to changes in the gut microbiome, and studies have linked microglial activation to acute and chronic pain in a variety of models, including pelvic pain. We have previously reported that mice deficient for the lipase acyloxyacyl hydrolase (AOAH) develop pelvic allodynia and exhibit symptoms, comorbidities, and gut dysbiosis mimicking IC/BPS. Here, we assessed the role of AOAH in microglial activation and pelvic pain. RNAseq analyses using the ARCHS4 database and confocal microscopy revealed that AOAH is highly expressed in wild type microglia but at low levels in astrocytes, suggesting a functional role for AOAH in microglia. Pharmacologic ablation of CNS microglia with PLX5622 resulted in decreased pelvic allodynia in AOAH-deficient mice and resurgence of pelvic pain upon drug washout. Skeletal analyses revealed that AOAH-deficient mice have an activated microglia morphology in the medial prefrontal cortex and paraventricular nucleus, brain regions associated with pain modulation. Because microglia express Toll-like receptors and respond to microbial components, we also examine the potential role of dysbiosis in microglial activation. Consistent with our hypothesis of microglia activation by leakage of gut microbes, we observed increased serum endotoxins in AOAH-deficient mice and increased activation of cultured BV2 microglial cells by stool of AOAH-deficient mice. Together, these findings demonstrate a role for AOAH in microglial modulation of pelvic pain and thus identify a novel therapeutic target for IC/BPS.

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What role of the cGAS-STING pathway plays in chronic pain?

Chronic pain interferes with daily functioning and is frequently accompanied by depression. Currently, traditional clinic treatments do not produce satisfactory analgesic effects and frequently result in various adverse effects. Pathogen recognition receptors (PRRs) serve as innate cellular sensors of danger signals, sense invading microorganisms, and initiate innate and adaptive immune responses. Among them, cGAS-STING alerts on the presence of both exogenous and endogenous DNA in the cytoplasm, and this pathway has been closely linked to multiple diseases, including auto-inflammation, virus infection, and cancer. An increasing numbers of evidence suggest that cGAS-STING pathway involves in the chronic pain process; however, its role remains controversial. In this narrative review, we summarize the recent findings on the involvement of the cGAS-STING pathway in chronic pain, as well as several possible mechanisms underlying its activation. As a new area of research, this review is unique in considering the cGAS-STING pathway in sensory neurons and glial cells as a part of a broader understanding of pain, including potential mechanisms of inflammation, immunity, apoptosis, and autophagy. It will provide new insight into the treatment of pain in the future.

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Kappa opioids inhibit the GABA/glycine terminals of rostral ventromedial medulla projections in the superficial dorsal horn of the spinal cord.

Descending projections from neurons in the rostral ventromedial medulla (RVM) make synapses within the superficial dorsal horn (SDH) of the spinal cord that are involved in the modulation of nociception, the development of chronic pain and itch, and an important analgesic target for opioids. This projection is primarily inhibitory, but the relative contribution of GABAergic and glycinergic transmission is unknown and there is limited knowledge about the SDH neurons targeted. Additionally, the details of how spinal opioids mediate analgesia remain unclear, and no study has investigated the opioid modulation of this synapse. We address this using ex vivo optogenetic stimulation of RVM fibres in conjunction with whole-cell patch-clamp recordings from the SDH in spinal cord slices. We demonstrate that both GABAergic and glycinergic neurotransmission is employed and show that SDH target neurons have diverse morphological and electrical properties, consistent with both inhibitory and excitatory interneurons. Then, we describe a subtype of SDH neurons that have a glycine-dominant input, indicating that the quality of descending inhibition across cells is not uniform. Finally, we discovered that the kappa-opioid receptor agonist U69593 presynaptically suppressed most RVM-SDH synapses. By contrast, the mu-opioid receptor agonist DAMGO acted both pre- and post-synaptically at a subset of synapses, and the delta-opioid receptor agonist deltorphin II had little effect. These data provide important mechanistic information about a descending control pathway that regulates spinal circuits. This information is necessary to understand how sensory inputs are shaped and develop more reliable and effective alternatives to current opioid analgesics. Abstract figure legend We combined ex vivo optogenetic stimulation of RVM fibres with whole cell electrophysiology of SDH neurons to investigate the final synapse in a key descending pain modulatory pathway. We demonstrate that both glycine and GABA mediate signalling at the RVM-SDH synapse, that the SDH targets of RVM projections have diverse electrical and morphological characteristics, and that presynaptic inhibition is directly and consistently achieved by kappa opioid agonists. Opioid receptors shown are sized relative to the proportion of neurons that responded to its specific agonists (81 and 84percent of DF and non-DF neurons responded to kappa opioid receptor agonists, respectively. Responses that occurred in <255 percentage of neurons are not indicated here). This article is protected by copyright. All rights reserved.

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Periarticular Injection in Total Joint Arthroplasty: The Clinical Practice Guidelines of the American Association of Hip and Knee Surgeons, American Society of Regional Anesthesia and Pain Medicine, American Academy of Orthopaedic Surgeons, Hip Society, a

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Research progress of targeting NLRP3 inflammasome in peripheral nerve injury and pain.

Nerve injury and nerve pain are common diseases caused by neuroinflammation. Numerous studies have shown that the activation of NLRP3 (nod-like receptor family, pyrin domain-containing 3) inflammasome is involved in a various inflammatory response, such as Alzheimer's disease, diabetes, nerve damage and other diseases. The NLRP3 inflammasome is a complex containing NLRP3 protein, ASC (apoptosis-associated speckle-like protein), and pro-caspase-1, which is highly expressed and activated to promote the secretion of IL-1β and IL-18 in response to the stimulation of danger-associated molecular patterns (DAMPs) and pathogen-associated molecular patterns (PAMPs) in immune cells such as macrophages and dendritic cells. The activation of NLRP3 inflammasome can cause cell death through caspase-1-mediated cell pyroptosis and plays an important role in the development of nervous system injury and inflammation-related diseases. This discussion aims to summarize the mechanisms of nerve damage and pain caused by excessive activation of the NLRP3 inflammasome.

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Regional Nerve Blocks in Primary Total Hip Arthroplasty: The Clinical Practice Guidelines of the American Association of Hip and Knee Surgeons, American Society of Regional Anesthesia and Pain Medicine, American Academy of Orthopaedic Surgeons, Hip Societ

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Regional Nerve Blocks in Primary Total Knee Arthroplasty: The Clinical Practice Guidelines of the American Association of Hip and Knee Surgeons, American Society of Regional Anesthesia and Pain Medicine, American Academy of Orthopaedic Surgeons, Hip Socie

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Effectiveness of a whole health model of care emphasizing complementary and integrative health on reducing opioid use among patients with chronic pain.

The opioid crisis has necessitated new approaches to managing chronic pain. The Veterans Health Administration (VHA) Whole Health model of care, with its focus on patient empowerment and emphasis on nonpharmacological approaches to pain management, is a promising strategy for reducing patients' use of opioids. We aim to assess whether the VHA's Whole Health pilot program impacted longitudinal patterns of opioid utilization among patients with chronic musculoskeletal pain.

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Safety and tolerability of erenumab in individuals with episodic or chronic migraine across age groups: a pooled analysis of placebo-controlled trials.

Erenumab, a fully human monoclonal antibody that targets the calcitonin gene-related peptide receptor, has demonstrated efficacy and safety in the prevention of episodic and chronic migraine. There exists an unmet need to establish the safety of erenumab in older individuals, in view of existing multiple comorbidities, polypharmacy, and age-related physiological changes. This pooled analysis of five large migraine-prevention studies examined the safety of erenumab stratified across age groups, particularly in older populations.

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GWAS meta-analysis of intrahepatic cholestasis of pregnancy implicates multiple hepatic genes and regulatory elements.

Intrahepatic cholestasis of pregnancy (ICP) is a pregnancy-specific liver disorder affecting 0.5-2% of pregnancies. The majority of cases present in the third trimester with pruritus, elevated serum bile acids and abnormal serum liver tests. ICP is associated with an increased risk of adverse outcomes, including spontaneous preterm birth and stillbirth. Whilst rare mutations affecting hepatobiliary transporters contribute to the aetiology of ICP, the role of common genetic variation in ICP has not been systematically characterised to date. Here, we perform genome-wide association studies (GWAS) and meta-analyses for ICP across three studies including 1138 cases and 153,642 controls. Eleven loci achieve genome-wide significance and have been further investigated and fine-mapped using functional genomics approaches. Our results pinpoint common sequence variation in liver-enriched genes and liver-specific cis-regulatory elements as contributing mechanisms to ICP susceptibility.

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Ketamine in Total Joint Arthroplasty: The Clinical Practice Guidelines of the American Association of Hip and Knee Surgeons, American Society of Regional Anesthesia and Pain Medicine, American Academy of Orthopaedic Surgeons, Hip Society, and Knee Society

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Corticosteroids in Total Joint Arthroplasty: The Clinical Practice Guidelines of the American Association of Hip and Knee Surgeons, American Society of Regional Anesthesia and Pain Medicine, American Academy of Orthopaedic Surgeons, Hip Society, and Knee

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Exosomes carried miR-181c-5p alleviates neuropathic pain in CCI rat models.

Mesenchymal stem cells (MSCs) derived exosomes (Exos) are one of the most promising candidate for the treatment of this condition. However, the underlying molecular mechanism remains uncertain. Here we investigated the therapeutic effect of exosomal miR-181c-5p (ExomiR-181c-5p) on a rat model of neuropathic pain induced by sciatic nerve chronic constriction injury (CCI). In this study NP model was established using the CCI method. NP levels were assessed using PWT and PWL. Microarray analysis and RT-PCR were used to determine the relative expression of miR-181c-5p. MSC-derived exosomes were extracted using the total exosome isolation reagent characterized by WB and NTA. MiR-181c-5p was loading into Exos using electroporation. The inflammation response in microglia cells and CCI rats were assessed by ELISA assay respectively. Our study demonstrates that miR-181c-5p expression was obviously decreased in a time-dependent manner in CCI rats. MiR-181c-5p was effectively electroporated and highly detected in MSC-derived Exos. ExomiR-181c-5p internalized by microglia cells and inhibit the secretion of inflammation factors. ExomiR-181c-5p intrathecal administration alleviated neuropathic pain and neuroinflammation response in CCI rats. Taken together, ExomiR-181c-5p alleviated CCI-induced NP by inhibiting neuropathic inflammation. ExomiR-181c-5p may be a valid alternative for the treatment of neuropathic pain and has vast potential for future development.

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Determining the Influencing Factors on Acceptance of eHealth Pain Management Interventions Among Patients With Chronic Pain Using the Unified Theory of Acceptance and Use of Technology: Cross-sectional Study.

Chronic pain is a complex disease with high prevalence rates, and many individuals who are affected do not receive adequate treatment. As a complement to conventional therapies, eHealth interventions could provide many benefits to a multimodal treatment approach for patients with chronic pain, whereby future use is associated with the acceptance of these interventions.

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VTAMA (Tapinarof) Cream* for Plaque Psoriasis.

VTAMA (Tapinarof) 1% cream is a newly approved topical agent for treating plaque psoriasis. The active ingredient, tapinarof, binds to and activates aryl hydrocarbon receptors that positively regulate immune response and skin homeostasis. Tapinarof has presented promising results in two identical phase 3 randomized, double-blind, vehicle-controlled trials, where the primary efficacy end points were observed in 35.4% and 40.2% of patients in the tapinarof group compared to 6.0% and 6.3% of patients in the vehicle group. Tapinarof was applied once daily to affected psoriasis lesions for 12 weeks. Adverse events associated with tapinarof application were folliculitis, contact dermatitis, and headache. (. 2022;20:298-300).

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Research Progress of Long Non-coding RNAs in Spinal Cord Injury.

Spinal cord injury (SCI) can result in a partial or complete loss of motor and sensory function below the injured segment, which has a significant impact on patients' quality of life and places a significant social burden on them. Long non-coding RNA (LncRNA) is a 200-1000 bp non-coding RNA that has been shown to have a key regulatory role in the progression of a variety of neurological illnesses. Many studies have demonstrated that differentially expressed LncRNAs following spinal cord injury can participate in inflammatory damage, apoptosis, and nerve healing by functioning as competitive endogenous RNA (ceRNA); at the same time, it has a significant regulatory effect on sequelae such neuropathic pain. As a result, we believe that LncRNAs could be useful as a molecular regulatory target in the diagnosis, treatment, and prognosis of spinal cord injury.

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Deciding on the appropriate pharmacotherapy for the treatment of endometriosis.

Endometriosis is a chronic estrogen-dependent disease that afects one out of ten women worldwide leading to chronic pelvic pain and infertility. Despite decades of research endometriosis still represents a challenge for doctors and patients in terms of diagnosis and treatment. Current options for the appropriate pharmacotherapy in women with pain-related endometriosis are well described in the several other guidelines but high-quality evidence is not available for all. The medical treatment of endometriosis relies on hormonal medications that block menstruation in attempt to control pain and hopefully delay or avoid surgery. Thorough medical evaluation is mandatory to identify other causes of pelvic pain such as irritable bowel syndrome, interstitial cystitis and myofascial pain as well as rule out obstructive disease and suspicious adnexal masses. Drug choice should be individualized taking into consideration the side-effects profile as well as tolerability, costs, risks and benefits as one size does not fit all.As we gain more knowledge on the pathological cascade leading to endometriosis, the possibility of identifying specific agents which could block essential pathways and prevent disease progression and development increases.

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Peak alpha frequency as a candidate biomarker of pain sensitivity: the importance of distinguishing slow from slowing.

The study by Valentini et al (2022) observed that the peak alpha frequency (PAF) of participants became slower after they were exposed to painful, as well as non-painful but unpleasant stimuli. The authors interpreted this as a challenge to our previous studies which propose that the speed of resting PAF, independently of pain-induced changes to PAF, can be a reliable biomarker marker for gauging individual pain sensitivity. While investigations into the role that PAF plays in pain perception are timely, we have some concerns about the assumptions and methodology employed by Valentini et al. Moreover, we believe the authors here have also misrepresented some of our previous work. In the current commentary, we detail the critical differences between our respective studies, with the ultimate aim of guiding future investigations.

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Recognition and Assessment of Pain-Related Behaviors in Avian Species: An Integrative Review.

The appropriate recognition and assessment of pain in animals is an essential tool that can be used by veterinary professionals, rehabilitators, household caregivers, and others to provide supportive care and analgesia to patients. Although the use of behavioral, postural, and facial changes to recognize pain have been studied in popular domestic species such as dogs (), cats (), and rabbits (), very little is known relative to avian species. The purpose of this article is to provide a literature review comprising structured searches on the topic of avian pain recognition. The emphasis of the searches were based on the behavioral and postural alterations that have thus far been explored. The literature review was performed in the months of August-September 2020 over 5 online databases: MEDLINE/ PubMed, CAB Direct, Biosis, Zoological Record, and Scopus. Additional "snowballing" was incorporated by looking at the references and articles that cited the 126 articles from the initial abstract and full-text screening. Of the 194 full-text articles reviewed, 132 sources of literature were included in the final analysis. From these 132 sources of literature, 31.8% were general review articles in which avian pain behaviors were described irrespective of species, with others being specific to a particular species (chickens 47.8%, turkeys 7.6%, parrots 3.8%, pigeons [] 3%, raptors 3%, and "other" 3%-2 on ducks, 1 on emus [], and 1 on Eurasian blue tits []). Pain stimulus varied depending on species, although the vast majority of the pain stimuli involved welfare issues such as beak trimming, limb abnormalities, and keel bone fractures in chickens. Although information regarding this topic remains limited for many avian species, this review provides a more thorough understanding of behavioral indicators of pain in species such as chickens, turkeys, psittacines, pigeons, raptors, and select others. It is the hope that this review will motivate further interest and future analgesia research for the improvement of avian welfare.

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Reductions in Acute Medication Use and Healthcare Resource Utilization in Patients with Chronic Migraine: A Secondary Analysis of a Phase 3, Randomized, Double-Blind, Placebo-Controlled Study of Galcanezumab with Open-Label Extension (REGAIN).

To analyze secondary objectives of the REGAIN study related to acute headache medication use and healthcare resource utilization (HCRU) in patients with chronic migraine treated with galcanezumab, a monoclonal antibody to calcitonin gene-related peptide.

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Current status and challenges of drug development for hormonal treatment of endometriosis: a systematic review of randomized control trials.

The aim of this systematic review is to summarize the data obtained from randomized controlled trials looking at new pharmacologic treatments for endometriosis published over the last decade with a focus on hormonal therapeutic options for endometriosis-associated pelvic pain (EAPP), excluding studies focusing on fertility.

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Vagal Nerve Stimulation: A Bibliometric Analysis of Current Research Trends.

Vagal nerve stimulation (VNS) has become established as an effective tool for the management of various neurologic disorders. Consequently, a growing number of VNS studies have been published over the past four decades. This study presents a bibliometric analysis investigating the current trends in VNS literature.

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The Tibial Fracture-Pin Model: A Clinically Relevant Mouse Model of Orthopedic Injury.

The tibial fracture-pin model is a mouse model of orthopedic trauma and surgery that recapitulates the complex muscle, bone, nerve, and connective tissue damage that manifests with this type of injury in humans. This model was developed because previous models of orthopedic trauma did not include simultaneous injury to multiple tissue types (bone, muscle, nerves) and were not truly representative of human complex orthopedic trauma. The authors therefore modified previous models of orthopedic trauma and developed the tibial fracture-pin model. This modified fracture model consists of a unilateral open tibial fracture with intramedullary nail (IMN) internal fixation and simultaneous tibialis anterior (TA) muscle injury, resulting in mechanical allodynia that lasts up to 5 weeks post injury. This series of protocols outlines the detailed steps to perform the clinically relevant orthopedic trauma tibial fracture-pin model, followed by a modified hot plate assay to examine nociceptive changes after orthopedic injury. Taken together, these detailed, reproducible protocols will allow pain researchers to expand their toolkit for studying orthopedic trauma-induced pain.

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CGRP and Migraine: What Have We Learned From Measuring CGRP in Migraine Patients So Far?

The multi-functional neuropeptide calcitonin gene-related peptide (CGRP) plays a major role in the pathophysiology of migraine. The detection of elevated CGRP levels during acute migraine headache was the first evidence of the importance of the peptide. Since then, elevated CGRP levels have been detected not only during spontaneous and experimentally induced migraine attacks but also interictally. However, the detection of CGRP in peripheral blood shows conflicting results. In this respect, alternative detection methods are needed and have been already proposed. This article summarizes what we have learned from studies investigating CGRP in jugular and peripheral blood and reviews the latest state of research concerning the detection of CGRP in saliva and tear fluid as well as their contribution to our understanding of migraine pathophysiology.

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Assessment of Nerve Injury-induced Mechanical Hypersensitivity in Rats using an Orofacial Operant Pain Assay.

Pain has sensory and affective components. Unlike traditional, reflex-based pain assays, operant pain assays can produce more clinically relevant results by addressing the cognitive and motivational aspects of pain in rodents. This paper presents a protocol for assessing mechanical hypersensitivity following chronic constriction injury of the infraorbital nerves (CCI-ION) in rats using an orofacial operant pain system. Before CCI-ION surgery, rats were trained in an orofacial pain assessment device (OPAD) to drink sweetened condensed milk while making facial contact with the metal spiked bars and lick-tube. In this assay, rats can choose between receiving milk as a positive reinforcer or escaping an aversive mechanical stimulus that is produced by a vertical row of small pyramid-shaped spikes on each side of the reward access hole. Following 2 weeks of training in the OPAD and before the CCI-ION surgery, baseline mechanical sensitivity data were recorded for 5 days for each rat during a 10 min testing session. During a session, the operant system automatically records the number of reward bottle activations (licks) and facial contacts, contact duration, and latency to the first lick, among other measures. Following baseline measurements, rats underwent either CCI-ION or sham surgery. In this protocol, mechanical hypersensitivity was quantified by measuring the number of licks, latency to the first lick, the number of contacts, and the ratio of licks to facial contacts (L/F). The data showed that CCI-ION resulted in a significant decrease in the number of licks and the L/F ratio and an increase in the latency to the first lick, indicating mechanical hypersensitivity. These data support the use of operant-based pain assays to assess mechanical pain sensitivity in preclinical pain research.

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Decoding Neuropathic Pain: Can We Predict Fluctuations of Propagation Speed in Stimulated Peripheral Nerve?

To understand neural encoding of neuropathic pain, evoked and resting activity of peripheral human C-fibers are studied microneurography experiments. Before different spiking patterns can be analyzed, spike sorting is necessary to distinguish the activity of particular fibers of a recorded bundle. Due to single-electrode measurements and high noise contamination, standard methods based on spike shapes are insufficient and need to be enhanced with additional information. Such information can be derived from the activity-dependent slowing of the fiber propagation speed, which in turn can be assessed by introducing continuous "background" 0.125-0.25 Hz electrical stimulation and recording the corresponding responses from the fibers. Each fiber's speed propagation remains almost constant in the absence of spontaneous firing or additional stimulation. This way, the responses to the "background stimulation" can be sorted by fiber. In this article, we model the changes in the propagation speed resulting from the history of fiber activity with polynomial regression. This is done to assess the feasibility of using the developed models to enhance the spike shape-based sorting. In addition to human microneurography data, we use animal recordings with a similar stimulation protocol as higher signal-to-noise ratio data example for the models.

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Chinese expert consensus on minimally invasive interventional treatment of trigeminal neuralgia.

Trigeminal neuralgia is a common condition that is associated with severe pain, which seriously affects the quality of life of patients. When the efficacy of drugs is not satisfactory or adverse drug reactions cannot be tolerated, minimally invasive interventional therapy has become an important treatment because of its simple operation, low risk, high repeatability and low cost. In recent years, minimally invasive interventional treatments, such as radiofrequency thermocoagulation (RF) of the trigeminal nerve and percutaneous microcompression (PMC), have been widely used in the clinic to relieve severe pain in many patients, however, some related problems remain to be addressed. The Pain Association of the Chinese Medical Association organizes and compiles the consensus of Chinese experts to standardize the development of minimally invasive interventional treatment of trigeminal neuralgia to provide a basis for its clinical promotion and application.

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Altered expression of vesicular glutamate transporter-2 and cleaved caspase-3 in the locus coeruleus of nerve-injured rats.

Neuropathic pain is a debilitating chronic condition provoked by a lesion in the nervous system and it induces functional alterations to the noradrenergic locus coeruleus (LC), affecting distinct dimensions of pain, like sensorial hypersensitivity, pain-induced depression, and anxiety. However, the neurobiological changes induced by nerve damage in the LC remain unclear. Here, we analyzed excitatory and inhibitory inputs to the LC, as well as the possible damage that noradrenergic neurons suffer after the induction of neuropathic pain through chronic constriction injury (CCI). Neuropathic pain was induced in male Sprague-Dawley rats, and the expression of the vesicular glutamate transporter 1 or 2 (VGLUT1 or VGLUT2), vesicular GABA transporter (VGAT), and cleaved caspase-3 (CC3) was analyzed by immunofluorescence 7 (CCI7d) or 28 days after the original lesion (CCI28d). While no significant differences in the density of VGLUT1 puncta were evident, CCI7d induced a significant increase in the perisomatic VGLUT2/VGAT ratio relative to Sham-operated and CCI28d animals. By contrast, when the entire region of LC is evaluated, there was a significant reduction in the density of VGLUT2 puncta in CCI28d animals, without changes in VGLUT2/VGAT ratio relative to the CCI7d animals. Additionally, changes in the noradrenergic soma size, and a lower density of mitochondria and lysosomes were evident in CCI28d animals. Interestingly, enhanced expression of the apoptotic marker CC3 was also evident in the CCI28d rats, mainly co-localizing with glial fibrillary acidic protein but not with any neuronal or noradrenergic marker. Overall, short-term pain appears to lead to an increase of markers of excitatory synapses in the perisomatic region of noradrenergic cells in the LC, an effect that is lost after long-term pain, which appears to activate apoptosis.

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Research in Mindfulness Interventions for Patients With Fibromyalgia: A Critical Review.

Fibromyalgia is one of the most common causes of widespread chronic pain. It has a huge impact on the quality of life, namely because it appears earlier in life than most of the chronic pain conditions. Furthermore, emotional-cognitive distress factors, such as depression and anxiety, are a common feature in patients with fibromyalgia. The neurobiological mechanisms underlying fibromyalgia remain mostly unknown. Among non-pharmacological treatments, cognitive-behavioral therapy has been used during the last decade, namely with the enrolment of patients in programs of mindfulness-based stress reduction (MBSR) and in mindfulness-based interventions (MBI). We critically analyzed the literature to search for scientific evidence for the use of MBI in fibromyalgia. The studies were evaluated as to several outcomes of fibromyalgia improvement along with aspects of the study design which are currently considered relevant for research in mindfulness. We conclude that despite the sparsity of well-structured longitudinal studies, there are some promising results showing that the MBI are effective in reducing the negative aspects of the disease. Future design of studies using MBI in fibromyalgia management should be critically discussed. The importance of active controls, evaluation of sustained effects along with investigation of the subserving neurobiological mechanisms and detailed reports of possible adverse effects should be considered.

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Opioid deprescribing: Qualitative perspectives from those with chronic non-cancer pain.

Deprescribing is the systematic process of discontinuing medications when the harms outweigh the benefits. This study aimed to identify barriers and facilitators in people with chronic non-cancer pain when deprescribing opioid analgesics, and their views on resources that assist with deprescribing.

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Update on Idiopathic Intracranial Hypertension Management.

Idiopathic Intracranial Hypertension (IIH) is a secondary headache with a steadily growing incidence. Currently, there is little evidence to guide the treatment of IIH.

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Assessment of epidermoid cyst with trigeminal neuralgia before neuroendoscopy: A high-resolution MR study based on 3D-FIESTA and MR angiography.

To assess the value of preoperative 3D-FIESTA and MR angiography (MRA) in endoscopic resection of epidermoid cysts presenting with trigeminal neuralgia (TN).

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Suggestions in Hypnosis to Aid Pain Education (SHAPE) in People with Chronic Low-Back Pain: A Pilot Feasibility Randomized, Controlled Trial.

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An Advanced Practice Provider Guide to Peripheral Nerve Stimulation.

To describe the team approach of an interventional pain management practice, with particular emphasis on advanced practice providers (APPs), in the selection, education, care, and management of peripheral nerve stimulation (PNS) patients.

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It is time anti-CGRP monoclonal antibodies be considered first-line prophylaxis for migraine.

The result of more than thirty years of research, anti-CGRP monoclonal antibodies are currently the state of the art for migraine preventive therapy. Their efficacy and safety, supported by an already large and growing body of evidence, are added by many other advantages: an early onset of action, favorable posology, negligible pharmacological interaction, and a broad-reaching efficacy in many challenging clinical contexts. When compared to standard prophylactics, these novel medications seem at least as efficacious, clearly more tolerable and, consequently, with a superior adherence profile. Furthermore, recently published analyses indicate that they are cost-effective, especially among those with chronic migraine. Yet, current guidelines endorse their use only after multiple other preventives have failed or have been deemed not tolerable. Although this recommendation may have been sensible at first, the now available data strongly point that time has come for anti-CGRP monoclonal antibodies to be acknowledged as first-line treatments for migraine patients with severe disability. For these individuals, delaying treatment until several other alternatives have failed incurs in significant losses, both economically and to many relevant aspects of their lives.

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Why are CGRP monoclonal antibodies not yet the first line treatment in migraine prevention?

Migraine is a prevalent disorder and a cause of high disability, influenced by modifiable and non-modifiable risk factors. Comorbid and psychiatric illnesses are prevalent in migraine patients and should be considered when choosing preventive drugs. There have been unforeseen problems with the use of preventive treatment of migraine with oral drugs, mainly due to side-effects that cannot be tolerated and lack of efficacy, leading to high discontinuation rates. Anti-CGRP monoclonal antibodies (mAbs) have shown better tolerance profiles, based on the low dropout rates in clinical trials due to adverse events. First-line therapy is a term most expressed in some medical specialties that adopt standardized protocol treatments and may not be suitable for treating migraine. Regarding efficacy, mAbs don't seem to perform much better than the current prophylactic oral drugs in reduction of monthly migraine days compared to placebo. Monoclonal antibodies against CGRP pathway have been prescribed recently, which raises some concern about their safety in the long term. Only side effects observation will confirm whether CGRP blockade causes susceptibility to severe side-effects, at least to specific subpopulations. CGRP may play a role in regulating uteroplacental blood flow and myometrial and uterine relaxation, as well as blood pressure control, raising the suspicion that its blockade could cause complications during pregnancy. Recent guidelines retain the recommendation of starting preventive treatment of migraine with oral drugs. Both the fact that it is new and costs are the reason why guidelines recommend the prescription of mAbs only after failure of at least two oral drugs.

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Alopecia signals associated with calcitonin gene-related peptide inhibitors in the treatment or prophylaxis of migraine: A pharmacovigilance study.

Although rarely observed in clinical trials, alopecia has been reported in migraine patients treated with calcitonin gene-related peptide (CGRP) inhibitors during the postmarketing period. This study sought to assess whether CGRP inhibitors are associated with disproportionate alopecia reporting relative to other drugs including those indicated for migraine treatment or prophylaxis in a real-world setting.

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HMGB1 in the mPFC governs comorbid anxiety in neuropathic pain.

Whether neuroinflammation causes comorbid mood disorders in neuropathic pain remains elusive. Here we investigated the role of high mobility group box 1 protein (HMGB1), a proinflammatory cytokine, in the medial prefrontal cortex (mPFC) in anxiety comorbidity of neuropathic pain.

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Understanding chronic ocular surface pain: An unmet need for targeted drug therapy.

Chronic ocular surface pain (COSP) may be defined as a feeling of pain, perceived as originating from the ocular surface, that persists for >3 months. COSP is a complex multifactorial condition associated with several risk factors that may significantly interfere with an individual's daily activities, resulting in poor quality of life (QoL). COSP is also likely to have a high burden on patients with substantial implications on global healthcare costs. While patients may use varied terminology to describe symptoms of COSP, any ocular surface damage in the ocular sensory apparatus (nociceptive, neuropathic, inflammatory, or combination thereof) resulting in low tear production, chronic inflammation, or nerve abnormalities (functional and/or morphological), is typically associated with COSP. Considering the heterogeneity of this condition, it is highly recommended that advanced multimodal diagnostic tools are utilized to help discern the nociceptive and neuropathic pain pathways in order to provide targeted treatment and effective clinical management. The current article provides an overview of COSP, including its multifactorial pathophysiology, etiology, prevalence, clinical presentation, impact on QoL, diagnosis, current management, and unmet medical needs.

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A simple, bed-side tool to assess evoked pressure pain intensity.

Existing equipment for quantitative sensory testing is generally expensive and not easily applicable in a clinical setting thus simple bed-side devices are warranted. Pressure hyperalgesia is a common finding in patients with musculoskeletal pain and an experimental model is delayed-onset muscle soreness (DOMS). DOMS is characterised by muscle hyperalgesia and some studies report facilitation of temporal summation of pain. This study aimed to detect DOMS induced muscle hyperalgesia and temporal summation of pain using a newly developed bed-side quantitative sensory testing device to deliver standardised pressure.

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Diabetic Mononeuropathies and Diabetic Amyotrophy.

This brief review describes the etiology, pathophysiology, clinical features, therapy and prognosis of the diabetic mononeuropathies and diabetic amyotrophy and neuropathic cachexia. Mononeuropathies include cranial neuropathies, of which the oculomotor nerve is most commonly affected, and are thought to be due to microvascular occlusion. Peripherally, entrapment neuropathies occur in both the upper and lower limbs and are due to compression of an already damaged nerve in anatomically restricted channels. Diabetic radiculopathies occur in the dermatones of the thorax and abdomen, mimicking intraabdominal or intrathoracic pathology. I also describe the features of the rare but very distinctive diabetic amyotrophy and neuropathic cachexia. Overall, the prognosis from these conditions is excellent with residual pain or muscle weakness being rare with the exception of diabetic amyotrophy where the prognosis is dependent upon cooperation with intensive rehabilitation. Therapies include "watchful waiting," physical therapy and rarely surgical intervention, which may be urgently needed for nerve decompression and reversal of motor defects.

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Tension-type headache and low back pain reconsidered.

The natural history and clinical course of tension-type headache and non-specific low back pain are reconsidered. By closer examination, these two conditions appear to share several specific clinical features. Both are muscular pain conditions along the spine, they have a preponderance in women, they may occur spontaneously or follow a trivial traumatic incident, and they both have a high risk of chronicity. The affected muscles are tender with tender points. EMG indicates diffuse hyperactivity and abnormal activation pattern, and motor control of the affected muscles and adjacent muscle groups is discoordinated. These shared features suggest analogous pathophysiology involving the neuromotor control of affected and adjacent muscle groups in the cervical and lumbar regions, respectively. As recently suggested for the whiplash disease, we suggest the term spinal dyssynergia for this specific pattern of pathology. This suggestion provides a new perspective for the understanding of these diseases by placing their cause within the central nervous system and not in the spine or spinal musculature. This perspective warrants further clinical, neurophysiological, and neuropharmacological studies of this 'family' of common yet poorly understood clinical muscular pain conditions along the spine.

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TRP channels and monoterpenes: Past and current leads on analgesic properties.

The activation of the transient receptor potential (TRP) channels expressed by sensory neurons is essential to the transduction of thermal and mechanical sensory information. In the setting of chronic inflammatory conditions, the activation of the melastatin family member 8 (TRPM8), the TRP vanilloid 1 (TRPV1), and the TRP ankyrin 1 (TRPA1) is correlated with pain hypersensitivity reactions. Monoterpenes, among which pulegone and menthol, a major class of phytocompounds present in essential oils of medicinal plants, are known modulators of those TRP channels activity. In the present review, we correlate the monoterpene content of plants with their historical therapeutic properties. We then describe how monoterpenes exert their anti-inflammatory and antihyperalgesia effects through modulation of TRP channels activity. Finally, we discuss the importance and the potential of characterizing new plant extracts and reassessing studied plant extracts for the development of ethnopharmacology-based innovative treatments for chronic pain. This review suggests that monoterpene solutions, based on composition from traditional healing herbs, offer an interesting avenue for the development of new phytotherapeutic treatments to alleviate chronic inflammatory pain conditions.

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Emerging Evidence for Intrathecal Management of Neuropathic Pain Following Spinal Cord Injury.

A high prevalence of patients with spinal cord injury (SCI) suffer from chronic neuropathic pain. Unfortunately, the precise pathophysiological mechanisms underlying this phenomenon have yet to be clearly elucidated and targeted treatments are largely lacking. As an unfortunate consequence, neuropathic pain in the population with SCI is refractory to standard of care treatments and represents a significant contributor to morbidity and suffering. In recent years, advances from SCI-specific animal studies and translational models have furthered our understanding of the neuronal excitability, glial dysregulation, and chronic inflammation processes that facilitate neuropathic pain. These developments have served advantageously to facilitate exploration into the use of neuromodulation as a treatment modality. The use of intrathecal drug delivery (IDD), with novel pharmacotherapies, to treat chronic neuropathic pain has gained particular attention in both pre-clinical and clinical contexts. In this evidence-based narrative review, we provide a comprehensive exploration into the emerging evidence for the pathogenesis of neuropathic pain following SCI, the evidence basis for IDD as a therapeutic strategy, and novel pharmacologics across impactful animal and clinical studies.

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