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Ketamine is often used for the management of refractory chronic pain. There is, however, a paucity of trials exploring its analgesic effect several weeks after intravenous administration or in association with magnesium. The authors hypothesized that ketamine in neuropathic pain may provide pain relief and cognitive-emotional benefit versus placebo and that a combination with magnesium may have an additive effect for 5 weeks.
Learn More >An accelerating basic science literature is providing key insights into the mechanisms by which spinal neuropeptide Y (NPY) inhibits chronic pain. A key target of pain inhibition is the G-coupled neuropeptide Y1 receptor (Y1). Y1 is located in key sites of pain transmission, including the peptidergic subpopulation of primary afferent neurons and a dense subpopulation of small, excitatory, glutamatergic/somatostatinergic interneurons (Y1-INs) that are densely expressed in the dorsal horn, particularly in superficial lamina I-II. Selective ablation of spinal Y1-INs with an NPY-conjugated saporin neurotoxin attenuates the development of peripheral nerve injury-induced mechanical and cold hypersensitivity. Conversely, conditional knockdown of NPY expression or intrathecal administration of Y1 antagonists reinstates hypersensitivity in models of chronic latent pain sensitization. These and other results indicate that spinal NPY release and the consequent inhibition of pain facilitatory Y1-INs represent an important mechanism of endogenous analgesia. This mechanism can be mimicked with exogenous pharmacological approaches (e.g. intrathecal administration of Y1 agonists) to inhibit mechanical and thermal hypersensitivity and spinal neuron activity in rodent models of neuropathic, inflammatory, and postoperative pain. Pharmacological activation of Y1 also inhibits mechanical- and histamine-induced itch. These immunohistochemical, pharmacological, and cell type-directed lesioning data, in combination with recent transcriptomic findings, point to Y1-INs as a promising therapeutic target for the development of spinally directed NPY-Y1 agonists to treat both chronic pain and itch.
Learn More >Thalamocortical dysrhythmia is a key pathology of chronic neuropathic pain, but few studies have investigated thalamocortical networks in chronic low back pain (cLBP) given its non-specific etiology and complexity. Using fMRI, we propose an analytical pipeline to identify abnormal thalamocortical network dynamics in cLBP patients and validate the findings in two independent cohorts. We first identify two reoccurring dynamic connectivity states and their associations with chronic and temporary pain. Further analyses show that cLBP patients have abnormal connectivity between the ventral lateral/posterolateral nucleus (VL/VPL) and postcentral gyrus (PoCG) and between the dorsal/ventral medial nucleus and insula in the less frequent connectivity state, and temporary pain exacerbation alters connectivity between the VL/VPL and PoCG and the default mode network in the more frequent connectivity state. These results extend current findings on thalamocortical dysfunction and dysrhythmia in chronic pain and demonstrate that cLBP pathophysiology and clinical pain intensity are associated with distinct thalamocortical network dynamics.
Learn More >Diabetic peripheral neuropathy (DPN) is a highly frequent and debilitating clinical complication of diabetes that lacks therapies. Cellular oxidative stress regulates post-translational modifications, including SUMOylation. Here, using unbiased screens, we identified key enzymes in metabolic pathways and ion channels as novel molecular targets of SUMOylation that critically regulated their activity. Sensory neurons of diabetic patients and diabetic mice demonstrated changes in the SUMOylation status of metabolic enzymes and ion channels. In support of this, profound metabolic dysfunction, accelerated neuropathology, and sensory loss were observed in diabetic gene-targeted mice selectively lacking the ability to SUMOylate proteins in peripheral sensory neurons. TRPV1 function was impaired by diabetes-induced de-SUMOylation as well as by metabolic imbalance elicited by de-SUMOylation of metabolic enzymes, facilitating diabetic sensory loss. Our results unexpectedly uncover an endogenous post-translational mechanism regulating diabetic neuropathy in patients and mouse models that protects against metabolic dysfunction, nerve damage, and altered sensory perception.
Learn More >Recent meta-analyses have shown mindfulness-based interventions (MBIs) to be effective for chronic pain, but no pooled estimates of the effect of MBIs on acute pain are available. This meta-analysis was conducted to fill that gap. A literature search was conducted in 4 databases. Articles were eligible if they reported on randomized controlled trials of MBIs for people with acute pain and one of the following outcomes: pain severity, pain threshold, pain tolerance, or pain-related distress. Two authors independently extracted the data, assessed risk of bias, and provided GRADE ratings. Twenty-two studies were included. There was no evidence of an effect of MBIs on the primary outcome of pain severity in clinical {Hedges' g = 0.52; (95% confidence interval [CI] -0.241 to 1.280)} or experimental settings (Hedges' g = 0.04; 95% CI [-0.161 to 0.247]). There was a beneficial effect of MBIs on pain tolerance (Hedges' g = 0.68; 95% CI [0.157-1.282]) and pain threshold (Hedges' g = 0.72; 95% CI [0.210-1.154]) in experimental studies. There was no evidence of an effect of MBIs compared to control for pain-related distress in clinical (Hedges' g = 0.16; 95% CI [-0.018 to 0.419]) or experimental settings (Hedges' g = 0.44; 95% CI [-0.164 to 0.419]). GRADE assessment indicated that except for pain tolerance, the data were of low or very low quality. There is moderate evidence that MBIs are efficacious in increasing pain tolerance and weak evidence for pain threshold. However, there is an absence of good-quality evidence for the efficacy of MBIs for reducing the pain severity or pain-related distress in either clinical or experimental settings.
Learn More >Pulsed electromagnetic field (PEMF) therapy is a potentially useful treatment for osteoarthritis (OA), but its effectiveness is still controversial. This study aimed to examine the effects of PEMF therapy and PEMF parameters on symptoms and quality of life (QOL) in patients with OA.
Learn More >Regeneration after injury occurs in axons that lie in the peripheral nervous system but fails in the central nervous system, thereby limiting functional recovery. Differences in axonal signalling in response to injury that might underpin this differential regenerative ability are poorly characterized. Combining axoplasmic proteomics from peripheral sciatic or central projecting dorsal root ganglion (DRG) axons with cell body RNA-seq, we uncover injury-dependent signalling pathways that are uniquely represented in peripheral versus central projecting sciatic DRG axons. We identify AMPK as a crucial regulator of axonal regenerative signalling that is specifically downregulated in injured peripheral, but not central, axons. We find that AMPK in DRG interacts with the 26S proteasome and its CaMKIIα-dependent regulatory subunit PSMC5 to promote AMPKα proteasomal degradation following sciatic axotomy. Conditional deletion of AMPKα1 promotes multiple regenerative signalling pathways after central axonal injury and stimulates robust axonal growth across the spinal cord injury site, suggesting inhibition of AMPK as a therapeutic strategy to enhance regeneration following spinal cord injury.
Learn More >The chronification of pain can be attributed to changes in membrane receptors and channels underlying neuronal plasticity and signal transduction largely within nociceptive neurons that initiate and maintain pathological pain states. These proteins are subject to dynamic modification by post-translational modifications (PTM), creating a code that controls protein function in time and space. Phosphorylation is an important PTM that affects ∼30% of proteins in vivo. Increased phosphorylation of various nociceptive ion channels and of their modulators underlies sensitization of different pain states. Cyclin-dependent kinases are proline-directed serine/threonine kinases that impact various biological and cellular systems. Cdk5, one member of this kinase family, and its activators p35 and p39 are expressed in spinal nerves, dorsal root ganglia and in the dorsal horn of the spinal cord. In neuropathic pain conditions expression and/or activity of Cdk5 is increased, implicating Cdk5 in nociception. Experimental evidence suggests that Cdk5 is regulated via its own phosphorylation, through increasing p35's interaction with Cdk5, and via cleavage of p35 into p25. This narrative review discusses the molecular mechanisms of Cdk5-mediated regulation of target proteins involved in neuropathic pain. We focus on Cdk5-substrates that have been linked to nociceptive pathways, including channels (e.g., transient receptor potential cation channel, voltage-gated calcium channel), proteins involved in neurotransmitter release (e.g., synaptophysin, collapsin response mediator protein 2), and receptors (e.g., glutamate, purinergic, and opioid). By altering the phosphoregulatory "set-point" of proteins involved in pain signaling, Cdk5 thus appears to be an attractive target for treating neuropathic pain conditions.
Learn More >Diminished synaptic inhibition in the spinal dorsal horn is a major contributor to pathological pain syndromes of neuropathic or inflammatory origin. Drugs that enhance the activity of dorsal horn α2/α3GABAARs normalize exaggerated nociceptive responses in rodents with neuropathic nerve lesions or peripheral inflammation but lack most of the typical side effects of less specific GABAergic drugs. It is however still unknown whether such drugs also reduce the clinically more relevant conscious perception of pain. Here, we investigated the effects of the α2/α3GABAAR subtype-selective modulator TPA023B on the tonic aversive component of pain in mice with peripheral inflammation or neuropathy. In neuropathic mice with a chronic constriction injury of the sciatic nerve, TPA023B not only reversed hyperalgesia to tactile and heat stimuli, but was also highly effective in the conditioned place preference test. In the formalin test, TPA023B not only reduced licking of the injected paw but also reversed facial pain expression scores in the mouse grimace scale assay. Taken together, our results demonstrate that α2/α3GABAA receptor subtype-selective modulators not only reduce nociceptive withdrawal responses but also alleviate the tonic aversive components of chronic pain.
Learn More >Fibromyalgia is a common and challenging chronic pain disorder with few, if any, highly effective and well tolerated treatments. Alpha-lipoic acid (ALA) is a non-sedating antioxidant with evidence of efficacy in the treatment of symptomatic diabetic neuropathy that has not been evaluated in the setting of fibromyalgia treatment. Thus, we conducted a single-centre, proof-of-concept, randomized, placebo-controlled, crossover trial of ALA for the treatment of fibromyalgia. Twenty-seven participants were recruited and 24 participants completed both treatment periods of the trial. The median maximal tolerated dose of ALA in this trial was 1,663 mg/day. Treatment-emergent adverse events with ALA were infrequent and not statistically different from placebo. For the primary outcome of pain intensity, and for several other validated secondary outcomes, there were no statistically significant differences between placebo and ALA. A post hoc exploratory subgroup analysis showed a significant interaction between gender and treatment with a significant favourable placebo-ALA difference in pain for males, but not for females. Overall, the results of this trial do not provide any evidence to suggest promise for ALA as an effective treatment for fibromyalgia, which is predominantly prevalent in females. This negative clinical trial represents an important step in a collective strategy to identify new, better tolerated and more effective treatments for fibromyalgia.
Learn More >Pain after total knee arthroplasty (TKA) is a prevalent condition. This study compared the effectiveness of tapentadol extended release (ER) 50 mg x 2, oxycodone controlled release (CR) 10 mg x 2 and placebo; as added to a multimodal analgesic regime both in-hospital and at home the first week after TKA. The study was randomized and blinded for investigators, staff, outcome assessors and patients. Follow-up included pain intensity on mobilization, pain at rest, worst pain in the previous 24 hours, and adverse effects measured on 0-10 numeric rate scales. A total of 134 patients in three study groups received their allocated intervention and were included in the analysis. The primary outcome pain on mobilization the 7 first postoperative days reported as mean pain Area Under the Curve (AUC) was 528.1 (SD 267.5, IQR 356.6 to 665.4) for placebo, 427.2 (SD 203.9, IQR 303.6 to 544.3) for tapentadol ER and 507.9 (SD 243.7, IQR 292.4 to 686.8) for oxycodone CR (p=0.12). With the exception of constipation being less prevalent in the tapentadol ER group (p=0.02), we found no significant differences between treatment groups for the secondary outcomes. Tapentadol ER as an add-on to multimodal analgesia did not significantly improve pain relief when compared to oxycodone CR or placebo. Constipation was lowest in the tapentadol ER group.
Learn More >High mobility group box 1 protein (HMGB1) is increasingly regarded as an important player in the spinal regulation of chronic pain. While it has been reported that HMGB1 induces spinal glial activation in a Toll-like receptor (TLR)4-dependent fashion, the aspect of sexual dimorphisms has not been thoroughly addressed. Here, we examined whether the action of TLR4-activating, partially reduced disulfide HMGB1 on microglia induces nociceptive behaviors in a sex-dependent manner. We found disulfide HMGB1 to equally increase microglial Iba-1 immunoreactivity in lumbar spinal dorsal horn in male and female mice, but evoke higher cytokine and chemokine expression in primary microglial culture derived from males compared to females. Interestingly, TLR4 ablation in myeloid-derived cells, which include microglia, only protected male mice from developing HMGB1-induced mechanical hypersensitivity. Spinal administration of the glial inhibitor, minocycline, with disulfide HMGB1 also prevented pain-like behavior in male mice. To further explore sex difference, we examined the global spinal protein expression using liquid chromatography-mass spectrometry (LC-MS/MS) and found several antinociceptive and anti-inflammatory proteins to be upregulated in only male mice subjected to minocycline. One of the proteins elevated, alpha-1-antitrypsin, partially protected males but not females from developing HMGB1-induced pain. Targeting downstream proteins of alpha-1-antitrypsin failed to produce robust sex differences in pain-like behavior, suggesting that several proteins identified by LC-MS/MS are required to modulate the effects. Taken together, the current study highlights the importance of mapping sex dimorphisms in pain mechanisms and point to processes potentially involved in the spinal antinociceptive effect of microglial inhibition in male mice.
Learn More >Patients with neuropathic pain often experience exaggerated pain and anxiety. Central sensitization has been linked with the maintenance of neuropathic pain and may become an autonomous pain generator. Conversely, emerging evidence accumulated that central sensitization is initiated and maintained by ongoing nociceptive primary afferent inputs. However, it remains elusive what mechanisms underlie this phenomenon and which peripheral candidate contributes to central sensitization that accounts for pain hypersensitivity and pain-related anxiety. Previous studies have implicated peripherally-localized cGMP-dependent protein kinase I (PKG-I) in plasticity of nociceptors and spinal synaptic transmission as well as inflammatory hyperalgesia. However, whether peripheral PKG-I contributes to cortical plasticity and hence maintains nerve injury-induced pain hypersensitivity and anxiety is unknown. Here we demonstrated significant upregulation of PKG-I in ipsilateral L3 DRG, no change in L4 DRG and downregulation in L5 DRG upon spared nerve injury (SNI). Genetic ablation of PKG-I specifically in nociceptors or posttreatment with intervertebral foramen injection of PKG-I antagonist, KT5823 attenuated the development and maintenance of SNI-induced bilateral pain hypersensitivity and anxiety. Mechanistic analysis revealed that activation of PKG-I in nociceptors is responsible for synaptic potentiation in ACC upon peripheral neuropathy via presynaptic mechanisms involving BDNF signaling. Our results revealed that PKG-I expressed in nociceptors is a key determinant for cingulate synaptic plasticity after nerve injury, which contributes to the maintenance of pain hypersensitivity and anxiety. Thereby, this study presents a strong basis for opening up a novel therapeutic target, PKG-I in nociceptors for treatment of comorbidity of neuropathic pain and anxiety with least side effects.
Learn More >The subgenual anterior cingulate cortex (sgACC) plays an important role in pain modulation. We previously demonstrated sex differences in sgACC functional connectivity (FC) in healthy individuals. Given that many chronic pain conditions show sex differences in prevalence, here we tested the hypothesis that people with chronic pain exhibit a sex-specific pattern of abnormal sgACC FC. We acquired resting state functional magnetic resonance imaging (fMRI) data from 156 (82W:74M) healthy participants and 38 (19W:19M) people with chronic low back pain resulting from ankylosing spondylitis (AS), a condition that predominantly affects men. We confirmed that there are sex differences in sgACC FC in our large cohort of healthy adults; women had greater sgACC FC with the precuneus, a key node of the default mode network, and men had greater sgACC FC with the posterior insula and the operculum. Next, we identified an interaction effect between sex and pain status (healthy/chronic pain) for sgACC FC. Within the chronic pain group, women had greater sgACC FC than men to the salience, default mode, and sensorimotor networks. Compared to healthy women, women with chronic pain also had greater sgACC FC to the precuneus and ACC and lower FC to the hippocampus and frontal regions. No differences in sgACC FC were seen in men with vs. without chronic pain. Our findings indicate that abnormal sgACC circuitry is unique to women but not men with AS-related chronic pain. These sex differences may impact the benefit of therapeutics that target the sgACC for chronic pain.
Learn More >The differentiation of chronic primary pain syndromes into those with widespread versus regional musculoskeletal pain has been characterized by controversial discussions about common or distinct mechanisms and core clinical and sensory criteria. For example, the recent revision of fibromyalgia criteria has discarded sensory characteristics such as number of "tender points". This study examined empirical evidence related to this diagnostic shift and aimed to identify basic sensory-clinical pain phenotypes in patients with chronic local primary pain (chronic primary back pain, CBP) and patients with chronic widespread primary pain (fibromyalgia syndrome, FMS). Combined sensory-clinical pain phenotypes of 185 patients with prior CBP and FMS diagnoses were derived by a stepwise data-reduction through descriptive statistical, correlational, principal components and latent class analyses. Clusters were cross-validated by linear discriminant analysis. Four clusters of patients were identified, requiring four pressure pain sensitivity markers (number of sensitive tender and control points, pain intensity and pressure pain threshold at the trapezius) and two clinical pain characteristics (pain regions, present pain intensity). Subsequent discriminant analysis revealed that three discriminant functions of pressure sensitivity markers sufficed to differentiate the clusters. These sensory-clinical phenotypes differed also in somatic symptoms and impairment but neither in psychopathology nor in psychosocial co-factors. The results highlight the relevance of sensory testing in combination with clinical pain assessment in chronic primary pain syndromes.
Learn More >Adaptations in brain communication are associated with multiple pain disorders and are hypothesized to promote the transition from acute to chronic pain. Despite known increases in brain synaptic activity, it is unknown if and how changes in pathways and networks contribute to persistent pain. A tunable rat model that induces transient or persistent temporomandibular joint pain was used to characterize brain network and sub-circuit changes when sensitivity is detected in both transient and persistent pain groups and later when sensitivity is present only for the persistent pain group. Brain activity was measured by F-FDG PET imaging and used to construct inter-subject correlation networks; network connectivity distributions, diagnostics, and community structure were assessed. Activation of sub-circuits was tested by structural equation modeling. Findings reveal differences in the brain networks at day 7 between the persistent and transient pain groups, a time when peripheral sensitivity is detected in both groups, but spontaneous pain occurs only in the persistent pain group. At day 7, increased (p≤0.01) clustering, node strength, network segregation, and activation of prefrontal-limbic pathways are observed only in the group that develops persistent pain. Later, increased clustering and node strength are more pronounced with persistent pain, particularly within the limbic system, and decrease when pain resolves. Pre-treatment with intraarticular etanercept to attenuate pain confirms these adaptations are associated with pain onset. Results suggest that early and sustained brain changes can differentiate persistent and transient pain, implying they could be useful as prognostic biomarkers for persistent pain and in identifying therapeutic targets.
Learn More >Cognitive behavioral therapy (CBT) is a psychological intervention that involves development of coping strategies to reduce the experience of pain. Although CBT is a promising intervention to reduce headache days in patients with migraine, it may not be effective for all patients. Thus, there is a need to identify markers that could predict which patients will respond to CBT. We aimed to determine if baseline brain function and amygdalar connectivity, assessed by fMRI, or pain modulation capacities, assessed by the conditioned pain modulation (CPM) response, can predict a reduction in headache days after CBT in adolescents with migraine. Patients with migraine (n = 20; age range 10-17 years) completed 8 weekly CBT sessions. The CPM response was examined in the trapezius and the leg. Headache days significantly decreased after CBT (p<0.001). Greater functional connectivity before CBT between the right amygdala and frontal gyrus, anterior cingulate cortex, and precentral gyrus was related to greater headache reduction after CBT. Greater reduction in headache days after CBT was related with less efficient CPM response before CBT at the trapezius (r=-0.492, p=0.028) but not at the leg. This study found that headache reduction after CBT was related to right amygdala connectivity with frontal and sensorimotor regions at baseline as well as baseline pain modulation capacities. These findings suggest that individual differences in brain function and pain modulation can be associated with clinical improvements and help with determination of CBT responsiveness.
Learn More >GABA/glycine-mediated neuronal inhibition critically depends on intracellular chloride (Cl) concentration which is mainly regulated by the K-Cl co-transporter 2 (KCC2) in the adult central nervous system (CNS). KCC2 heterogeneity thus affects information processing across CNS areas. Here, we uncover a gradient in Cl extrusion capacity across the superficial dorsal horn (SDH) of the spinal cord (laminae I-II: LI-LII), which remains concealed under low Cl load. Under high Cl load or heightened synaptic drive, lower Cl extrusion is unveiled in LI, as expected from the gradient in KCC2 expression found across the SDH. Blocking TrkB receptors increases KCC2 in LI, pointing to differential constitutive TrkB activation across laminae. Higher Cl lability in LI results in rapidly collapsing inhibition, and a form of activity-dependent synaptic plasticity expressed as a continuous facilitation of excitatory responses. The higher metaplasticity in LI as compared to LII differentially affects sensitization to thermal and mechanical input. Thus, inconspicuous heterogeneity of Cl extrusion across laminae critically shapes plasticity for selective nociceptive modalities.
Learn More >Depression and anxiety co-occur with chronic pain, and all three are thought to be caused by dysregulation of shared brain systems related to emotional processing associated with body sensations. Understanding the connection between emotional states, pain, and bodily sensations may help understand chronic pain conditions. We developed a mobile platform for measuring pain, emotions, and associated bodily feelings in chronic pain patients in their daily life conditions. Sixty-five chronic back pain patients reported the intensity of their pain, 11 emotional states, and the corresponding body locations. These variables were used to predict pain 2 weeks later. Applying machine learning, we developed two predictive models of future pain, emphasizing interpretability. One model excluded pain-related features as predictors of future pain, and the other included pain-related predictors. The best predictors of future pain were interactive effects of (a) body maps of fatigue with negative affect and (b) positive affect with past pain. Our findings emphasize the contribution of emotions, especially emotional experience felt in the body, to understanding chronic pain above and beyond the mere tracking of pain levels. The results may contribute to the generation of a novel artificial intelligence framework to help in the development of better diagnostic and therapeutic approaches to chronic pain.
Learn More >Migraine with aura is a highly prevalent disorder involving transient neurological disturbances associated with migraine headache. While the pathophysiology is incompletely understood, findings from clinical and basic science studies indicate a potential key role of the thalamus in the mechanisms underlying migraine with and without aura. Two recent, clinic-based MRI studies investigated the volumes of individual thalamic nuclei in migraine patients with and without aura using two different data analysis methods. Both studies found differences of thalamic nuclei volumes between patients and healthy controls, but the results of the studies were not consistent. Here, we investigated whether migraine with aura is associated with changes in thalamic volume by analysing MRI data obtained from a large, cross-sectional population-based study which specifically included women with migraine with aura (N = 156), unrelated migraine-free matched controls (N = 126), and migraine aura-free co-twins (N = 29) identified from the Danish Twin Registry. We used two advanced, validated analysis methods to assess the volume of the thalamus and its nuclei; the MAGeT Brain Algorithm and a recently developed FreeSurfer-based method based on a probabilistic atlas of the thalamic nuclei combining ex vivo MRI and histology. These approaches were very similar to the methods used in each of the two previous studies. Between-group comparisons were corrected for potential effects of age, educational level, BMI, smoking, alcohol, and hypertension using a linear mixed model. Further, we used linear mixed models and visual inspection of data to assess relations between migraine aura frequency and thalamic nuclei volumes in patients. In addition, we performed paired t-tests to compare volumes of twin pairs (N = 29) discordant for migraine with aura. None of our analyses showed any between-group differences in volume of the thalamus or of individual thalamic nuclei. Our results indicate that the pathophysiology of migraine with aura does not involve alteration of thalamic volume.
Learn More >There are currently no rapid, operant pain behaviors in rodents that use a self-report to directly engage higher-order brain circuitry. We have developed a pain detection assay consisting of a lick behavior in response to optogenetic activation of predominantly nociceptive peripheral afferent nerve fibers in head-restrained transgenic mice expressing ChR2 in TRPV1 containing neurons. TRPV1-ChR2-EYFP mice (n = 5) were trained to provide lick reports to the detection of light-evoked nociceptive stimulation to the hind paw. Using simultaneous video recording, we demonstrate that the learned lick behavior may prove more pertinent in investigating brain driven pain processes than the reflex behavior. Within sessions, the response bias of transgenic mice changed with respect to lick behavior but not reflex behavior. Furthermore, response similarity between the lick and reflex behaviors diverged near perceptual threshold. Our nociceptive lick-report detection assay will enable a host of investigations into the millisecond, single cell, neural dynamics underlying pain processing in the central nervous system of awake behaving animals.
Learn More >Computational models of pain consider how the brain processes nociceptive information and allow mapping neural circuits and networks to cognition and behaviour. To date, they have generally have assumed two largely independent processes: perceptual inference, typically modelled as an approximate Bayesian process, and action control, typically modelled as a reinforcement learning process. However, inference and control are intertwined in complex ways, challenging the clarity of this distinction. Here, we consider how they may comprise a parallel hierarchical architecture that combines inference, information-seeking, and adaptive value-based control. This sheds light on the complex neural architecture of the pain system, and takes us closer to understanding from where pain 'arises' in the brain.
Learn More >Several recent studies suggest that placebos administered without deception (i.e., non-deceptive placebos) can help people manage a variety of highly distressing clinical disorders and nonclinical impairments. However, whether non-deceptive placebos represent genuine psychobiological effects is unknown. Here we address this issue by demonstrating across two experiments that during a highly arousing negative picture viewing task, non-deceptive placebos reduce both a self-report and neural measure of emotional distress, the late positive potential. These results show that non-deceptive placebo effects are not merely a product of response bias. Additionally, they provide insight into the neural time course of non-deceptive placebo effects on emotional distress and the psychological mechanisms that explain how they function.
Learn More >Oxytocin (OT) is a great facilitator of social life but, although its effects on socially relevant brain regions have been extensively studied, OT neuron activity during actual social interactions remains unexplored. Most OT neurons are magnocellular neurons, which simultaneously project to the pituitary and forebrain regions involved in social behaviors. In the present study, we show that a much smaller population of OT neurons, parvocellular neurons that do not project to the pituitary but synapse onto magnocellular neurons, is preferentially activated by somatosensory stimuli. This activation is transmitted to the larger population of magnocellular neurons, which consequently show coordinated increases in their activity during social interactions between virgin female rats. Selectively activating these parvocellular neurons promotes social motivation, whereas inhibiting them reduces social interactions. Thus, parvocellular OT neurons receive particular inputs to control social behavior by coordinating the responses of the much larger population of magnocellular OT neurons.
Learn More >Pain is the most debilitating symptom in juvenile idiopathic arthritis. As pain correlates poorly to the extent of joint pathology, therapies that control joint inflammation are often inadequate as analgesics. We test the hypothesis that juvenile joint inflammation leads to sensitisation of nociceptive circuits in the central nervous system, which is maintained by cytokine expression in the spinal cord. Here, transient joint inflammation was induced in postnatal day (P)21 and P40 male Sprague-Dawley rats with a single intra-articular ankle injection of complete Freund's adjuvant. Hindpaw mechanical pain sensitivity was assessed using von Frey hair and weight bearing tests. Spinal neuron activity was measured using in vivo extracellular recording and immunohistochemistry. Joint and spinal dorsal horn TNFα, IL1β and IL6 protein expression was quantified using western blotting. We observed greater mechanical hyperalgesia following joint inflammation in P21 compared to P40 rats, despite comparable duration of swelling and joint inflammatory cytokine levels. This is mirrored by spinal neuron hypersensitivity, which also outlasted the duration of active joint inflammation. The cytokine profile in the spinal cord differed at the two ages: prolonged upregulation of spinal IL6 was observed in P21, but not P40 rats. Finally, spinal application of anti-IL-6 antibody (30ng) reduced the mechanical hyperalgesia and neuronal activation. Our results indicate that persistent upregulation of pro-inflammatory cytokines in the spinal dorsal horn is associated with neuronal sensitisation and mechanical hyperalgesia in juvenile rats, beyond the progress of joint pathology. In addition, we provide proof of concept that spinal IL6 is a key target for treating persistent pain in JIA.
Learn More >To improve understanding of the respiratory behavior of oliceridine, a μ-opioid receptor agonist that selectively engages the G-protein-coupled signaling pathway with reduced activation of the β-arrestin pathway, the authors compared its utility function with that of morphine. It was hypothesized that at equianalgesia, oliceridine will produce less respiratory depression than morphine and that this is reflected in a superior utility.
Learn More >Decreased dopaminergic activity and increased kappa opioid activity in the mesolimbic system underlie the negative emotional states related to chronic pain. However, it is not known whether these changes are just consequence of chronic pain or contribute to the sensorial changes associated with chronic pain. In this study, we asked whether the mesolimbic dopamine and kappa opioid systems contribute to the development and maintenance of chronic hyperalgesia, one of the most common sensorial changes related to chronic pain. The lesion of the dopaminergic cells of the ventral tegmental area prevented the transition from acute to chronic hyperalgesia when performed in pain-free rats, but did not affect the maintenance of chronic hyperalgesia, when performed in chronic pain in rats. As hyperalgesia becomes chronic, the dopamine levels in the nucleus accumbens decrease. The blockade of the kappa opioid receptors in the nucleus accumbens both prevented and reversed the development of chronic hyperalgesia, but did not affect its maintenance. Complementarily, the pharmacological activation of the kappa opioid receptors in the nucleus accumbens facilitated the transition from acute to chronic hyperalgesia. None of these interventions affected acute hyperalgesia. These findings suggest that the mesolimbic dopamine and kappa opioid systems specifically drive the pain chronification process, without affecting acute pain or the maintenance of chronic pain.
Learn More >Chronic pain is a significant global health issue. For most individuals with chronic pain, biomedical treatments do not provide adequate relief. Given the evidence that neurophysiological abnormalities are associated with pain, it is reasonable to consider treatments that target these factors, such as neurofeedback (NF). The primary objectives of this review were to summarize the current state of knowledge regarding: (1) the different types of NF and NF protocols that have been evaluated for pain management; (2) the evidence supporting each NF type and protocol; (3) if targeted brain activity changes occur with NF training; and (4) if such brain activity change is associated with improvements on treatment outcomes. Inclusion criteria were intentionally broad to encompass every empirical study using NF in relation to pain. We considered all kinds of NF, including both electroencephalogram- (EEG-) and functional magnetic resonance imagining- (fMRI-) based. We searched the following databases from inception through September 2019: Pubmed, Ovid, Embase, Web of Science, PsycINFO. The search strategy consisted of a combination of key terms referring to all NF types and pain conditions (e.g., neurofeedback, rt-fMRI-NF, BOLD, pain, migraine). A total of 6,552 citations were retrieved; 24 of these that were included in the review. Most of the studies were of moderate quality, included a control condition and but did not include a follow-up. They focused on studying pain intensity (83%), pain frequency, and other variables (fatigue, sleep, depression) in samples of adults ( = 7-71) with headaches, fibromyalgia and other pain conditions. Most studies (79%) used EEG-based NF. A wide variety of NF types and protocols have been used for pain management aiming to either increase, decrease or regulate brain activity in certain areas theoretically associated with pain. Given the generally positive results in the studies reviewed, the findings indicate that NF procedures have the potential for reducing pain and improving other related outcomes in individuals with chronic pain. However, the current evidence does not provide definitive conclusions or allow for reliable recommendations on which protocols or methods of administration may be the most effective. These findings support the need for continued – but higher quality – research in this area.
Learn More >Dorsal horn excitatory interneurons that express gastrin-releasing peptide (GRP) are part of the circuit for pruritogen-evoked itch. They have been extensively studied in a transgenic line in which enhanced green fluorescent protein (eGFP) is expressed under control of the Grp gene. The GRP-eGFP cells are separate from several other neurochemically-defined excitatory interneuron populations, and correspond to a class previously defined as transient central cells. However, mRNA for GRP is widely distributed among excitatory interneurons in superficial dorsal horn. Here we show that although Grp mRNA is present in several transcriptomically-defined populations, eGFP is restricted to a discrete subset of cells in the GRP::eGFP mouse, some of which express the neuromedin receptor 2 and likely belong to a cluster defined as Glut8. We show that these cells receive much of their excitatory synaptic input from MrgA3/MrgD-expressing nociceptive/pruritoceptive afferents and C-low threshold mechanoreceptors. Although the cells were not innervated by pruritoceptors expressing brain natriuretic peptide (BNP) most of them contained mRNA for NPR1, the receptor for BNP. In contrast, these cells received only ~ 10% of their excitatory input from other interneurons. These findings demonstrate that the GRP-eGFP cells constitute a discrete population of excitatory interneurons with a characteristic pattern of synaptic input.
Learn More >In mammals, temperature-sensitive TRP channels make membrane conductance of cells extremely temperature dependent, allowing the detection of temperature ranging from noxious cold to noxious heat. We progressively deleted the distal carboxyl terminus domain (CTD) of the cold-activated melastatin receptor channel, TRPM8. We found that the enthalpy change associated with channel gating is proportional to the length of the CTD. Deletion of the last 36 amino acids of the CTD transforms TRPM8 into a reduced temperature-sensitivity channel (Q ∼4). Exposing the intracellular domain to a denaturing agent increases the energy required to open the channel indicating that cold drives channel gating by stabilizing the folded state of the CTD. Experiments in the presence of an osmoticant agent suggest that channel gating involves a change in solute-inaccessible volume in the CTD of ∼1,900 Å This volume matches the void space inside the coiled coil according to the cryogenic electron microscopy structure of TRPM8. The results indicate that a folding-unfolding reaction of a specialized temperature-sensitive structure is coupled to TRPM8 gating.
Learn More >Chronic pain is a debilitating condition that affects roughly a third to a half of the world's population. Despite its substantial effect on society, treatment for chronic pain is modest, at best, notwithstanding its side effects. Hence, novel therapeutics are direly needed. Emerging evidence suggests that calcium plays an integral role in mediating neuronal plasticity that underlies sensitization observed in chronic pain states. The endoplasmic reticulum and the mitochondria are the largest calcium repositories in a cell. Here, we review how stressors, like accumulation of misfolded proteins and oxidative stress, influence endoplasmic reticulum and mitochondria function and contribute to chronic pain. We further examine the shuttling of calcium across the mitochondrial-associated membrane as a mechanism of cross-talk between the endoplasmic reticulum and the mitochondria. In addition, we discuss how endoplasmic reticulum stress, mitochondrial impairment, and calcium dyshomeostasis are implicated in various models of neuropathic pain. We propose a novel framework of endoplasmic reticulum-mitochondria signaling in mediating pain hypersensitivity. These observations require further investigation in order to develop novel therapies for chronic pain.
Learn More >To identify risk factors for pain and functional deterioration in people with knee and hip osteoarthritis (OA) to form the basis of a future 'stratification tool' for OA development or progression.
Learn More >Evaluate the effectiveness of an intensive interdisciplinary pain treatment (IIPT) day-hospital program as compared to an outpatient multimodal treatment (MMT) for youth with chronic pain.
Learn More >Almost a third of those undergoing knee replacement for osteoarthritis have poor outcomes despite technically successful surgery. Preoperative neuropathic-like pain and/or pain sensitisation may increase the risk of pain following joint replacement.
Learn More >Obesity in adolescents is increasing in frequency and is associated with short-term and long-term negative consequences that include the exacerbation of co-occurring chronic pain.
Learn More >This study estimates the socioeconomic impact of migraine headaches on paid and unpaid work productivity in the adult German population in 1 year.
Learn More >Chronic pain presents a huge burden for individuals and society and evidence suggests intrinsic links with loneliness, social exclusion and sleep. Research examining how these factors interact is warranted. We aimed to explore the relationships between social exclusion, loneliness, acute and chronic pain, and the influence of poor sleep, in the general UK population. A cross-sectional analysis of UKBiobank participants with baseline data for acute and chronic pain, loneliness and sleep. Principal components analysis (PCA) used data relating to social isolation and deprivation to establish a composite measure of social exclusion. Binary logistic regression analyses were performed. 502,528 UKBiobank participants (mean age = 56.6years, 54.4%female, 94.6%white) were included in the analysis. PCA suggested three social exclusion factors "social participation", "individual deprivation" and "area deprivation". Loneliness significantly predicted acute (OR:1.887; 95%CI1.857-1.917) and chronic pain (OR:1.843; 95%CI1.816-1.870). Each social exclusion factor alone and in combination significantly predicted pain with largest effects for individuals scoring high on all social exclusion factors, for acute (OR:2.087; 95%CI2.026-2.150) and chronic (OR:2.314; 95%CI2.249-2.380) pain. Coefficients remained statistically significant when models were adjusted for demographics and sleep. Social exclusion (as a multifaceted construct) and loneliness are associated with an increased prevalence of acute and chronic pain. Poor sleep has a potential mediating effect on these associations. Exploration of the incidence of pain in loneliness and social exclusion in the general population is warranted. From a public health perspective these findings could be used to design social interventions to prevent or manage pain and mitigate social exclusion.
Learn More >Chronic pain is one of the most common and interfering symptoms experienced by people with MS. There is an opportunity to shift the paradigm from interventions delivered after pain has become chronic to early, proactive interventions to alter the impact of MS-related pain. The purpose of this study was to develop and test a remotely delivered single-session group intervention to modify the pain trajectory for individuals with early MS. Research Method/Design: This was a single-center 2-group pilot randomized (1:1) controlled trial comparing a novel videoconference-delivered single-session pain intervention to a waitlist control. Participants were = 27 adults who were diagnosed with MS in the preceding 36 months and who had moderate or worse pain. The study team developed the intervention to introduce pain coping and commonly used cognitive, behavioral, and acceptance-based approaches for adaptive coping. Participants completed outcome assessments on pain intensity, interference, and coping at pretreatment, posttreatment, and 3-months posttreatment.
Learn More >Self-compassion meditation, which involves compassion toward the self in moments of suffering, shows promise for improving pain-related functioning, but its underlying mechanisms are unknown. This longitudinal, exploratory pilot study investigated the effects of a brief (eight contact hours, two weeks of home practice) self-compassion training on pain-related brain processing in chronic low back pain (cLBP).
Learn More >To compare medication use and health resource utilization between migraineurs with evidence of opioid use at emergency department visit versus no opioid use at emergency department visit, and to examine predictors of opioid use among migraineurs at emergency department visits.
Learn More >Transcranial direct current stimulation (tDCS) over the primary motor cortex (M1) has an antalgic effect on acute experimental pain in healthy volunteers. Many published studies have used online stimulation (i.e., tDCS performed during painful stimulation). On the other hand, daily tDCS sessions have been proposed as a therapy for chronic pain (offline tDCS). In such cases, the therapeutic potential depends on the possible aftereffects of each tDCS session. We set out to investigate whether a single tDCS session before application of a classical experimental pain paradigm (the Cold Pressor Test, CPT) would be capable of modulating physiological measures of anxiety as well as pain perception. tDCS was applied to 30 healthy volunteers, 18 to 28 years old (mean 18.5), with the anode positioned over either the left M1 or the left dorsolateral prefrontal cortex (l-DLPFC), which has been linked to the affective aspects of experienced pain, including anxiety. All volunteers underwent the CPT procedure before and after a tDCS session. Real 2 mA tDCS sessions for 20 minutes were compared to sham stimulations. No significant difference was found for any variable after real tDCS sessions when compared to the sham simulations. This result suggests that effective offline tDCS for chronic pain might have different mechanisms of action. Cumulative effects, functional targeting and the unintended simultaneous stimulation of both M1 and the l-DLPFC are likely responsible for the therapeutic effects of tDCS sessions in the clinical setting.
Learn More >Chronic itch is a debilitating symptom of inflammatory skin diseases, but the underlying mechanism is poorly understood. We have recently demonstrated that astrocytes in the spinal dorsal horn become reactive in models of atopic and contact dermatitis via activation of the transcription factor STAT3 and critically contribute to chronic itch. In general, STAT3 is transiently activated; however, STAT3 activation in reactive astrocytes of chronic itch model mice persistently occurs via an unknown mechanism.
Learn More >Ischemic neuropathy is common in subjects with critical limb ischemia, frequently causing chronic neuropathic pain. However, neuropathic pain caused by ischemia is hard to control despite the restoration of an adequate blood flow. Here, we used a rat model of ischemic-reperfusion nerve injury (IRI) to investigate possible effects of hepatocyte growth factor (HGF) against ischemic neuropathy. Hemagglutinating virus of Japan (HVJ) liposomes containing plasmids encoded with HGF was delivered into the peripheral nervous system by retrograde axonal transport following its repeated injections into the tibialis anterior muscle in the right hindlimb. First HGF gene transfer was done immediately after IRI, and repeated at 1, 2 and 3 weeks later. Rats with IRI exhibited pronounced mechanical allodynia and thermal hyperalgesia, decreased blood flow and skin temperature, and lowered thresholds of plantar stimuli in the hind paw. These were all significantly improved by HGF gene transfer, as also were sciatic nerve conduction velocity and muscle action potential amplitudes. Histologically, HGF gene transfer resulted in a significant increase of endoneurial microvessels in sciatic and tibial nerves and promoted nerve regeneration which were confirmed by morphometric analysis. Neovascularization was observed in the contralateral side of peripheral nerves as well. In addition, IRI elevated mRNA levels of P2X3 and P2Y1 receptors, and transient receptor potential vanilloid receptor subtype 1 (TRPV1) in sciatic nerves, dorsal root ganglia and spinal cord, and these elevated levels were inhibited by HGF gene transfer. In conclusion, HGF gene transfer is a potent candidate for treatment of acute ischemic neuropathy caused by reperfusion injury, because of robust angiogenesis and enhanced nerve regeneration.
Learn More >This systematic review and meta-analysis examined the effectiveness of multidisciplinary based rehabilitation (MBR) in comparison to active physical interventions for adults with chronic pain.
Learn More >The opioid epidemic is a significant public health problem largely driven by opioid prescriptions for chronic pain. Among those with chronic pain, anxiety and depressive symptoms have been linked to opioid misuse, and individual differences in anxiety and depressive symptoms among adults with chronic pain may be important for better understanding pain. Yet, little work has examined mechanisms that may link anxiety and depressive symptoms to opioid misuse among adults with chronic pain. Anxiety sensitivity, or the fear of anxiety-related physical sensations, may be one candidate construct that has been linked independently to anxiety and depressive symptoms as well as opioid misuse.
Learn More >Thousands of individuals die each year from opioid-related overdoses. While naloxone (Narcan®) is currently the most widely employed treatment to reverse opioid toxicity, high or repeated doses of this antidote often lead to precipitated opioid withdrawal (POW). We hypothesized that a slow linear release of naloxone from a nanoparticle would induce fewer POW symptoms compared to high-dose free naloxone. First, we measured the acute impact of covalent naloxone nanoparticles (Nal-cNPs) on morphine-induced antinociception in the hotplate test. We found that Nal-cNP treatment blocked the antinociceptive effect of morphine within 15 min of administration. Next, we tested the impact of Nal-cNPs on POW symptoms in male morphine-dependent mice. To induce morphine dependence, mice were treated with 5 mg/kg morphine (or saline) twice-daily for six consecutive days. On day 7 mice received 5 mg/kg morphine (or saline) injections 2 hr prior to receiving treatment of either unmodified free naloxone, a high or low dose of Nal-cNP, empty nanoparticle (cNP-empty), or saline. Behavior was analyzed for 0-6 hr followed by 24 and 48 hr time points after treatment. As expected, free naloxone induced a significant increase in POW behavior in morphine-dependent mice compared to saline-treated mice upon free naloxone administration. In comparison, reduced POW behavior was observed with both doses of Nal-cNP. Side effects of Nal-cNP on locomotion and fecal boli production were measured and no significant side-effects were observed. Overall, our data show that sustained release of naloxone from a covalent nanoparticle does not induce severe POW symptoms in morphine-dependent mice.
Learn More >Patients' pain behavior plays an important role in the interaction between patients and their partners, as acknowledged in operant models of pain. However, despite the considerable research attention to pain behaviors, the underlying motives of such behaviors are still unclear. The current study explores the motives to engage in pain behaviors, and the possible discrepancies between patients' and partners' perceptions of those motives.
Learn More >Temporomandibular disorder is a common musculoskeletal pain condition with development of chronic symptoms in 49% of patients. Although a number of biological factors have shown an association with chronic temporomandibular disorder in cross-sectional and case control studies, there are currently no biomarkers that can predict the development of chronic symptoms. The PREDICT study aims to undertake analytical validation of a novel peak alpha frequency (PAF) and corticomotor excitability (CME) biomarker signature using a human model of the transition to sustained myofascial temporomandibular pain (masseter intramuscular injection of nerve growth factor [NGF]). This article describes, a priori, the methods and analysis plan.
Learn More >Fibromyalgia (FM) is a condition marked by widespread chronic pain and an array of somatic and psychological symptoms. The primary objective of this study was to explore daily associations between physical activity and pain intensity among a sample of women with FM and the potential moderation of this association by pain catastrophizing.
Learn More >The aim of this study was to determine simple risk factors for severe pain intensity (≥7 points on a numeric rating scale [NRS]), to analyse their relation to other patient-reported outcome measures and to develop a simple prediction model.
Learn More >Entrapment neuropathies such as carpal tunnel syndrome, radiculopathies, or radicular pain are the most common peripheral neuropathies and also the most common cause for neuropathic pain. Despite their high prevalence, they often remain challenging to diagnose and manage in a clinical setting. Summarising the evidence from both preclinical and clinical studies, this review provides an update on the aetiology and pathophysiology of entrapment neuropathies. Potential mechanisms are put in perspective with clinical findings. The contemporary assessment is discussed and diagnostic pitfalls highlighted. The evidence for the noninvasive and surgical management of common entrapment neuropathies is summarised and future areas of research are identified.
Learn More >Opioid consumption for those in comprehensive inpatient rehabilitation units is high because of the complexity of their injuries. Notably, pain in rehabilitation leads to worsened clinical outcomes because of maladaptive behaviors and poor engagement during therapies. It is critical to developing evidence-based pharmacobehavioral interventions. Based on principles of classical conditioning, conditioning open-label placebo (COLP) is a promising approach for reducing opioid use in comprehensive inpatient rehabilitation, and this technique takes advantage of the possibility of association learning and opioid pharmacology to promote evoked placebo-driven analgesia.
Learn More >In the central nervous system, the inhibitory GABAB receptor is the archetype of heterodimeric G protein-coupled receptors (GPCRs). Receptor interaction with partner proteins has emerged as a novel mechanism to alter GPCR signaling in pathophysiological conditions. We propose here that GABAB activity is inhibited through the specific binding of fibulin-2, an extracellular matrix protein, to the B1a subunit in a rat model of neuropathic pain. We demonstrate that fibulin-2 hampers GABAB activation, presumably through decreasing agonist-induced conformational changes. Fibulin-2 regulates the GABAB-mediated presynaptic inhibition of neurotransmitter release and weakens the GABAB-mediated inhibitory effect in neuronal cell culture. In the dorsal spinal cord of neuropathic rats, fibulin-2 is overexpressed and colocalized with B1a. Fibulin-2 may thus interact with presynaptic GABAB receptors, including those on nociceptive afferents. By applying anti-fibulin-2 siRNA , we enhanced the antinociceptive effect of intrathecal baclofen in neuropathic rats, thus demonstrating that fibulin-2 limits the action of GABAB agonists . Taken together, our data provide an example of an endogenous regulation of GABAB receptor by extracellular matrix proteins and demonstrate its functional impact on pathophysiological processes of pain sensitization.
Learn More >The nucleus accumbens shell (NAcSh) regulates emotional and motivational responses, a function mediated, in part, by integrating and prioritizing extensive glutamatergic projections from limbic and paralimbic brain regions. Each of these inputs is thought to encode unique aspects of emotional and motivational arousal. The projections do not operate alone, but rather are often activated simultaneously during motivated behaviors, during which they can interact and coordinate in shaping behavioral output. To understand the anatomical and physiological bases underlying these inter-projection interactions, the current study in mice of both sexes focused on how the basolateral amygdala projection to the NAcSh (BLAp) regulates, and is regulated by, projections from the medial prefrontal cortex (mPFCp) and paraventricular nucleus of the thalamus (PVTp). Using a dual-color SynaptoTag technique combined with a backfilling spine imaging strategy, we found that all three afferent projections primarily targeted the secondary dendrites of NAcSh medium spiny neurons, forming putative synapses. We detected a low percentage of BLAp contacts closely adjacent to mPFCp or PVTp presumed synapses, and, on some rare occasions, the BLAp formed heterosynaptic interactions with mPFCp or PVTp profiles or appeared to contact the same spines. Using dual-rhodopsin optogenetics, we detected signs of dendritic summation of BLAp with PVTp and mPFCp inputs. Furthermore, high-frequency activation of BLAp synchronous with the PVTp or mPFCp resulted in a transient enhancement of the PVTp, but not mPFCp, transmission. These results provide anatomical and functional indices that the BLAp interacts with the mPFCp and PVTp for informational processing within the NAcSh.The nucleus accumbens regulates emotional and motivational responses by integrating extensive glutamatergic projections, but the anatomical and physiological bases on which these projections integrate and interact remain underexplored. Here, we used dual-color synaptic markers combined with backfilling of nucleus accumbens medium spiny neurons to reveal some unique anatomical alignments of presumed synapses from the basolateral amygdala, medial prefrontal cortex, and paraventricular nucleus of thalamus. We also used dual-rhodopsin optogenetics in brain slices, which reveal a nonlinear interaction between some, but not all, projections. These results provide compelling anatomical and physiological mechanisms through which different glutamatergic projections to the nucleus accumbens, and possibly different aspects of emotional and motivational arousal, interact with each other for final behavioral output.
Learn More >Chronic constriction injury of the sciatic nerve in rats causes peripheral neuropathy leading to pain-like behaviors commonly seen in humans. Neuropathy is a leading cause of neuropathic pain, which involves a complex cellular and molecular response in the peripheral nervous system with interactions between neurons, glia, and infiltrating immune cells. In this study, we utilize a nonsteroidal anti-inflammatory drug -loaded nanoemulsion to deliver the cyclooxygenase-2 inhibitor, Celecoxib, directly to circulating monocytes following nerve injury, which provides long-lasting pain relief. However, it is not fully understood how cyclooxygenase-2 inhibition in a macrophage traveling to the site of injury impacts gene expression in the dorsal root ganglia. To elucidate aspects of the molecular mechanisms underlying pain-like behavior in chronic constriction injury, as well as subsequent pain relief with treatment, we employ RNAseq transcriptome profiling of the dorsal root ganglia associated with the injured sciatic nerve in rats. Using high throughput RNA sequencing in this way provides insight into the molecular mechanisms involved in this neuroinflammatory response. We compare the transcriptome from the dorsal root ganglias of the following study groups: chronic constriction injury animals administered with cyclooxygenase-2 inhibiting celecoxib-loaded nanoemulsion, chronic constriction injury animals administered with vehicle treatment, a drug-free nanoemulsion, and a group of naïve, unoperated and untreated rats. The results show an extensive differential expression of 115 genes. Using the protein annotation through evolutionary relationship classification system, we have revealed pain-related signaling pathways and underlying biological mechanisms involved in the neuroinflammatory response. Quantitative polymerase chain reaction validation confirms expression changes for several genes. This study shows that by directly inhibiting cyclooxygenase-2 activity in infiltrating macrophages at the injured sciatic nerve, there is an associated change in the transcriptome in the cell bodies of the dorsal root ganglia.
Learn More >Opioids are the most effective analgesics used in the clinical management of cancer pain or non-cancer pain. However, chronic opioids therapy can cause many side effects including respiratory depression, nausea, sedation, itch, constipation, analgesic tolerance, hyperalgesia, high addictive potential, and abuse liability. Opioids exert their effects through binding to the opioid receptors belonging to the G-protein coupled receptors (GPCRs) family, including mu opioid receptor (MOR), delta opioid receptor (DOR), and kappa opioid receptor (KOR). Among them, MOR is essential for opioid-induced analgesia and also responsible for adverse effects of opioids. Importantly, MOR can form heterodimers with other opioid receptors and non-opioid receptors and , and has distinct pharmacological properties, different binding affinities for ligands, downstream signaling, and receptor trafficking. This mini review summarized recent progress on the function of Mu opioid receptor heterodimers, and we proposed that targeting mu opioid receptor heterodimers may represent an opportunity to develop new therapeutics, especially for chronic pain treatment.
Learn More >The transient receptor potential vanilloid 1 (TRPV1) ion channel is a member of the family of Transient Receptor Potential (TRP) channels that acts as a molecular detector of noxious signals in primary sensory neurons. Activated by capsaicin, heat, voltage and protons, it is also well known for its desensitization, which led to the medical use of topically applied TRPV1 agonist capsaicin for its long-lasting analgesic effects. Here we report three novel small molecules, which were identified using a Structure-Based Virtual Screening for TRPV1 from the ZINC database. The three compounds were tested using electrophysiological assays, which confirmed their capsaicin-like agonist activity. von Frey filaments were used to measure the analgesic effects of the compounds applied topically on tactile allodynia induced by intra-plantar carrageenan. All compounds had anti-nociceptive activity, but two of them showed faster and longer lasting analgesic effects than capsaicin. The present results suggest that TRPV1 agonists different from capsaicin could be used to develop topical analgesics with faster onset and more potent effects.
Learn More >Chronic non-specific low back pain is a major public health problem. Evidence supports the effectiveness of exercise as an intervention. Due to a paucity of direct comparisons of different exercise categories, medical guidelines were unable to make specific recommendations regarding the type of exercise working best in improving chronic low back pain. This network meta-analysis (NMA) of randomised controlled trials aims to investigate the comparative efficacy of different exercise interventions in patients with chronic non-specific low back pain.
Learn More >The neuropeptide nociceptin/orphanin FQ (N/OFQ) can be released by stressors and is associated with disorders of emotion regulation and reward processing. N/OFQ and its receptor, NOP, are enriched in dopaminergic pathways, and intra-ventricular agonist delivery decreases dopamine levels in the dorsal striatum, nucleus accumbens (NAc), and ventral tegmental area (VTA). We used whole cell electrophysiology in acute rat midbrain slices to investigate synaptic actions of N/OFQ. N/OFQ was primarily inhibitory, causing outward currents in both immunocytochemically identified dopaminergic (tyrosine hydroxylase positive (TH(+)) and non-dopaminergic (TH(-)) VTA neurons (effect at 1 μM: 20 ± 4 pA). Surprisingly, this effect was mediated by augmentation of postsynaptic GABAR currents, unlike the substantia nigra pars compacta (SNc), where the N/OFQ induced outward currents were K channel dependent. A smaller population, 19% of all VTA neurons, responded to low concentrations N/OFQ with inward currents (10 nM: -11 ± 2 pA). Following 100 nM N/OFQ, the response to a second N/OFQ application was markedly diminished in VTA neurons (14 ± 10% of first response), but not in SNc neurons (90 ± 20% of first response). N/OFQ generated outward currents in medial prefrontal cortex (mPFC)-projecting VTA neurons, but inward currents in a subset of posterior anterior cingulate cortex-projecting VTA neurons. While N/OFQ inhibited NAc-projecting VTA cell bodies, it had little effect on electrically or optogenetically evoked terminal dopamine release in the NAc measured with fast scan cyclic voltammetry. These results extend our understanding of the N/OFQ system in brainstem circuits implicated in many neurobehavioral disorders. The neuropeptide nociceptin/orphanin FQ (N/OFQ) and its receptor (NOP) are engaged under conditions of stress and are associated with reward processing disorders. Both peptide and receptor are highly enriched in ventral tegmental area (VTA) pathways underlying motivation and reward. Using whole cell electrophysiology in rat midbrain slices we found: 1) NOPs are functional on both dopaminergic and non-dopaminergic VTA neurons; 2) N/OFQ differentially regulates VTA neurons based on neuroanatomical projection target; and 3) repeated application of N/OFQ produces evidence of receptor desensitization in VTA but not SNc neurons. These results reveal candidate mechanisms by which the NOP system regulates motivation and emotion.
Learn More >Chronic pain affects many adults. To improve our daily practice, we need to understand multidisciplinary approaches, integrated treatment plans and the biopsychosocial context of these patients. To date, almost 15 000 chronic pain patients have been referred to the Maastricht University Pain Center in the Netherlands.
Learn More >To examine the association between initial patterns of prescription opioid supply (POS) and risk of all-cause mortality among an insured opioid-naïve patient population in the United States (US).
Learn More >Determine whether common migraine comorbidities affect the efficacy and safety of lasmiditan, a 5-HT receptor agonist approved in the United States for the acute treatment of migraine. In SPARTAN and SAMURAI (double-blind Phase 3 clinical trials), patients with migraine were randomized to oral lasmiditan 50 mg (SPARTAN only), 100 mg, 200 mg, or placebo. Lasmiditan increased the proportion of pain-free and most bothersome symptom (MBS)-free patients at 2 hours after dose compared with placebo. Most common treatment-emergent adverse events (TEAEs) were dizziness, paraesthesia, somnolence, fatigue, nausea, muscular weakness, and hypoesthesia. Based upon literature review of common migraine comorbidities, Anxiety, Allergy, Bronchial, Cardiac, Depression, Fatigue, Gastrointestinal, Hormonal, Musculoskeletal/Pain, Neurological, Obesity, Sleep, and Vascular Comorbidity Groups were created. Using pooled results, efficacy and TEAEs were assessed to compare patients with or without a given common migraine comorbidity. To compare treatment groups, p-values were calculated for treatment-by-subgroup interaction, based on logistic regression with treatment-by-comorbidity condition status (Yes/No) as the interaction term; study, treatment group, and comorbidity condition status (Yes/No) were covariates. Differential treatment effect based upon comorbidity status was also examined. Trial registration at clinicaltrials.gov: SAMURAI (NCT02439320) and SPARTAN (NCT02605174). Across all the Comorbidity Groups, with the potential exception of fatigue, treatment-by-subgroup interaction analyses did not provide evidence of a lasmiditan-driven lasmiditan versus placebo differential treatment effect dependent on Yes versus No comorbidity subgroup for either efficacy or TEAE assessments. The efficacy and safety of lasmiditan for treatment of individual migraine attacks appear to be independent of comorbid conditions.
Learn More >The objective of this study was to evaluate the psychometric properties of the 17-item Tampa Scale for Kinesiophobia (TSK) in youth.
Learn More >Several analgesic α-conotoxins have been isolated from marine cone snails. Structural modification of native peptides has provided potent and selective analogues for two of its known biological targets-nicotinic acetylcholine and γ-aminobutyric acid (GABA) G protein-coupled (GABA) receptors. Both of these molecular targets are implicated in pain pathways. Despite their small size, an incomplete understanding of the structure-activity relationship of α-conotoxins at each of these targets has hampered the development of therapeutic leads. This review scrutinises the -terminal domain of the α-conotoxin family of peptides, a region defined by an invariant disulfide bridge, a turn-inducing proline residue and multiple polar sidechain residues, and focusses on structural features that provide analgesia through inhibition of high-voltage-activated Ca channels. Elucidating the bioactive conformation of this region of these peptides may hold the key to discovering potent drugs for the unmet management of debilitating chronic pain associated with a wide range of medical conditions.
Learn More >Pain is a subjective experience characterized by sensory (intensity) and emotional (unpleasantness) aspects. Although literature reports behavioral effects on pain due to smell and taste influence, to our knowledge the relationship between tonic pain induced by a capsaicin cream and these chemosensory systems has never been explored before. The aim of this study was to investigate the modulation of olfactory and gustatory substances having different valence on tonic pain perception mediated by a capsaicin cream application.
Learn More >Chemotherapy-induced peripheral neuropathy (CIPN) is among the most disabling and frustrating problems for cancer survivors. The neurotoxicity caused by cisplatin varies greatly among patients, and few predictors of appearance, duration of symptoms, susceptibility, or severity are available. A deeper understanding of the mechanisms underlying individual differences in status, severity, or sensitivity in response to cisplatin treatment is therefore required. By analyzing the GSE64174 gene expression profile and constructing a weighted gene co-expression network analysis (WGCNA) network, we screened gene modules and hub genes related to CIPN status, severity and sensitivity. We first identified the transcriptome profile of mouse dorsal root ganglion (DRG) samples and transformed their genes to human DRG counterparts. We then constructed WGCNA gene modules via optimal soft-threshold power-identification and module-preservation analysis. Comprehensive analysis and identification of module hub genes were performed via functional-enrichment analysis and significant common hub genes were identified, including "Cytoscape_cytoHubba," "Cytoscape_MCODE," and "Metascape_MCODE." Brown, green, and blue modules were selected to represent CIPN sensitivity, status and severity, resepectively, via trait-module correlational analysis. Additionally, functional enrichment analysis results indicated that these three modules were associated with some crucial biological functions, such as neutrophil migration, chemokine-mediated signaling pathway, and PI3K-Akt signaling pathway. We then identified seven common hub genes via three methods, including CXCL10, CCL21, CCR2, CXCR4, TLR4, NPY1R, and GALR2, related to CIPN status, severity and sensitivity. Our results provide possible targets and mechanism insights into the development and progress of CIPN, which can guide further transformation and pre-clinical research.
Learn More >There is increasing evidence that the toll-like receptor 4 (TLR4) signaling pathway contribute to development of hyperalgesia in the trigeminal system. The aim of the present study was to investigate the role of TLR4 in the trigeminal ganglion (TG) in facial hyperalgesia induced by injection of Lipopolysaccharide (LPS) or intraoral mucosal incision, which is an orofacial postoperative pain model, in male Wistar rats. The TLR4 antagonist (LPS-RS, 20 µg/10 µL) was administrated 30 min before LPS injection into the TG (10 µg/10 µL) or oral mucosa (10 µg/50 µL). In the postoperative pain model, rats were treated with LPS-RS (20 µg/10 µL) into the TG for three consecutive days after the incision. Facial heat and mechanical hyperalgesia were assessed hourly after LPS injection or intraoral incision. In addition, expression of NFκB was assessed in the TG on day 3 after intraoral incision. Our results showed that blockade of TLR4 in the TG attenuated facial heat and mechanical hyperalgesia induced by LPS or by mucosal incision, and that both conditions are associated to increase of phosphorylated NFκB in the TG. In conclusion, the present study suggests that activation of TLR4-NFκB signaling pathway in the TG contributes to the development of facial heat and mechanical hyperalgesia and may contribute to pain in inflammatory oral conditions.
Learn More >Chronic low back pain (cLBP) can interfere with daily activities, and individuals with elevated pain-related fear (also known as kinesiophobia or the fear of injury due to movement) can develop worse long-term disability. Graded exposure (GEXP) protocols use successive participation in avoided activities to help individuals overcome fearful movement appraisals and encourage activity. We sought to develop a series of GEXP virtual reality (VR) walking and reaching scenarios to increase the exposure and engagement of people with high kinesiophobia and cLBP.
Learn More >Persistent pain in older adults is a widely prevalent and disabling condition that is the manifestation of multiple contributing physical, mental, social, and age-related factors. To effectively treat pain, the clinician must assess and address contributing factors using a comprehensive approach that includes pharmacologic and nonpharmacologic therapies within the context of a strong therapeutic relationship among the patient, caregivers, and a multidisciplinary team. This article reviews the current understanding of persistent pain in older adults and suggests a general approach to its assessment and management, followed by specific considerations for musculoskeletal pain conditions commonly seen in older adults.
Learn More >Adolescent idiopathic scoliosis is one of the most common spinal deformities in children and adolescents requiring extensive surgical intervention. Due to the nature of surgery, spinal fusion increases their risk of experiencing persistent postsurgical pain. Up to 20% of adolescents report pain for months or years after corrective spinal fusion surgery.
Learn More >The opioid epidemic is a significant public health crisis in the United States, and chronic pain is a leading precipitating and maintaining factor for opioid misuse. To better understand substance misuse generally, research has examined motivational models of why people use substances, and pain management and affect-driven coping are cited as primary reasons for opioid misuse. Further, research examining psychosocial predictors of opioid misuse has identified anxiety sensitivity (AS; fear of anxiety-related physical sensations) as a unique predictor of opioid misuse severity, and it is possible that AS is uniquely related to opioid pain management and coping motives, which in turn, are related to opioid misuse. Therefore, the current study examined AS as a predictor of opioid pain management and coping motives, as well as the indirect effect of AS, through opioid motives, on opioid misuse status, among 292 adults (Mage = 45.76, SD = 11.20, 68.9% female) with chronic low back pain. Results for the current study support hypotheses that AS is significantly associated with pain management and coping motives (over and above variance of pain intensity) and indirectly associated with opioid misuse status through both motives. These results highlight the importance of better understanding opioid use motives in the context of chronic pain and provide potential treatment targets to add to a growing body of literature targeting psychosocial factors for opioid misuse. (PsycInfo Database Record (c) 2020 APA, all rights reserved).
Learn More >Migraine prevalence is three times higher in women than in men during fertile years, which is mainly due to sex hormone differences. The majority of women suffering from migraine without aura report improvement of their migraine attacks during pregnancy. Migraine attacks with aura can also improve during pregnancy, but more often remain the same or worsen. Anovulation caused by lactation is generally associated with a decrease in migraine attacks in breastfeeding women. This chapter describes the current knowledge on acute and prophylactic treatment options of migraine and other primary headache disorders during pregnancy and lactation. Further, clinical profiles of secondary headaches during pregnancy and the postpartum period are summarized.
Learn More >The human immunodeficiency virus (HIV) remains a major burden to the health care system and neuropathic pain is the most common neurological complication of HIV infection. Since current treatment strategies often lack satisfying pain relief, cannabinoids are discussed as a new option. We investigated cannabidivarin as treatment for HIV-associated neuropathic pain. We conducted a randomized, double-blind, placebo-controlled cross-over study. Patients underwent two successive treatment phases (4 weeks each) and were treated with cannabidivarin (400mg/d) or placebo in a randomized order. A 3-week wash-out phase was designed to eliminate potential carry-over effects. Patients were followed up for 3 weeks after the end of the second treatment phase. The primary endpoint was pain intensity on an 11-point numeric rating scale, recorded in a diary. Secondary endpoints were additional pain medication, pain characteristics and quality of life. We included 32 patients. The mean pain intensity under cannabidivarin was 0.62 points higher compared to placebo (p=0.16; 95% CI -0.27 to 1.51). Cannabidivarin did not influence the amount of additional pain medication, pain characteristics or quality of life. The incidence of adverse events was similar during both treatments. No suspected unexpected adverse reactions occurred during either treatment. Cannabidivarin was safe but failed to reduce neuropathic pain in HIV-patients. This may be explained by a lack of cannabinoid receptor activation, as indicated by preclinical experiments. Although a larger patient number might be desirable, we would not expect a change in the conclusions since the present differences are far from statistical significance. Therefore, we would currently not consider CBDV as a clinically meaningful treatment option for neuropathic pain.
Learn More >Non-specific low back pain (NLBP) causes an enormous burden to patients and tremendous costs for health care systems worldwide. Frequently, treatments are not oriented to existing guidelines. In the future, digital elements may be promising tools to support guideline-oriented treatment in a broader range of patients. The cluster-randomized controlled "Rise-uP" trial aims to support a General Practitioner (GP)-centered back pain treatment (Registration No: DRKS00015048) and includes the following digital elements: 1) electronic case report form (eCRF), 2) a treatment algorithm for guideline-based clinical decision making of GPs, 3) teleconsultation between GPs and pain specialists for patients at risk for development of chronic back pain, and 4) a multidisciplinary mobile back pain app for all patients (Kaia App).
Learn More >Opioid tolerance remains a challenging problem, which limits prolonged drug usage in clinics. Previous studies have shown a fundamental role of platelet-derived growth factor receptor β submit (PDGFRβ) in morphine tolerance. The aim of this study was to investigate the mechanisms of spinal PDGFRβ activation in morphine tolerance.
Learn More >Some patients undergoing thoracotomy may suffer from chronic post-thoracotomy pain (CPTP). Treatment of CPTP has been a clinical challenge and the underlying mechanisms of CPTP remain elusive. Recently, sonic hedgehog (Shh) signaling has been shown to be associated with various pain states but its role in the pathogenesis of CPTP is still unclear.
Learn More >The present study aimed to investigate the effects of high-mobility group box-1 (HMGB-1) on mechanical pain hypersensitivity and the underlying mechanism. Mouse primary astrocytes were isolated and treated as specified. A CCK-8 assay was used to determine cytotoxicity and a gap junctional communication assay was performed. Ethidium bromide (EtBr) uptake was used to evaluate the hemichannel activity of primary astrocytes. A mouse model of neuropathic pain was developed and paw withdrawal threshold was used to evaluate hind paw sensitivity. RT-qPCR and Western blot were used to determine mRNA and protein expression of genes, respectively. ELISA was used to measure the release of inflammatory cytokines. Treatment with HMGB-1 increased the expression of both toll-like receptor-4 (TLR-4) and connexin 43 (Cx43)in mouse primary astrocytes. HMGB-1 also promoted gap junctional intercellular communication and hemichannel function. Our results also demonstrated that HMGB-1 regulated Cx43 through the JNK signaling pathway, and Cx43 was involved in HMGB-1-mediated inflammation in astrocytes. In vivo analysis supported the idea that HMGB-1-induced mechanical hypersensitivity was associated with Cx43. We therefore conclude that HMGB-1-induced mechanical pain hypersensitivity occurs through modulating astrocytic Cx43 via the TLR-4/JNK signaling pathway.
Learn More >Osteoarthritis (OA) causes chronic joint pain and significantly impacts daily activities. Hence, developing novel treatment options for OA has become an increasingly important area of research. Recently, studies have reported that exogenous, as well as endogenous, hypothalamic-neurohypophysial hormones, oxytocin (OXT) and arginine-vasopressin (AVP), significantly contribute to nociception modulation. Moreover, the parvocellular OXT neurone (parvOXT) extends its projection to the superficial spinal dorsal horn, where it controls the transmission of nociceptive signals. Meanwhile, AVP produced in the magnocellular AVP neurone (magnAVP) is released into the systemic circulation where it contributes to pain management at peripheral sites. The parvocellular AVP neurone (parvAVP), as well as corticotrophin-releasing hormone (CRH), suppresses inflammation via activation of the hypothalamic-pituitary adrenal (HPA) axis. Previously, we confirmed that the OXT/AVP system is activated in rat models of pain. However, the roles of endogenous hypothalamic-neurohypophysial hormones in OA have not yet been characterised. In the present study, we investigated whether the OXT/AVP system is activated in a knee OA rat model. Our results show that putative parvOXT is activated and the amount of OXT-monomeric red fluorescent protein 1 positive granules in the ipsilateral superficial spinal dorsal horn increases in the knee OA rat. Furthermore, both magnAVP and parvAVP are activated, concurrent with HPA axis activation, predominantly modulated by AVP, and not CRH. The OXT/AVP system in OA rats was similar to that in systemic inflammation models, including adjuvant arthritis; however, magnocellular OXT neurones (magnOXT) were not activated in OA. Hence, localised chronic pain conditions, such as knee OA, activate the OXT/AVP system without impacting magnOXT.
Learn More >Objectives Fibromyalgia is a chronic widespread pain (CWP) syndrome of unknown etiology with substantial burden of illness and functional impairment. Pain acceptance has emerged as an interesting target of therapy in chronic pain populations, but few studies have yet been done on the effect of pain acceptance on patients with fibromyalgia. The aim of the present study was to examine the relationship between pain acceptance and its impact on function and symptoms in fibromyalgia with both a cross-sectional and longitudinal design. Methods Three hundred and sixty five participants aged 22-70 with fibromyalgia were recruited from the Norwegian Fibromyalgia Association (NFA). They filled out a questionnaire containing the Fibromyalgia Impact Questionnaire (FIQ), measurement of function and symptoms, and Chronic Pain Acceptance Questionnaire (CPAQ), measurement of pain acceptance, in addition to sociodemographic and clinical variables such as degree of fibromyalgia, depression and pain duration (T1 measures). One year after, 87 of the participants filled out the FIQ and clinical measures once again (T2 measures). Unadjusted and adjusted linear regression analyses were performed both for cross-sectional measures at T1 and for longitudinal measures from T1 to T2, with FIQ score as the outcome variable and CPAQ score at T1 as one of the main independent variables. Results Higher CPAQ score was significantly associated with a lower FIQ score at T1, also when adjusting for age, education, work, depression and Fibromyalgianess Score (p<0.01). Lower FIQ score indicate less impact of fibromyalgia on functioning. In addition, two adjusted linear regression models found higher pain acceptance (CPAQ score) at T1 to be associated with lower negative impact of fibromyalgia on function and symptoms (FIQ score) at T2 (p<0.01). Conclusions Higher pain acceptance is associated with better functional level and less symptoms in fibromyalgia, both cross-sectionally and when measurements are separated in time. Further research should include experimental studies with acceptance-based interventions for this patient group.
Learn More >This prospective study characterized corneal nerve pathway function in individuals with dry eye symptoms. In total, 34% of individuals had a corneal sensitivity outside the 10-90% range or persistent pain after placement of topical anesthesia.
Learn More >The aim of this study was to assess the correlation of inflammatory and pain genes polymorphisms with the presence of temporomandibular disorder (TMD) patients and with pressure pain sensitivity.
Learn More >Retrospective review and literature review OBJECTIVE.: To provide an update on The Cochrane Back and Neck (CBN) activities.
Learn More >The anterior cingulate cortex (ACC) is activated by noxious stimuli and is involved in the affective component of pain processing; but its role in the sensory component of pain remains largely unknown. Studies have verified that Chemokine (C-X-C motif) receptor 3 (CXCR3) is involved in nociceptive sensitization in the spinal cord after peripheral nerve injury; however, the expression of CXCR3 in the ACC and its role in neuropathic pain has not been reported. Here, we showed that CXCR3 co-localized with neurons in the ACC and the upregulation of CXCR3 corresponded with hypersensitive behaviors after a chronic constriction injury of the sciatic nerve. Pharmacological blockade of CXCR3 using local injection of its inhibitor, AMG487, into the ACC significantly attenuated hyperalgesia induced by chronic constriction injury and suppressed the phosphorylation of extracellular signal-regulated kinase (ERK). Collectively, these results suggest that CXCR3 in the ACC is involved in hyperalgesia induced by peripheral nerve injury and ERK may be a downstream target.
Learn More >Low back-related leg pain (LBLP) is a challenge for healthcare providers to manage. Neuropathic pain (NP) is highly prevalent in presentations of LBLP and an accurate diagnosis of NP in LBLP is essential to ensure appropriate intervention. In the absence of a gold standard, the objective of this systematic review was to evaluate the diagnostic utility of patient history, clinical examination and screening tool data for identifying NP in LBLP.
Learn More >Neuropathic pain, which results from impairment of the somatosensory system, has affected about 8% population around the world and leads to considerable burdens for patients and world health care system. However, its underlying mechanisms remain poorly understood. In this study, we hypothesized that miR-24-3p was involved in the progression of neuropathic pain in CCI rat models. By measuring miR-24-3p expression in CCI rats, we found that miR-24-3p expression was increased in CCI rats, suggesting miR-24-3p might participate in neuropathic pain progression. Next, by conducting a serial in vitro and vivo experiments, we found that miR-24-3p regulated the Wnt5a/β-Catenin Signaling levels to promote neuropathic pain progression via targeting LPAR3 in CCI rats. Furthermore, we explored the upstream regulator of miR-24-3p by conducting bioinformatics analysis, we found that circular RNA cZRANB1 might sponge to miR-24-3p. Then we applied biotinylated RNA pull-down and luciferase reporter assays to assess the association between cZRANB1 and miR-24-3p. It was found that cZRANB1 mediated LPAR3 expression via sponging miR-24-3p. Collectively, our study suggests that cZRNAB1 regulated Wnt5a/β-Catenin Signaling expression via miR-24-3p/LPAR3 axis in CCI rat models.
Learn More >Current recommendations controversially discuss local infiltration techniques as specific treatment for refractory pain syndromes. Evidence of effectiveness remains inconclusive and local infiltration series are discussed as a therapeutic option in patients not responding to standard therapy. The aim of this study was to investigate the effectiveness of infiltration series with techniques such as sphenopalatine ganglion (SPG) block and ganglionic local opioid analgesia (GLOA) for the treatment of neuropathic pain in the head and neck area in a selected patient group.
Learn More >This study investigated relationships between post-traumatic stress symptoms (PTSS) and pain disability. Fifty people with chronic pain (probable PTSD, = 22) completed measures assessing pain interference, PTSS, fear avoidance, and pain self-efficacy. We hypothesized that people with probable PTSD would have higher fear avoidance and lower pain self-efficacy; and that PTSS would be indirectly associated with pain disability via fear avoidance and self-efficacy. People with probable PTSD had higher fear avoidance, but there were no differences in self-efficacy, pain severity or disability. There was an indirect association between PTSS and pain disability via fear avoidance, but not via self-efficacy.
Learn More >Epidemiological studies have shown that 6.9-10% of people suffer from neuropathic pain, a complex painful condition which is often undertreated. Data regarding the effectiveness of treatment options for patients with neuropathic pain is inconsistent, and there is no single treatment option that shows cost-effectiveness across studies.
Learn More >Given the ubiquitous nature of opioids in the treatment of pain, it is an interesting paradox that this class of medications also represents one of the least understood components of clinical pain medicine. For many years, there has been intense interest in the mechanisms of opioid activity, but this has not resulted in a corresponding increase in convincing clinical data. This review focuses primarily on the evidence surrounding the long-term use of opioids in chronic pain, but discussions of this research are often conflated with the very different data governing acute and cancer-related pain, where evidence of efficacy is clearer. It is therefore important to clarify the evidence-based indications for opioid therapy. There remains very little evidence that opioids improve function or quality of life beyond 3 months in people with chronic pain conditions. In all three patient populations, the development of tolerance, dependence, hyperalgesia and withdrawal are key phenomena that affect the patient experience, and in particular the decision to remain on opioids in the long term. This is a common thread that connects the opioid literature in all of these spheres, and justifies the burgeoning interest in these phenomena in the basic science literature. There is an urgent need to address these negative consequences of opioid use, in order to maximize the therapeutic benefit that opioids can offer.
Learn More >Knee osteoarthritis (OA) is a global problem that causes significant pain and physical dysfunction, substantially impacting on quality of life and imposing enormous cost to the healthcare system. Exercise is pivotal to OA management, yet uptake by people with knee OA is inadequate. Limited access to appropriately skilled health professionals, such as physiotherapists, for prescription of an exercise program and support with exercise is a major barrier to optimal care. Internet-enabled video consultations permit widespread reach. However, services offering video consultations with physiotherapists for musculoskeletal conditions are scant in Australia where there is typically no Government or private health insurer funding for such services. The paucity of robust evidence demonstrating video consultations with physiotherapists are clinically effective, safe and cost-effective for knee OA is hampering implementation of, and willingness of healthcare policymakers to pay for, these services.
Learn More >This study aimed to evaluate whether the development and/or maintenance of chronic-latent muscle hyperalgesia is modulated by P2X3 receptors. We also evaluate the expression of P2X3 receptors and PKCε of dorsal root ganglions during these processes. A mouse model of chronic-latent muscle hyperalgesia, induced by carrageenan and evidenced by PGE, was used. Mechanical muscle hyperalgesia was measured by Randall-Selitto analgesimeter. The involvement of P2X3 receptors was analyzed by using the selective P2X3 receptors antagonist A-317491 by intramuscular or intrathecal injections. Expression of P2X3 and PKCε in dorsal root ganglion (L4-S1) were evaluated by Western blotting. Intrathecal blockade of P2X3 receptors previously to carrageenan prevented the development and maintenance of acute and chronic-latent muscle hyperalgesia, while intramuscular blockade of P2X3 receptors previously to carrageenan only reduced the acute muscle hyperalgesia and had no effect on chronic-latent muscle hyperalgesia. Intrathecal, but not intramuscular, blockade of P2X3 receptors immediately before PGE, in animals previously sensitized by carrageenan, reversed the chronic-latent muscle hyperalgesia. There was an increase in total and phosphorylated PKCε 48 h after the beginning of acute muscle hyperalgesia, and in P2X3 receptors at the period of chronic muscle hyperalgesia. P2X3 receptors expressed on spinal cord dorsal horn contribute to transition from acute to chronic muscle pain. We also suggest an interaction of PKCε and P2X3 receptors in this process. Therefore, we point out P2X3 receptors of the spinal cord dorsal horn as a pharmacological target to prevent the development or reverse the chronic muscle pain conditions.
Learn More >Post-herpetic neuralgia (PHN) is a common herpes zoster (HZ) complication, where pain persists 90 days after the initial HZ diagnosis. Evaluating PHN risk is essential for determining the burden on patients and health-care systems, but research shows variable estimates. The extent to which these differences are related to the assessment method has not been examined. The purpose of this study is to compare the proportion of PHN among HZ patients measured by medical chart review and self-report surveys.
Learn More >Obesity has been linked to an increased prevalence of migraine, and to increased migraine attack frequency, but several questions are left unanswered by previous studies. We examined the relationship between obesity and headache in a large, population-based study where we could take into account body fat distribution, migraine subtypes and tension-type headache.
Learn More >Stimulation of the occipital or trigeminal nerves has been successfully used to treat chronic refractory neurovascular headaches such as migraine or cluster headache, and painful neuropathies. Convergence of trigeminal and occipital sensory afferents in the 'trigeminocervical complex' (TCC) from cutaneous, muscular, dural, and visceral sources is a key mechanism for the input-induced central sensitization that may underlie the altered nociception. Both excitatory (glutamatergic) and inhibitory (GABAergic and glycinergic) mechanisms are involved in modulating nociception in the spinal and medullary dorsal horn neurons, but the mechanisms by which nerve stimulation effects occur are unclear. This study was aimed at investigating the acute effects of electrical stimulation of the greater occipital nerve (GON) on the responses of neurons in the TCC to the mechanical stimulation of the vibrissal pad.
Learn More >Contributing to the welfare of others has been shown to have positive effects on people's social and psychological well-being (PWB). The current study examined whether social contribution (SC) could alleviate the negative effects of chronic pain on PWB through perceived social support (PSS) among midlife and older adults. The study consisted of 520 participants with chronic pain from the two waves of the Midlife in the United States dataset (MIDUS II and III). Results from the longitudinal moderated mediation analysis indicated that SC at Time 2 (T2) significantly buffered the negative effect of pain interference (PI) at Time 1 (T1) on PSS at T2, which indirectly alleviated the negative effect of PI at T1 on PWB at T2. The study suggested the protective role of SC and prosocial behaviors in mitigating the detrimental effects of chronic pain on social support and PWB.
Learn More >Neuropathic pain is a chronic condition that remains a major clinical problem owing to high resistance to available therapy. Recent studies have indicated that chemokine signaling pathways are crucial in the development of painful neuropathy; however, the involvement of CC chemokine receptor 4 (CCR4) has not been fully elucidated thus far. Therefore, the aim of our research was to investigate the role of CCR4 in the development of tactile and thermal hypersensitivity, the effectiveness of morphine/buprenorphine, and opioid-induced tolerance in mice exposed to chronic constriction injury (CCI) of the sciatic nerve. The results of our research demonstrated that a single intrathecal or intraperitoneal administration of C021, a CCR4 antagonist, dose dependently diminished neuropathic pain-related behaviors in CCI-exposed mice. After sciatic nerve injury, the spinal expression of and remained unchanged in contrast to that of , which was significantly upregulated until day 14 after CCI. Importantly, our results provide evidence that in naive mice, CCL2 may evoke pain-related behaviors through CCR4 because its pronociceptive effects are diminished by C021. In CCI-exposed mice, the pharmacological blockade of CCR4 enhanced the analgesic properties of morphine/buprenorphine and delayed the development of morphine-induced tolerance, which was associated with the silencing of IBA-1 activation in cells and decrease in CCL2 production. The obtained data suggest that the pharmacological blockade of CCR4 may be a new potential therapeutic target for neuropathic pain polytherapy.
Learn More >Posttraumatic stress disorder (PTSD) and fibromyalgia syndrome (FMS) are two commonly co-occurring conditions among women veterans. Each contributes to functional impairment that is compounded in those with both diagnoses. This emphasizes the need for integrated evidence-based treatments aimed at reducing symptoms of both. This pilot study examined feasibility and preliminary effectiveness of an integrated treatment combining elements of cognitive behavioral therapy for chronic pain and cognitive processing therapy in a small sample of women veterans with PTSD and FMS.
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