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Patients with neuropathic pain often experience comorbid psychiatric disorders. Cellular plasticity in the anterior cingulate cortex (ACC) is assumed as a critical interface for pain perception and emotion. However, substantial efforts thus far are focused on intracellular mechanisms of plasticity rather than extracellular alterations that might trigger and facilitate intracellular changes. Laminin is a key element of extracellular matrix (ECM) consisting of one α-, β- and γ-chain and implicated in several pathophysiological processes. Here we showed that Laminin β1 (LAMB1) in ACC is significantly downregulated upon peripheral neuropathy. Knocking down ACC LAMB1 exacerbated pain sensitivity and induced anxiety and depression. Mechanistic analysis revealed that loss of LAMB1 causes actin dysregulation via interaction with integrin beta1 and subsequent Src-dependent RhoA/LIMK/cofilin pathway, leading to increased presynaptic transmitter release probability and abnormal postsynaptic spine remodeling, which in turn orchestrates structural and functional plasticity of pyramidal neurons and eventually results in pain hypersensitivity and anxiodepression. This study shed new light on the functional capability of ECM, LAMB1 in modulating pain plasticity and revealed a mechanism that conveys extracellular alterations to intracellular plasticity. Moreover, we identified cingulate LAMB1/integrin β1 as a promising therapeutic strategy for treatment of neuropathic pain and associated anxiodepression.
Learn More >Chronic pain is characterized by discrete pain episodes of unpredictable frequency and duration. This hinders the study of pain mechanisms and contributes to the use of pharmacological treatments associated with side effects, addiction and drug tolerance. Here, we show that a closed-loop brain-machine interface (BMI) can modulate sensory-affective experiences in real time in freely behaving rats by coupling neural codes for nociception directly with therapeutic cortical stimulation. The BMI decodes the onset of nociception via a state-space model on the basis of the analysis of online-sorted spikes recorded from the anterior cingulate cortex (which is critical for pain processing) and couples real-time pain detection with optogenetic activation of the prelimbic prefrontal cortex (which exerts top-down nociceptive regulation). In rats, the BMI effectively inhibited sensory and affective behaviours caused by acute mechanical or thermal pain, and by chronic inflammatory or neuropathic pain. The approach provides a blueprint for demand-based neuromodulation to treat sensory-affective disorders, and could be further leveraged for nociceptive control and to study pain mechanisms.
Learn More >Mechanosensation is the ability to detect dynamic mechanical stimuli (e.g., pressure, stretch, and shear stress) and is essential for a wide variety of processes, including our sense of touch on the skin. How touch is detected and transduced at the molecular level has proved to be one of the great mysteries of sensory biology. A major breakthrough occurred in 2010 with the discovery of a family of mechanically gated ion channels that were coined PIEZOs. The last 10 years of investigation have provided a wealth of information about the functional roles and mechanisms of these molecules. Here we focus on PIEZO2, one of the two PIEZO proteins found in humans and other mammals. We review how work at the molecular, cellular, and systems levels over the past decade has transformed our understanding of touch and led to unexpected insights into other types of mechanosensation beyond the skin.
Learn More >Chronic pain is the leading cause of disability worldwide and is commonly associated with comorbid disorders. However, the role of diet in chronic pain is poorly understood. Of particular interest is the Western-style diet, enriched with ω-6 polyunsaturated fatty acids (PUFAs) that accumulate in membrane phospholipids and oxidise into pronociceptive oxylipins. Here we report that mice administered an ω-6 PUFA-enriched diet develop persistent nociceptive hypersensitivities, spontaneously active and hyper-responsive glabrous afferent fibres and histologic markers of peripheral nerve damage reminiscent of a peripheral neuropathy. Linoleic and arachidonic acids accumulate in lumbar dorsal root ganglia, with increased liberation via elevated phospholipase (PLA)2 activity. Pharmacological and molecular inhibition of PLA2G7 or diet reversal with high levels of ω-3 PUFAs attenuate nociceptive behaviours, neurophysiologic abnormalities and afferent histopathology induced by high ω-6 intake. Additionally, ω-6 PUFA accumulation exacerbates allodynia observed in preclinical inflammatory and neuropathic pain models and is strongly correlated with multiple pain indices of clinical diabetic neuropathy. Collectively, these data reveal dietary enrichment with ω-6 PUFAs as a new aetiology of peripheral neuropathy and risk factor for chronic pain and implicate multiple therapeutic considerations for clinical pain management.
Learn More >Patients classified as having whiplash-associated disorder (WAD) grade II, which reflects approximately 93% of patients with WAD who are commonly managed by health care professionals, exhibit both physical (eg, pain and disability) and psychological (eg, fear of movement, anxiety, posttraumatic stress) problems that, in approximately 50% of cases, persist beyond 3 months. There is still much ongoing debate regarding factors predictive of poor recovery. The strongest associations have been found for high initial pain and disability following whiplash injury. In addition, a growing body of evidence supports the clinical importance of characteristic features, such as disturbed nociceptive processing (eg, local or general hyperalgesia to cold and mechanical stimuli), inefficient cognitions and beliefs about pain/movement/recovery, and posttraumatic stress symptoms, in the development and maintenance of physical and psychological manifestations in patients with WAD. For this reason, the field shifted away from single interventions that mainly follow a biomedical approach, such as exercise therapy and activity programs, to gold standard multimodal care (at least 2 distinct therapeutic modalities given by 1 or more health care professionals) that acknowledges the biopsychological nature of WAD. To date, there exist several multimodal care approaches to managing WAD; however, for most the efficacy has been found to be rather limited. One may argue that the limited success of some approaches can be attributed to the fact that they focused mainly on rehabilitating the physical symptoms (eg, pain, disability) rather than also the associated cognitive (eg, catastrophizing) and psychological (eg, posttraumatic stress symptoms) symptoms of the condition, leaving much room for improvement. In this article, current and previous evidence is used to explain why and how a comprehensive and multimodal treatment for people with WAD-consisting of a combination of pain neuroscience education, cognition-targeted exercise therapy, and stress management-can be applied in clinical practice.
Learn More >Lysophosphatidic acid (LPA) is involved in the pathophysiology of cholestatic pruritus and neuropathic pain. Slowly conducting peripheral afferent C-nerve fibers are crucial in the sensations of itch and pain. In animal studies, specialized neurons ("pruriceptors") have been described, expressing specific receptors e.g. from the Mrgpr family. Human nerve fibers involved in pain signaling ("nociceptors") can elicit itch if activated by focalized stimuli such as cowhage spicules.In this study, we scrutinized the effects of LPA in humans by two different application modes on the level of psychophysics and single nerve fiber recordings (microneurography). In healthy human subjects, intracutaneous LPA microinjections elicited burning pain, whereas LPA application via inactivated cowhage spicules evoked a moderate itch sensation. LPA microinjections induced heat hyperalgesia and hypersensitivity to higher electrical stimulus frequencies. Pharmacological blockade of TRPA1 or TRPV1 reduced heat hyperalgesia but not acute chemical pain. Microneurography revealed an application mode-dependent differential activation of mechano-sensitive (CM) and mechano-insensitive (CMi) C-fibers. LPA microinjections activated a greater proportion of CMi and more strongly than CM fibers; spicule-application of LPA activated CM and CMi fibers to a similar extent but excited CM more and CMi fibers less intensely than microinjections.In conclusion, we show for the first time in humans that LPA can cause pain as well as itch dependent on the mode of application and activates afferent human C-fibers. Itch may arise from focal activation of few nerve fibers with distinct spatial contrast to unexcited surrounding afferents, and a specific combination of activated fiber subclasses might contribute.
Learn More >Accumulating evidence suggests hippocampal impairment under chronic pain phenotype. However, it is unknown whether neuropathic behaviors are related to dysfunction of the hippocampal circuitry. Here we enhanced hippocampal activity by pharmacological, opto- and chemo-genetic techniques to determine hippocampal influence on neuropathic pain behaviors. We found that excitation of the dorsal (DH), but not the ventral (VH), hippocampus induces analgesia in two rodent models of neuropathic pain (SNI and SNL), and in rats and mice. Optogenetic and pharmacological manipulations of DH neurons demonstrated that DH-induced analgesia was mediated by NMDA and μ-opioid receptors. In addition to analgesia, optogenetic stimulation of DH in SNI mice also resulted in enhanced real-time conditioned place preference for the chamber where DH was activated, a finding consistent with pain relief. Similar manipulations in VH were ineffective. Using chemo-fMRI, where awake resting-state fMRI was combined with viral vector mediated chemogenetic activation (PSAM/PSEM) of DH neurons, we demonstrated changes of functional connectivity between DH and thalamus and somatosensory regions that tracked the extent of relief from tactile allodynia. Moreover, we examined hippocampal functional connectivity in humans, and observe differential reorganization of its anterior and posterior subdivisions between subacute and chronic backpain. Altogether, these results imply that downregulation of DH circuitry during chronic neuropathic pain aggravates pain-related behaviors. Conversely, activation of DH reverses pain-related behaviors through local excitatory and opioidergic mechanisms affecting DH functional connectivity. Thus, the present study exhibits a novel causal role for the DH but not VH in controlling neuropathic pain-related behaviors.
Learn More >The aim of this study was to investigate the effect on observationally acquired placebo analgesia of a model's self-confidence as well as the observer's self-esteem and self-efficacy. In addition, we aimed to verify the stability of the placebo effect induced by observational learning. Participants (N = 60) were randomly assigned to one of three groups: a self-confident model, an unself-confident model, and a control group. In the experimental groups, participants watched a videotaped model who rated the intensity of electrocutaneous pain stimuli applied in the placebo condition as lower than those applied in the non-placebo condition. The different levels of self-confidence in these groups were manifested in the body posture and facial expressions of the model as well as in specific behavior that accompanied the assessment of pain. Then, 16 electrocutaneous pain stimuli of the same intensity, preceded by the placebo or non-placebo, were applied to participants. In both experimental groups, in contrast to the control group, participants experienced less pain in the placebo than in the non-placebo condition. Although the magnitude of placebo analgesia did not differ between the experimental groups, multiple regression analysis revealed that the perceived self-confidence of the model, but not the self-efficacy or self-esteem of the observer, was a significant predictor of the placebo effect. Moreover, placebo analgesia induced by observational learning did not extinguish over the course of the experiment. These results support the premise that the observers' perception of a model's self-confidence plays a significant role in placebo effects. PERSPECTIVE: The results of this study open the discussion on the role of model's features in the effectiveness of observational learning in the induction of placebo effects. The study provides the very first suggestion that the perceived self-confidence of the model may be related to the magnitude of the observationally induced placebo analgesia. It suggests that self-confidence of other patients and medical staff might affect individual pain experiences.
Learn More >Chronic pain is treated with multimodal rehabilitation programs, targeting improvement in several health aspects. These treatments must be evaluated multidimensionally, which is a methodological challenge.
Learn More >The relaxin peptide signaling system is involved in diverse physiological processes, but its possible roles in the brain, including nociception, are largely unexplored.
Learn More >To explore the prevalence of poor social support and loneliness among people with chronic headache, and how these might be effect modifiers in the relationships between chronic headache and stress, medication overuse, and self-rated health.
Learn More >The transition from childhood to adolescence and from adolescence to adulthood are vulnerable phases in life. In these phases, late or insufficient treatment of diseases may lead to chronification and favor development of additional disorders. In adolescents, migraine often has a highly negative impact on school performance and everyday life. The hypothesis of the present study was that adolescents with migraine have a higher risk for developing additional disorders such as psychiatric disorders or other pain syndromes in the course of the disease.
Learn More >Mitragynine (MG) is the most abundant alkaloid component of the psychoactive plant material "kratom", which according to numerous anecdotal reports shows efficacy in self-medication for pain syndromes, depression, anxiety, and substance use disorders. We have developed a synthetic method for selective functionalization of the unexplored C11 position of the MG scaffold (C6 position in indole numbering) via the use of an indole-ethylene glycol adduct and subsequent iridium-catalyzed borylation. Through this work we discover that C11 represents a key locant for fine-tuning opioid receptor signaling efficacy. 7-Hydroxymitragynine (7OH), the parent compound with low efficacy on par with buprenorphine, is transformed to an even lower efficacy agonist by introducing a fluorine substituent in this position (11-F-7OH), as demonstrated in vitro at both mouse and human mu opioid receptors (mMOR/hMOR) and in vivo in mouse analgesia tests. Low efficacy opioid agonists are of high interest as candidates for generating safer opioid medications with mitigated adverse effects.
Learn More >Neuropathic pain is a common disability produced by enhanced neuronal excitability after nervous system injury. The pathophysiological changes that underlie the generation and maintenance of neuropathic pain require modifications of transcriptional programs. In particular, there is an induction of pro-inflammatory neuromodulators levels, and changes in the expression of ion channels and other factors intervening in the determination of the membrane potential in neuronal cells. We have previously found that inhibition of the BET proteins epigenetic readers reduced neuroinflammation after spinal cord injury. Within the present study we aimed to determine if BET protein inhibition may also affect neuroinflammation after a peripheral nerve injury, and if this would beneficially alter neuronal excitability and neuropathic pain. For this purpose, C57BL/6 female mice underwent spared nerve injury (SNI), and were treated with the BET inhibitor JQ1, or vehicle. Electrophysiological and algesimetry tests were performed on these mice. We also determined the effects of JQ1 treatment after injury on neuroinflammation, and the expression of neuronal components important for the maintenance of axon membrane potential. We found that treatment with JQ1 affected neuronal excitability and mechanical hyperalgesia after SNI in mice. BET protein inhibition regulated cytokine expression and reduced microglial reactivity after injury. In addition, JQ1 treatment altered the expression of SCN3A, SCN9A, KCNA1, KCNQ2, KCNQ3, HCN1 and HCN2 ion channels, as well as the expression of the Na/K ATPase pump subunits. In conclusion, both, alteration of inflammation, and neuronal transcription, could be the responsible epigenetic mechanisms for the reduction of excitability and hyperalgesia observed after BET inhibition. PERSPECTIVE ITEM: Inhibition of BET proteins is a promising therapy for reducing neuropathic pain after neural injury.
Learn More >Benefits of phototherapy were characterized in multiple diseases including depression, circadian rhythm disruptions, and neurodegeneration. Studies on migraine and fibromyalgia patients revealed that green light-emitting diodes (GLED) exposure provides a pragmatic and safe therapy to manage chronic pain. In rodents, GLED reversed hypersensitivity related to neuropathic pain. However, little is known about the underlying mechanisms of GLED efficacy. Here, we sought to understand how green light modulates the endogenous opioid system. We first characterized how exposure to GLED stimulates release of β-endorphin and proenkephalin in the central nervous system of male rats. Moreover, by individually editing each of the receptors, we found that µ- and δ-opioid receptors are required for green light's antinociceptive effect in naïve rats and a model of HIV-induced peripheral neuropathy. We investigated how GLED could increase pain thresholds, and explored its potential in reversing hypersensitivity in a model of HIV-related neuropathy. Through behavioral and gene editing approaches, we identified that green light provides antinociception via modulation of the endogenous opioid system in the spinal cord. This work identifies a previously unknown mechanism by which GLED can improve pain management. Clinical translation of these results will advance the development of an innovative therapy devoid of adverse effects. PERSPECTIVE: Development of new pain management therapies, especially for HIV patients, is crucial as long-term opioid prescription is not recommended due to adverse side effects. Green light addresses this necessity. Characterizing the underlying mechanisms of this potentially groundbreaking and safe antinociceptive therapy will advance its clinical translation.
Learn More >Low temperatures can be fatal to insects, but many species have evolved the ability to cold acclimate, thereby increasing their cold tolerance. It has been previously shown that larvae perform cold-evoked behaviors under the control of noxious cold-sensing neurons (nociceptors), but it is unknown how the nervous system might participate in cold tolerance. Herein, we describe cold-nociceptive behavior among 11 drosophilid species; we find that the predominant cold-evoked larval response is a head-to-tail contraction behavior, which is likely inherited from a common ancestor, but is unlikely to be protective. We therefore tested the hypothesis that cold nociception functions to protect larvae by triggering cold acclimation. We found that Class III nociceptors are sensitized by and critical to cold acclimation and that cold acclimation can be optogenetically evoked, cold. Collectively, these findings demonstrate that cold nociception constitutes a peripheral neural basis for larval cold acclimation.
Learn More >Racial health disparities persist despite increased public awareness of systemic racism. Due to the inherent subjectivity of pain perception, assessment and management, physician-patient bias in pain medicine remains widespread. It is broadly accepted that increasing racial diversity in the field of medicine is a critical step towards addressing persistent inequities in patient care. To assess the current racial demographics of the pain medicine pipeline, we conducted a cross-sectional analysis of medical school matriculants and graduates, residents, and pain fellows in 2018. Our results show that the 2018 anesthesiology residency ERAS applicant pool consisted of 46.2% non-Hispanic White, 7.0% non-Hispanic Black and 5.8% Hispanic students. The population of 2018 anesthesiology residents included 63% non-Hispanic White, 6.8% non-Hispanic Black and 5.4% Hispanic persons. Of the total eligible resident pool for pain fellowships (n = 30,415) drawn from core specialties, 44% were non-Hispanic White, 4.9% non-Hispanic Black and 5.1% Hispanic. Similar proportions were observed for pain medicine and regional anesthesia fellows. We briefly discuss the implications of the shortage of non-Hispanic Black and Hispanic representation in pain medicine as it relates to the COVID-19 pandemic and suggest approaches to improving these disparities.
Learn More >Although the role of glutamate in migraine pathogenesis remains uncertain, there has been significant interest in the development of drug candidates that target glutamate receptors. Activation of trigeminovascular afferent fibers is now recognized as a crucial step to the onset of a migraine episode. New evidence suggests a dysfunction in peripheral glutamate regulation may play a role in this process.
Learn More >Migraine and trigemino-autonomic cephalalgia attacks are associated with an increase of α-calcitonin-gene related peptide levels in the ipsilateral jugular vein. It is however unknown whether trigeminal pain stimulation in healthy subjects without headache disorders also induces increase of calcitonin-gene related peptide levels.
Learn More >To incorporate recent research findings, expert consensus, and patient perspectives into updated guidance on the use of new acute and preventive treatments for migraine in adults.
Learn More >Pain neuroscience education (PNE) has received increasing research attention demonstrating beneficial effects on pain-related outcomes in adults. Conversely, studies on the effectiveness of PNE in children are scarce.
Learn More >Does feeling reassured after a consultation reduce future disability or healthcare use in people with acute low back pain (LBP)?
Learn More >Chronic pain affects about 20 % of the Canadian population and can lead to physical, psychological and social vulnerabilities. However, this condition remains poorly recognized and undertreated. During 2020, as the COVID-19 pandemic disrupted daily living and health care systems, the situation of people with chronic pain has drawn little public attention.
Learn More >To use 1) newly generated data, 2) existing evidence, and 3) expert opinion to create and validate a new cluster headache screening tool.
Learn More >Evidence from genome-wide and candidate gene association studies, familial aggregation and linkage analyses demonstrate the genetic contribution to fibromyalgia (FM) disease. This study aimed to identify genetic biomarkers of FM and its related comorbid disorders, by exploring 41 polymorphisms potentially involved in FM pathogenesis in families with at least one patient with FM.
Learn More >The positron emission tomography (PET) radiotracer [C]PBR28 has been increasingly used to image the translocator protein (TSPO) as a marker of neuroinflammation in a variety of brain disorders. Interrelatedly, similar clinical populations can also exhibit altered brain perfusion, as has been shown using arterial spin labelling in magnetic resonance imaging (MRI) studies. Hence, an unsolved debate has revolved around whether changes in perfusion could alter delivery, uptake, or washout of the radiotracer [C]PBR28, and thereby influence outcome measures that affect interpretation of TSPO upregulation. In this simultaneous PET/MRI study, we demonstrate that [C]PBR28 signal elevations in chronic low back pain patients are not accompanied, in the same regions, by increases in cerebral blood flow (CBF) compared to healthy controls, and that areas of marginal hypoperfusion are not accompanied by decreases in [C]PBR28 signal. In non-human primates, we show that hypercapnia-induced increases in CBF during radiotracer delivery or washout do not alter [C]PBR28 outcome measures. The combined results from two methodologically distinct experiments provide support from human data and direct experimental evidence from non-human primates that changes in CBF do not influence outcome measures reported by [C]PBR28 PET imaging studies and corresponding interpretations of the biological meaning of TSPO upregulation.
Learn More >Genetic variation in the catechol-O-methyltransferase (COMT) gene is associated with sensitivity to both acute experimental pain and chronic pain conditions. Four single nucleotide polymorphisms (SNPs) have traditionally been used to infer three common haplotypes designated as low, average and high pain sensitivity (LPS, APS and HPS) and are reported to affect both COMT enzymatic activity and pain sensitivity. One mechanism that may partly explain individual differences in sensitivity to pain is Conditioned Pain Modulation (CPM). We hypothesized that variation in CPM may have a genetic basis.
Learn More >Many online interventions for paediatric chronic pain have been developed and evaluated. In accordance with the biopsychosocial model, the recommended treatment approach for chronic pain is multidisciplinary. Despite this, multidisciplinary components within existing online interventions have not been examined. The objective of the present review was to summarise and evaluate the content of existing online interventions for paediatric chronic pain by mapping intervention content to evidence-based guidelines for chronic pain management.
Learn More >Chronic pain in children and adolescents gives rise to high health care costs. Successful treatment is supposed to reduce the economic burden. The objective of this study was to determine the changes in health care utilization and expenditures from one year before (Pre) intensive interdisciplinary pain treatment (IIPT) to the first (Post 1) and second (Post 2) years after discharge in a sample of pediatric chronic pain patients.
Learn More >The kappa opioid receptor is a constituent of the endogenous opioid analgesia system widely expressed in somatosensory nervous pathways and also in endometrial tissues. This work investigates the possible involvement of kappa opioid receptor on the nociceptive, behavioral and histopathological manifestations of endometriosis in a murine model. Female mice receiving endometrial implants develop a persistent mechanical hypersensitivity in the pelvic area that is stronger during the estrus phase of the estrous cycle. The kappa opioid receptor agonist U50,488H produces a dose-dependent relief of this mechanical hypersensitivity, regardless of the cycle phase. Repeated exposure to a low dose of U50,488H (1 mg/kg/day s.c. for one month) provides sustained relief of mechanical hypersensitivity, without tolerance development or sedative side effects. Interestingly, this treatment also inhibits a decreased rearing behavior associated with spontaneous pain or discomfort in endometriosis mice. This KOR-mediated pain relief does not prevent the anxiety-like behavior or the cognitive impairment exhibited by endometriosis mice, and the growth of endometriotic cysts is also unaltered. These data provide evidence of strong pain-relieving properties of kappa opioid receptor stimulation in female mice with endometriosis pain. The persistence of affective and cognitive manifestations suggests that these comorbidities are independent of pelvic pain and simultaneous treatment of these co-morbidities may be necessary for successful management of endometriosis.
Learn More >Communication between nerve cells depends on the balance between excitatory and inhibitory circuits. GABA, the major inhibitory neurotransmitter, regulates this balance and insufficient GABAergic activity is associated with numerous neuropathological disorders including pain. Of the various GABA receptor subtypes, the δ-containing receptors are particularly interesting drug targets in management of chronic pain. These receptors are pentameric ligand-gated ion channels composed of α, β and δ subunits and can be activated by ambient levels of GABA to generate tonic conductance. However, only a few ligands preferentially targeting δ-containing GABA receptors have so far been identified, limiting both pharmacological understanding and drug-discovery efforts, and more importantly, understanding of how they affect pain pathways. Here, we systemically review and discuss the known drugs and ligands with analgesics potential targeting δ-containing GABA receptors and further integrate the biochemical nature of the receptors with clinical perspectives in pain that might generate interest among researchers and clinical physicians to encourage analgesic discovery efforts leading to more efficient therapies.
Learn More >The adenosine triphosphate-binding cassette, subfamily B, member 1 gene (ABCB1) encodes P-glycoprotein (P-gp) that influences the intracellular transport of solutes including endogenous opioid peptides. The primary objective of this study was to determine the effects of the ABCB1 polymorphism c.3435C>T (rs10454642) on heat pain (HP) perception in a group of opioid-free adults with chronic pain.
Learn More >Insights into T cell form, function, and dysfunction are rapidly evolving. T cells have remarkably varied effector functions including protecting the host from infection, activating cells of the innate immune system, releasing cytokines and chemokines, and heavily contributing to immunological memory. Under healthy conditions, T cells orchestrate a finely tuned attack on invading pathogens while minimizing damage to the host. The dark side of T cells is that they also exhibit autoreactivity and inflict harm to host cells, creating autoimmunity. The mechanisms of T cell autoreactivity are complex and dynamic. Emerging research is elucidating the mechanisms leading T cells to become autoreactive and how such responses cause or contribute to diverse disease states, both peripherally and within the central nervous system. This review provides foundational information on T cell development, differentiation, and functions. Key T cell subtypes, cytokines that create their effector roles, and sex differences are highlighted. Pathological T cell contributions to diverse peripheral and central disease states, arising from errors in reactivity, are highlighted, with a focus on multiple sclerosis, rheumatoid arthritis, osteoarthritis, neuropathic pain, and type 1 diabetes.
Learn More >Osteoarthritis (OA) is a chronic degenerative musculoskeletal disease that causes articular damage and chronic pain, with a prevalence of up to 50% in individuals >60 years of age. Patients suffering from chronic painful conditions, including OA, also frequently report anxiety or depression. A systematic review and meta-analysis were performed to assess the correlation between pain severity and depressive and anxious symptomatology in OA patients.
Learn More >Protocol for crystal structure determination of the antagonist-bound human cannabinoid receptor CB2.
Human cannabinoid receptor CB2 plays an important role in the immune system and is an attractive therapeutic target for pain and for inflammatory and neurodegenerative diseases. However, the structural basis of CB2 agonist selectivity is still elusive. Here, we describe a detailed protocol for the determination of the crystal structure of antagonist AM10257-bound CB2. This methodology could be applied to the structural studies of CB2 with diverse antagonists and agonists or to other class A G-protein-coupled receptors. For complete details on the use and execution of this protocol, please refer to Li et al. (2019).
Learn More >We tested the hypothesis that the cognitive impairment associated with inflammatory pain may result from dysregulation of the top-down control of locus ceruleus's (LC) activity by the medial prefrontal cortex (mPFC). Injection of complete Freund's adjuvant (CFA) served as a model for inflammatory pain. The CFA injection decreased the thermal thresholds in both sexes but only the male mice showed increased anxiety-like behavior and diminished cognition, while the females were not affected. Increased calcium fluorescence, a marker for neuronal activity, was detected by photometry in the mPFC of males but not in females with CFA. Next, while chemogenetic inhibition of the projections from the mPFC to the LC improved the object recognition memory of males with pain, the inhibition of the mPFC to LC pathway in female mice produced anxiolysis and spatial memory deficits. The behavior results prompted us to compare the reciprocal innervation of mPFC and LC between the sexes. We used an anterograde transsynaptic tagging technique, which relies on postsynaptic cre transfer, to assess the innervation of LC by mPFC efferents. The males showed a higher rate of postsynaptic cre transfer into LC neurons from mPFC efferents than the females. And vice versa, a retrograde tracing experiment demonstrated that LC to mPFC projection neurons were more numerous in females when compared to males. In conclusion, we provide evidence that subtle differences in the reciprocal neuronal circuit between the LC and mPFC may contribute to sex differences associated with the adverse cognitive effects of inflammatory pain.
Learn More >Despite considerable evidence of chronic pain in adolescents, and its adverse consequences for their health and well-being, less is known about pain-related stigma that these youth face, such as pain disbelief by others. Adolescents with chronic pain may conceal their symptoms as a coping strategy to avoid pain-related stigma, contributing to further social isolation and disruptions in medical treatment. In the current study, we used focus group methodology to examine adolescent motivations for using concealment and the possible benefits and harmful consequences of this form of coping.
Learn More >Migraine is a symptomatically heterogeneous condition, of which headache is just one manifestation. Migraine is a disorder of altered sensory thresholding, with hypersensitivity among sufferers to sensory input. Advances in functional neuroimaging have highlighted that several brain areas are involved even prior to pain onset. Clinically, patients can experience symptoms hours to days prior to migraine pain, which can warn of impending headache. These symptoms can include mood and cognitive change, fatigue, and neck discomfort. Some epidemiological studies have suggested that migraine is associated in a bidirectional fashion with other disorders, such as mood disorders and chronic fatigue, as well as with other pain conditions such as fibromyalgia. This review will focus on the literature surrounding alterations in fatigue, mood, and cognition in particular, in association with migraine, and the suggested links to disorders such as chronic fatigue syndrome and depression. We hypothesize that migraine should be considered a neural disorder of brain function, in which alterations in aminergic networks integrating the limbic system with the sensory and homeostatic systems occur early and persist after headache resolution and perhaps interictally. The associations with some of these other disorders may allude to the inherent sensory sensitivity of the migraine brain and shared neurobiology and neurotransmitter systems rather than true co-morbidity.
Learn More >Hypertension and headache disorders are major contributors to public ill health, linked by a long-standing but questionable belief that hypertension is a conspicuous cause of headache. In Nepal, where hypertension is common and often untreated, we assessed the substance of this belief, hypothesising that, should hypertension be a significant cause of headache, a clear positive association between these disorders would exist.
Learn More >Morphine is widely used in pain management although the risk of side effects is significant. The use of biased agonists to the G protein of μ-opioid receptors has been suggested as a potential solution, although oliceridine and PZM21 have previously failed to demonstrate benefits in clinical studies. An amplification-induced confusion in the process of comparing G protein and beta-arrestin pathways may account for previously biased agonist misidentification. Here, we have devised a strategy to discover biased agonists with intrinsic efficacy. We computationally simulated 430 000 molecular dockings to the μ-opioid receptor to construct a compound library. Hits were then verified experimentally. Using the verified compounds, we performed simulations to build a second library with a common scaffold and selected compounds that showed a bias to μ- and δ-opioid receptors in a cell-based assay. Three compounds (ID110460001, ID110460002, and ID110460003) with a dual-biased agonistic effect for μ- and δ-opioid receptors were identified. These candidates are full agonists for the μ-opioid receptor and show specific binding modes. On the basis of our findings, we expect our novel compounds to act as more biased agonists compared to existing drugs, including oliceridine.
Learn More >Physicians and patients report frustration after primary care visits for chronic pain. The need to shift between multiple clinical topics to address competing demands during visits may contribute to this frustration.
Learn More >Migraine is the most common neurological disorder and one of the major causes of years lived with disability. Its treatment (especially of chronic forms) is often challenging and accompanied with adverse effects. Although new therapeutic approaches have recently emerged (eg, calcitonin gene-related peptide antibodies), these are linked to strict prescribing guidelines and therefore limited to only a minority of patients. Recently, randomised controlled trials have demonstrated that open-label placebo treatments can lead to significant and clinically relevant improvements of chronic pain conditions.
Learn More >Ideally, disease-modifying osteoarthritis (OA) drugs (DMOAD) should combine chondroprotective, anti-inflammatory, and analgesic effects in a single molecule. A fusion protein of interleukin-4 (IL-4) and IL-10 (IL4-10 FP) possesses these combined effects. In this study, the DMOAD activity of rat IL4-10 FP (rIL4-10 FP) was tested in a rat model of surgically induced OA under metabolic dysregulation.
Learn More >Lockdown measures due to the COVID-19 pandemic have led to lifestyle changes, which in turn may have an impact on the course of headache disorders. We aimed to assess changes in primary headache characteristics and lifestyle factors during the COVID-19 lockdown in Germany using digital documentation in the mobile application (app) M-sense.
Learn More >Major depressive disorder (MDD) and chronic pain are highly comorbid, and pain symptoms are associated with a poorer response to antidepressant medication treatment. It is unclear whether comorbid pain also is associated with a poorer response to treatment with repetitive transcranial magnetic stimulation (rTMS).
Learn More >Erenumab is a human anti-calcitonin gene-related peptide receptor monoclonal antibody approved for migraine prevention. Global studies have demonstrated its efficacy in chronic and episodic migraine (EM). Here we report the outcomes from a Phase 3 study of erenumab in Japanese patients with chronic migraine (CM) or EM.
Learn More >Randomized clinical trials (RCT) suggest a multidisciplinary approach to pain rehabilitation is superior to other active treatments in improving pain intensity, function, disability, and pain interference for patients with chronic pain, with small effect size (ds= 0.20-0.36) but its effectiveness remains unknown in real-world practice.
Learn More >: In the absence of head-to-head comparisons, the objective of this study was to conduct a network meta-analysis (NMA) to indirectly compare the relative efficacy and safety of rimegepant, ubrogepant, and lasmiditan for the acute treatment of migraine. : A systematic literature review was conducted to identify randomized controlled trials (RCTs) of rimegepant, ubrogepant and lasmiditan in adults with acute migraine. Outcomes included sustained pain freedom and -relief 2-48 hours post-dose, and adverse events. No RCTs were identified that directly compared these interventions. Therefore, a fixed-effects Bayesian NMA was conducted by identifying a connected (via comparison to placebo) network of RCTs. : Five RCTs were identified: rimegepant study 303 (n=1,466), ubrogepant ACHIEVE I and II (n=1,672 and n=1,686, respectively), and lasmiditan SAMURAI and SPARTAN (n=2,231 and n=3,005, respectively). Efficacy outcomes (pain freedom and relief at 2, 24, 48 hours) tended to be highest for lasmiditan 200 mg and rimegepant followed lower doses of lasmiditan and all doses of ubrogepant. However, lasmiditan 200 mg was also associated with higher rates of adverse events, particularly somnolence and dizziness. : Lasmiditan, rimegepant, and ubrogepant all performed significantly better than placebo with respect to pain freedom and pain relief. Efficacy results were similar for rimegepant and lasmiditan with rimegepant having higher rates of pain freedom and relief than lower doses of lasmiditan, while somnolence and dizziness outcomes were lower for rimegepant than higher doses of lasmiditan.
Learn More >The association between exposure to adverse childhood experiences (ACEs) and increased headache in adults has been well characterized. Childhood adversity and its effect on headache in children have not been as robustly investigated. This study examines the relationship of self-reported ACEs to frequent headache in an adolescent cohort.
Learn More >Contextual factors, such as participant/experimenter sex may moderate the placebo effects. We tested whether the participant and experimenter sex modulated placebo effects on experimentally induced pain and associated stress.
Learn More >The objective of this study was to identify the trajectories that patients take after initiating long-term opioid therapy (LTOT).
Learn More >Chronic neuropathic pain affects 7%-10% of the population. Deep brain stimulation (DBS) has shown variable but promising results in its treatment. This study prospectively assessed the long-term effectiveness of DBS in a series of patients with chronic neuropathic pain, correlating clinical results with neuroimaging. Sixteen patients received 5 years' post-surgical follow-up in a single center. Six had phantom limb pain after amputation and 10 had deafferentation pain after traumatic brachial plexus injury. Patient-reported outcome measures were completed before and after surgery, using VAS, UWNPS, BPI and SF-36 scores. Neuroimaging evaluated electrode location and effective volumes of activated tissue (VAT). Two subgroups were created based on the percentage of VAT superimposed upon the ventroposterolateral thalamic nucleus (eVAT), and clinical outcomes were compared. Analgesic effect was assessed at 5 years and compared to preoperative pain, with an improvement on VAS of 76.4% (p = 0.0001), on UW-NPS of 35.2% (p = 0.3582), on BPI of 65.1% (p = 0.0505) and on SF-36 of 5% (p = 0.7406). Eight patients with higher eVAT showed improvement on VAS of 67.5% (p=0.0017) while the remaining patients, with lower eVAT, improved by 50.6% (p=0.03607). DBS remained effective in improving chronic neuropathic pain after 5 years. While VPL-targeting contributes to success, analgesia is also obtained by stimulating surrounding posterior ventrobasal thalamic structures and related spinothalamocortical tracts.
Learn More >Critical illness is often painful, both from the underlying source of illness, as well as necessary procedures performed for the monitoring and care of these patients. Pain is often under-recognized in the critically ill, especially among those who cannot self-report, so accurate assessment and management continue to be major consideration in their care. Pain management in the intensive care unit (ICU) is an evolving practice, with a focus on accurate and frequent pain assessment, and targeted pharmacologic and non-pharmacologic treatment methods to maximize analgesia and minimize sedation. In this review, we will evaluate several validated methods of pain assessment in the ICU and present management options. We will review the evidence-based recommendations put forth by the largest critical care societies and several high-quality studies related to both the in-hospital approach to pain, as well as the short- and long-term consequences of untreated pain in ICU patients. We conclude with future directions.
Learn More >The coronavirus disease pandemic of 2019 (COVID-19) is a worldwide threat to public health that has significantly affected the United States. The pandemic poses a variety of health risks including stressful disruptions in social and economic activity. Understanding the pandemic's effects on already vulnerable populations, such as individuals with chronic pain, may inform healthcare preparation for future catastrophic events. Given the association between excessive discounting of delayed rewards and chronic pain, this study examined relationships between delay discounting, pain severity, and COVID-19 perceived stress in individuals with chronic pain. Individuals reporting chronic pain (N = 180; 41% female; 86% white; 59% with a college degree) were recruited via the Amazon Mechanical Turk platform in this cross-sectional study. Measures of pain severity, delay discounting, probability discounting, and COVID-19 perceived stress were collected. Delay discounting was a significant predictor of overall pain severity (p < .02) and COVID-19 perceived stress (p < .001). Also, the magnitude of COVID-19 perceived stress fully mediated the relationship between delay discounting and overall pain severity (p = .004). Probability discounting was not a significant predictor of pain severity or COVID-19 perceived stress (p > .05). These findings highlight the importance of excessive discounting of delayed rewards as a potential determinant of pain severity as well as predictor of perceived stress related to the COVID-19 pandemic. Thus, the discounting of delayed rewards is of particular therapeutic importance for individuals with chronic pain in the context of stressful events. (PsycInfo Database Record (c) 2021 APA, all rights reserved).
Learn More >Pain and fatigue are persistent problems in people with rheumatoid arthritis. Central sensitisation (CS) may contribute to pain and fatigue, even when treatment has controlled inflammatory disease. This study aims to validate a self-report 8-item questionnaire, the Central Aspects of Pain in Rheumatoid Arthritis (CAP-RA) questionnaire, developed to measure central pain mechanisms in RA, and to predict patient outcomes and response to treatment. A secondary objective is to explore mechanisms linking CS, pain and fatigue in people with RA.
Learn More >The association between diet and migraine has been reported in the literature, but only a few studies have evaluated whether the diet consumed by patients with migraine differs from individuals without migraine.
Learn More >Complex regional pain syndrome (CRPS) is a chronic pain condition often involving hyperalgesia and allodynia of the extremities. CRPS is divided into CRPS-I and CRPS-II. Type I occurs when there is no confirmed nerve injury. Type II is when there is known associated nerve injury. Female gender is a risk factor for developing CRPS. Other risk factors include fibromyalgia and rheumatoid arthritis. Unfortunately, the pathogenesis of CRPS is not yet clarified. Some studies have demonstrated different potential pathways. Neuropathic inflammation, specifically activation of peripheral nociceptors of C-fibers, has been shown to play a critical role in developing CRPS. The autonomic nervous system (ANS) is involved. Depending on whether it is acute or chronic CRPS, norepinephrine levels are either decreased or increased, respectively. Some studies have suggested the importance of genetics in developing CRPS. More consideration is being given to the role of psychological factors. Some association between a history of depression and/or post-traumatic stress disorder (PTSD) and the diagnosis of CRPS has been demonstrated. Treatment modalities available range from physical therapy, pharmacotherapy, and interventional techniques. Physical and occupational therapies include mirror therapy and graded motor imagery. Medical management with non-steroidal anti-inflammatory drugs (NSAIDs) has not shown significant improvement. There have been supporting findings in the use of short-course steroids, bisphosphonates, gabapentin, and ketamine. Antioxidant treatment has also shown some promise. Other pharmacotherapies include low-dose naltrexone and Botulinum toxin A (BTX-A). Sympathetic blocks are routinely used, even if their short- and long-term effects are not clear. Finally, spinal cord stimulation (SCS) has been used for decades. In conclusion, CRPS is a multifactorial condition that still requires further studying to better understand its pathogenesis, epidemiology, genetic involvement, psychological implications, and treatment options. Future studies are warranted to better understand this syndrome. This will provide an opportunity for better prevention, diagnosis, and treatment of CRPS.
Learn More >Previous studies have shown that persistent limb immobilization using a cast increases nociceptive behavior to somatic stimuli in rats. However, the peripheral neural mechanisms of nociception remain unclear. Using single-fiber electrophysiological recordings in vitro, we examined the general characteristics of cutaneous C-fiber afferents in the saphenous nerve and their responsiveness to mechanical and heat stimuli in a rat model of immobilization-induced pain by subjecting the rats to hindlimb cast immobilization for 4 weeks. The mechanical response of C-fibers appeared to increase in the model; however, statistical analysis revealed that neither the response threshold nor the response magnitude was altered. The general characteristics and heat responses of the C-fibers were not altered. The number of microglia and cell diameters significantly increased in the superficial dorsal horn of the lumbar spinal cord. Thus, activated microglia-mediated spinal mechanisms are associated with the induction of nociceptive hypersensitivity in rats after persistent cast immobilization.
Learn More >The rising opioid crisis has become a worldwide societal and public health burden, resulting from the abuse of prescription opioids. Targeting the κ-opioid receptor (KOR) in the periphery has emerged as a powerful approach to develop novel pain medications without central side effects. Inspired by the traditional use of sunflower () preparations for analgesic purposes, we developed novel stabilized KOR ligands (termed as helianorphins) by incorporating different dynorphin A sequence fragments into a cyclic sunflower peptide scaffold. As a result, helianorphin-19 selectively bound to and fully activated the KOR with nanomolar potency. Importantly, helianorphin-19 exhibited strong KOR-specific peripheral analgesic activity in a mouse model of chronic visceral pain, without inducing unwanted central effects on motor coordination/sedation. Our study provides a proof of principle that cyclic peptides from plants may be used as templates to develop potent and stable peptide analgesics applicable via enteric administration by targeting the peripheral KOR for the treatment of chronic abdominal pain.
Learn More >Pruritus (itch) is a debilitating symptom in liver diseases with cholestasis, which severely affects patients' quality of life. Limited treatment options are available for cholestatic itch, largely due to the incomplete understanding of the underlying molecular mechanisms. Several factors have been proposed as pruritogens for cholestatic itch, such as bile acids, bilirubin, lysophosphatidic acid, and endogenous opioids. Recently, two research groups independently identified Mas-related G protein-coupled receptor X4 (MRGPRX4) as a receptor for bile acids and bilirubin and demonstrated its likely role in cholestatic itch. This discovery not only opens new avenues for understanding the molecular mechanisms in cholestatic itch but provides a promising target for developing novel anti-itch treatments. In this review, we summarize the current theories and knowledge of cholestatic itch, emphasizing MRGPRX4 as a bile acid and bilirubin receptor mediating cholestatic itch in humans. We also discuss some future perspectives in cholestatic itch research.
Learn More >Novel treatments of neuropathic pain (NP) are urgently needed. Based on repeated observation of rapid relief of neuropathic cancer pain (NCP) after single doses of intravenous epidermal growth factor receptor inhibitor (EGFR-I), we have successfully treated patients with and without cancer who suffer from severe, treatment-refractory NP with EGFR-Is. Pain research is complicated by endpoint subjectivity. Patients with advanced cancer are heterogeneous, with complex, fluctuating clinical pictures, hampering feasibility of standard drug-trial procedures.
Learn More >α9-Containing nicotinic acetylcholine receptors (nAChRs) are key targets for the treatment of neuropathic pain. α-Conotoxin RgIA4 is a peptide antagonist of human α9α10 nAChRs with high selectivity. However, structural rearrangement reveals a potential liability for clinical applications. We herein report our designer RgIA analogues stabilized by methylene thioacetal as nonopioid analgesic agents. We demonstrate that replacing disulfide loop I [Cys-Cys] with methylene thioacetal in the RgIA skeleton results in activity loss, whereas substitution of loop II [Cys-Cys] can be accommodated. The lead molecule, RgIA-5524, exhibits highly selective inhibition of α9α10 nAChRs with an IC of 0.9 nM and much reduced degradation in human serum. studies showed that RgIA-5524 relieves chemotherapy-induced neuropathic pain in wild type but not α9 knockout mouse models, demonstrating that α9-containing nAChRs are necessary for the therapeutic effects. This work highlights the application of methylene thioacetal as a disulfide surrogate in conotoxin-based, disulfide-rich peptide drugs.
Learn More >To determine the acceptability and feasibility of acupuncture for the treatment of endometriosis-related chronic pelvic pain. A prospective, randomized controlled feasibility study. Outpatient setting in Sydney, Australia. Participants who were aged 18-45 years, had a confirmed laparoscopic diagnosis of endometriosis in the past 5 years, and had regular menstrual periods and mean pelvic pain scores ≥4/10. Sixteen acupuncture treatments delivered by registered acupuncturists using a standardized point protocol over 8 weeks, twice per week plus usual care compared with usual care alone. Primary outcome measures were feasibility, safety, and acceptability of the acupuncture intervention. Secondary outcomes were changes in self-reported pelvic pain scores, changes in quality of life as measured by the Endometriosis Health Profile (EHP-30), changes in descending pain modulation, and changes in systemic inflammation (plasma interleukin [IL-6] concentrations). Twenty-nine participants were eligible to participate, with 19 participants completing the trial. There was unequal withdrawals between groups; the acupuncture group had a withdrawal rate of 14% compared with 53% in usual care. Adverse events were uncommon (6.7%) and generally mild. A 1.9 point decrease in median nonmenstrual pain scores and a 2.0 decrease in median menstrual pain scores between baseline and end of trial were observed in the acupuncture group only. Improvements in all domains of the EHP-30 were seen in the acupuncture group, with no changes seen in usual care. There was no difference between baseline and end of treatment in IL-6 concentrations for either group. Acupuncture was an acceptable, well-tolerated treatment and it may reduce pelvic pain and improve quality of life; however, usual care was not an acceptable control group. anzctr.org.au: ACTRN12617000053325. Prospectively registered January 11, 2017.
Learn More >Cranial neuralgias are common in the setting of posttraumatic headache. They may exacerbate underlying primary headache disorders and therefore may be overlooked in clinical practice. Frequently, cranial neuralgias generate neuropathic symptoms such as lancinating pain and sensory dysesthesias. Cranial neuralgias are identified based on a clinical history of focal neuropathic pain and physical exam findings including tenderness with palpation and percussion, at times eliciting radiating pain or paresthesias in the corresponding sensory nerve distribution.
Learn More >In 2016, the Centers for Disease Control and Prevention analyzed the National Health Interview Survey data and found that the occurrence of chronic pain and high-impact chronic pain in the USA was 20.4% and 8%, respectively. Group-based Pain Management Programs have been viewed as significant treatments aiding patients with self-management of chronic pain. The onset of coronavirus disease 2019 (COVID-19) at the beginning of 2020, widely eliminated the in-person Group-based Pain Management Programs. The exploration of therapeutic contextual factors such as the therapeutic alliance and group dynamics in telehealth Group-based Pain Management Programs appears warranted for which reason the Therapeutic Group Context Questionnaire was developed.
Learn More >Current prophylactic drugs for cluster headache are associated with limited efficacy, serious side effects and poor tolerability. Greater occipital nerve injection (GON-injection) has been proven effective and safe as a single, one-time injection in episodic (ECH), and to a lesser extent, chronic cluster headache (CCH). We aim to analyse the effectiveness and safety of repeated GON-injections in medically intractable chronic cluster headache (MICCH).
Learn More >Neuromuscular impairments are frequently observed in patients with chronic neck pain (CNP). This study uniquely investigates whether changes in neck muscle synergies detected during gait are sensitive enough to differentiate between people with and without CNP. Surface electromyography (EMG) was recorded from the sternocleidomastoid, splenius capitis, and upper trapezius muscles bilaterally from 20 asymptomatic individuals and 20 people with CNP as they performed rectilinear and curvilinear gait. Intermuscular coherence was computed to generate the functional inter-muscle connectivity network, the topology of which is quantified based on a set of graph measures. Besides the functional network, spectrotemporal analysis of each EMG was used to form the feature set. With the use of Neighbourhood Component Analysis (NCA), we identified the most significant features and muscles for the classification/differentiation task conducted using K-Nearest Neighbourhood (K-NN), Support Vector Machine (SVM), and Linear Discriminant Analysis (LDA) algorithms. The NCA algorithm selected features from muscle network topology as one of the most relevant feature sets, which further emphasize the presence of major differences in muscle network topology between people with and without CNP. Curvilinear gait achieved the best classification performance through NCA-SVM based on only 16 features (accuracy: 85.00%, specificity: 81.81%, and sensitivity: 88.88%). Intermuscular muscle networks can be considered as a new sensitive tool for the classification of people with CNP. These findings further our understanding of how fundamental muscle networks are altered in people with CNP.
Learn More >Abnormalities in pain processing have been observed in patients with chronic pain conditions and in individuals who engage in self-harm, specifically nonsuicidal self-injurious behaviors (NSSI). Both increased and decreased pain sensitivity have been described in chronic pain patients, while decreased pain sensitivity is consistently observed in individuals with NSSI. The objective of the study was to identify the differential effects of chronic pain and NSSI on experimental pain sensitivity, specifically pressure pain threshold, in depressed patients. Moreover, the role that hopelessness may play between depression severity and pain sensitivity was also examined. Depressed patients with and without chronic pain, and with and without lifetime self-harm behaviors were analyzed into four groups. Group 1 (N = 42) included depressed patients with both Chronic pain ( +) and Self-harm ( +), Group 2 (N = 53) included depressed patients with Chronic pain ( +) but no Self-harm (-), Group 3 (N = 64) included depressed patients without Chronic pain (-), but Self-harm ( +), and Group 4 (N = 81) included depressed patients with neither Chronic pain (-) nor Self-harm (-). Healthy controls (N = 45) were also recruited from the community. Depressed patients with both Chronic pain ( +) and Self-harm ( +) reported higher pressure pain threshold measures when compared with the other groups. Mediation analysis indicated that hopelessness mediates the relationship between depression severity and pressure pain threshold. Our findings suggest that a multiprong approach including adequate mental health services and pain control for depressed patients with comorbid chronic pain and nonsuicidal self-harm is needed to yield effective outcomes.
Learn More >The angiotensin II type 2 receptor (ATR) has attracted much attention as a potential target for the relief of neuropathic pain, which represents an area of unmet clinical need. A series of 1,2,3,4-tetrahydroisoquinolines with a benzoxazole side-chain were discovered as potent ATR antagonists. Rational optimization resulted in compound , which demonstrated both excellent antagonistic activity against ATR and analgesic efficacy in a rat chronic constriction injury model. Its favorable physicochemical properties and oral bioavailability make it a promising therapeutic candidate for neuropathic pain.
Learn More >The nerve growth factor (NGF) plays an important role in the regulation of neuropathic pain. It has been demonstrated that calcitonin gene-related peptide (CGRP), a well-known contributor to neurogenic inflammation, increases neuroinflammatory pain induced by NGF. The inflammatory mediator that NGF most strongly induces is C-C chemokine ligand 19 (CCL19), which can recruit inflammatory cells by binding to the receptor CCR7 followed by promoting the response of neuroinflammation. However, the regulatory mechanism of NGF and CCL19 in tooth movement orofacial pain and the interaction between both are still unclear. In this study, male Sprague-Dawley rats were used to study the modulation of NGF on orofacial pain through CCL19 and the role of each in tooth movement pain in rats. The expression levels of CCL19 mRNA and protein were determined by real-time PCR and immunofluorescence, respectively. Pain levels were assessed by measuring the rats' bite force, which drops as pain rises. Meanwhile, by verifying the relationship between CGRP and CCL19, it was laterally confirmed that NGF could modulate tooth movement-induced mechanical hyperalgesia through CCL19. The results showed that the expression level of CCL19 rose with the increased NGF, and neurons expressing CGRP can express stronger CCL19. Compared with the baseline level, the bite force for all rats dropped sharply on day 1, reached its lowest level on day 3, and recovered gradually on day 5. All results indicated that NGF played an important role in tooth movement orofacial pain positively regulating CCL19 expression in the trigeminal ganglia of rats. Additionally, CCL19 increased the sensitivity to experimental tooth movement orofacial pain. NGF can regulate CCL19 expression, although it may regulate other inflammatory pathways as well. This is the first report on the interactions and modulations of tooth movement orofacial pain by NGF through CCL19 in rats.
Learn More >Chronic pain is challenging and costly to treat. Depression and anxiety co-occur with chronic pain. Identifying psychosocial mechanisms contributing to emotional outcomes among chronic pain patients can inform future iterations of this intervention.
Learn More >Functional Restorative Programmes (FRP) for persistent non-specific lower back pain have been shown to be effective, but they often lack sufficient detailed reporting of the intervention components to allow for accurate replication.
Learn More >For most procedures, there is insufficient evidence to guide clinicians in the optimal timing of advanced analgesic methods, which should be based on the expected time course of acute postoperative pain severity and aimed at time points where basic analgesia has proven insufficient.
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