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While opioids produce both analgesia and side-effects by action at mu-opioid receptors (MOR), at spinal and supraspinal sites, potency of different opioids to produce these effects vary. While it has been suggested that these differences might be due to bias for signaling via β-arrestin versus G protein alpha (Gα), recent studies suggest that G protein biased MOR agonists still produce clinically important side-effects. Since bias also exists in the role of Gα subunits, we evaluated the role of Gα subunits in analgesia, hyperalgesia, and hyperalgesic priming produced by fentanyl and morphine, in male rats. We found that intrathecal treatment with oligodeoxynucleotides antisense (AS-ODN) for Gα2, Gα3 and Gα markedly attenuated hyperalgesia induced by sub-analgesic dose (sub-AD) fentanyl, while AS-ODN for Gα1, as well as Gα2 and Gα3, but not Gα, prevented hyperalgesia induced by sub-AD morphine. AS-ODN for Gα1 and Gα2 unexpectedly analgesia induced by analgesic dose (AD) fentanyl, while Gα1 AS-ODN markedly AD morphine analgesia. Hyperalgesic priming, assessed by prolongation of prostaglandin E (PGE)-induced hyperalgesia, was not produced by systemic sub-AD and AD fentanyl in Gα3 and Gα AS-ODN-treated rats, respectively. In contrast, none of the Gα AS-ODNs tested affected priming induced by systemic sub-AD and AD morphine. We conclude that signaling by different Gα subunits is necessary for the analgesia and side-effects of two of the most clinically used opioid analgesics. Design of opioid analgesics that demonstrate selectivity for individual Gα may produce a more limited range of side-effects and enhanced analgesia. Biased mu-opioid receptor (MOR) agonists that preferentially signal through G proteins α-subunits over β-arrestins have been developed, as an approach to mitigate opioid side-effects. However, we recently demonstrated that biased MOR agonists also produce hyperalgesia and priming. We show that oligodeoxynucleotide antisense (AS-ODN) to different Gα subunits play a role in hyperalgesia and analgesia induced by sub-analgesic and analgesic dose (respectively), of fentanyl and morphine, as well as in priming. Our findings have the potential to advance our understanding of the mechanisms involved in adverse effects of opioid analgesics that could assist in the development of novel analgesics, preferentially targeting specific G protein α-subunits.
Learn More >Prdm12 is a conserved epigenetic transcriptional regulator that displays restricted expression in nociceptors of the developing peripheral nervous system. In mice, Prdm12 is required for the development of the entire nociceptive lineage. In humans, PRDM12 mutations cause congenital insensitivity to pain, likely because of the loss of nociceptors. Prdm12 expression is maintained in mature nociceptors suggesting a yet-to-be explored functional role in adults. Using Prdm12 inducible conditional knockout mouse models, we report that in adult nociceptors Prdm12 is no longer required for cell survival but continues to play a role in the transcriptional control of a network of genes, many of them encoding ion channels and receptors. We found that disruption of Prdm12 alters the excitability of dorsal root ganglion neurons in culture. Phenotypically, we observed that mice lacking Prdm12 exhibit normal responses to thermal and mechanical nociceptive stimuli but a reduced response to capsaicin and hypersensitivity to formalin-induced inflammatory pain. Together, our data indicate that Prdm12 regulates pain-related behavior in a complex way by modulating gene expression in adult nociceptors and controlling their excitability. The results encourage further studies to assess the potential of Prdm12 as a target for analgesic development.
Learn More >Patients with bi-allelic loss of function mutations in the voltage-gated sodium channel Nav1.7 present with congenital insensitivity to pain (CIP), whilst low threshold mechanosensation is reportedly normal. Using psychophysics (n = 6 CIP participants and n = 86 healthy controls) and facial EMG (n = 3 CIP participants and n = 8 healthy controls) we have found that these patients also have abnormalities in the encoding of affective touch which is mediated by the specialised afferents; C-low threshold mechanoreceptors (C-LTMRs). In the mouse we found that C-LTMRs express high levels of Nav1.7. Genetic loss or selective pharmacological inhibition of Nav1.7 in C-LTMRs resulted in a significant reduction in the total sodium current density, an increased mechanical threshold and reduced sensitivity to non-noxious cooling. The behavioural consequence of loss of Nav1.7 in C-LTMRs in mice was an elevation in the von Frey mechanical threshold and less sensitivity to cooling on a thermal gradient. Nav1.7 is therefore not only essential for normal pain perception but also for normal C-LTMR function, cool sensitivity and affective touch.
Learn More >The dorsal root ganglion is widely recognized as a potential target to treat chronic pain. A fundamental understanding of quantitative molecular and genomic changes during the late phase of pain is therefore indispensable. The authors performed a systematic literature review on injury-induced pain in rodent dorsal root ganglions at minimally 3 weeks after injury. So far, slightly more than 300 molecules were quantified on the protein or messenger RNA level, of which about 60 were in more than one study. Only nine individual sequencing studies were performed in which the most up- or downregulated genes varied due to heterogeneity in study design. Neuropeptide Y and galanin were found to be consistently upregulated on both the gene and protein levels. The current knowledge regarding molecular changes in the dorsal root ganglion during the late phase of pain is limited. General conclusions are difficult to draw, making it hard to select specific molecules as a focus for treatment.
Learn More >Adolescent pain is common and continues into adulthood, leading to negative long-term outcomes including substance-related morbidity: an empirical definition of its construct may inform the early detection of persistent pain trajectories. These secondary analyses of a classical twin study assessed whether: headaches, back pains, abdominal pain, chest pains, stabbing/throbbing pain, gastric pain/nausea, measured in 501 pairs across 5 waves between age 12-17, fit a unitary construct, or constitute independent manifestations. We then assessed which symptoms were associated with a steady, 'frequent pain' trajectory that is associated with risk for early opioid prescriptions. Item Response Theory results indicated that all 6 pain symptoms index a unitary construct. Binary logistic regressions identified 'back pain' as the only symptom consistently associated with membership in the 'frequent adolescent pain' trajectory (OR:1.66-3.38) at all 5 measurement waves. Receiver Operating Characteristic analyses computed the discriminating power of symptoms to determine participants' membership into the 'frequent' trajectory: they yielded acceptable (.7-.8) to excellent (.8-.9) area under the curve (AUC) values for all 6 symptoms. The highest AUC was attained by 'back pain' at age 14 (.835); for multiple cut-off thresholds of symptom frequency, 'back pain' showed good sensitivity/false alarm probability trade-offs, predominantly in the 13-14-15 age range, to predict the 'frequent pain' trajectory. These data support a unitary conceptualization and assessment of adolescent pain, which is advantageous for epidemiological, clinical, and translational purposes. Persistent back pain constitutes a sensitive indicator of a steady trajectory of adolescent pain.
Learn More >Activation of cannabinoid receptor type 1 (CB1) produces analgesia in a variety of preclinical models of pain; however, engagement of central CB1 receptors is accompanied by unwanted side effects, such as psychoactivity, tolerance and dependence. Therefore, some efforts to develop novel analgesics have focused on targeting peripheral CB1 receptors to circumvent central CB1-related side effects. In the present study, we evaluated the effects of acute and repeated dosing with the peripherally selective CB1-preferring agonist CB-13 on nociception and central CB1-related phenotypes in a model of inflammatory pain in mice. We also evaluated cellular mechanisms underlying CB-13-induced antinociception in vitro using cultured mouse dorsal root ganglion (DRG) neurons. CB-13 reduced inflammation-induced mechanical allodynia in male and female mice in a peripheral CB1 receptor-dependent manner and relieved inflammatory thermal hyperalgesia. In cultured mouse DRG neurons, CB-13 reduced TRPV1 sensitization and neuronal hyperexcitability induced by the inflammatory mediator prostaglandin E2, providing potential mechanistic explanations for the analgesic actions of peripheral CB1 receptor activation. With acute dosing, phenotypes associated with central CB1 receptor activation occurred only at a dose of CB-13 approximately 10-fold the ED50 for reducing allodynia. Strikingly, repeated dosing resulted in both analgesic tolerance and CB1 receptor dependence, even at a dose that did not produce central CB1 receptor-mediated phenotypes on acute dosing. This suggests repeated CB-13 dosing leads to increased CNS exposure and unwanted engagement of central CB1 receptors. Thus, caution is warranted regarding therapeutic use of CB-13 with the goal of avoiding CNS side effects. Nonetheless, the clear analgesic effect of acute peripheral CB1 receptor activation suggests that peripherally restricted cannabinoids are a viable target for novel analgesic development.
Learn More >Evidence suggests insulin centrally activates the sympathetic nervous system, and a chemical stimulus to tissues activates the sympathetic nervous system via thin fibre muscle afferents. Insulin is reported to modulate putative chemical sensitive channels in the dorsal root ganglion neurons of these afferents. In the present study, we demonstrate that insulin potentiates the responsiveness of thin fibre afferents to capsaicin at muscle tissue levels as well as at the level of dorsal root ganglion neurons. In addition, we demonstrate that insulin augments the sympathetic nerve activity response to capsaicin in vivo. These data suggests that sympathoexcitation is peripherally mediated via insulin-induced chemical sensitization. The present study proposes a possible physiological role of insulin in the regulation of chemical sensitivity in somatosensory thin fibre muscle afferents.
Learn More >In addition to diurnal rhythms in physiology and behavior, a variety of pathological conditions also exhibit marked day-night changes in symptom intensity, exemplified by allergic rhinitis, arthritis, asthma, myocardial infarction, congestive heart failure, stroke, and chronic pain disorders. Currently, novel therapeutic approaches are facilitated by the development of chemical compounds targeted to key proteins that cause diurnal exacerbation of pathological events. Neuropathic pain is a chronic condition that occurs by tumor-induced nerve compression, cancer cell infiltration into the nerve, diabetes, and herpes virus infection. One troublesome hallmark symptom of neuropathic pain is hypersensitivity to normally innocuous stimuli known as "mechanical allodynia" that is often refractory to common analgesic therapies. Millions of patients worldwide presently endure neuropathic pain. We summarize the recent insights gained into the mechanism of diurnal exacerbation of neuropathic pain hypersensitivity and introduce the strategy of circadian clock-based drug development.
Learn More >The aim of this study was to determine if prolactin signaling modulates stress-induced behavioral responses in a preclinical migraine model.
Learn More >Erenumab (ERE) is the first anti-calcitonin gene related peptide (CGRP) receptor monoclonal antibody approved for migraine prevention. A proportion of patients does not adequately respond to ERE.
Learn More >To evaluate the content validity and psychometric properties of the Activity Impairment in Migraine Diary (AIM-D).
Learn More >Fibromyalgia (FM) is a complex chronic pain condition. Its symptoms are nonspecific, and to date, no objective test exists to confirm FM diagnosis. Potential objective measures include the circulating levels of blood biomarkers. This systematic review and meta-analysis aim to review studies assessing blood biomarkers' levels in patients with FM compared with healthy controls. We systematically searched the PubMed, MEDLINE, EMBASE, and PsycINFO databases. Fifty-four studies reporting the levels of biomarkers in blood in patients with FM were included. Data were extracted, and the methodological quality was assessed independently by 2 authors. The methodological quality of 9 studies (17%) was low. The results of most studies were not directly comparable given differences in methods and investigated target immune mediators. Thus, data from 40 studies only were meta-analyzed using a random-effects model. The meta-analysis showed that patients with FM had significantly lower levels of interleukin-1 β and higher levels of IL-6, IL-8, tumor necrosis factor-alpha, interferon gamma, C-reactive protein, and brain-derived neurotrophic factor compared with healthy controls. Nevertheless, this systematic literature review and meta-analysis could not support the notion that these blood biomarkers are specific biomarkers of FM. Our literature review, however, revealed that these same individual biomarkers may have the potential role of identifying underlying pathologies or other conditions that often coexist with FM. Future research is needed to evaluate the potential clinical value for these biomarkers while controlling for the various confounding variables.
Learn More >A higher level of pain self-efficacy has been suggested as a predictor of a better outcome in patients with musculoskeletal disorders. The Pain Self-Efficacy Questionnaire (PSEQ) is one of the most frequently used patient-reported outcome measures for pain self-efficacy. The purpose of this study was to conduct a systematic review that would identify, appraise, and synthetize the psychometric properties of the PSEQ. Embase, MEDLINE, and CINAHL databases were searched for publications reporting on psychometric properties of the PSEQ in populations with musculoskeletal disorders. After applying selection criteria on identified citations, 28 studies (9853 participants) were included. The methodological quality as measured with the COSMIN risk of bias tool varied from to for most measurement properties. The results showed a weighted mean intraclass correlation coefficient of 0.86 (range: 0.75-0.93) for test-retest reliability for the original 10-item PSEQ and the minimal detectable change at 95% confidence interval was 11.52 out of 60 points. Effect size and standardized response mean values were 0.53 and 0.63, respectively, whereas the minimal clinically important difference ranged from 5.5 to 8.5 in patients with chronic low back pain. Internal consistency (Cronbach alpha) ranged from 0.79 to 0.95. The results also showed that the PSEQ has low to moderate correlations with measures of quality of life, disability, pain, pain interference, anxiety, depression, and catastrophizing. Finally, the PSEQ has been adapted and validated in 14 languages. Overall, the results demonstrate that the PSEQ has excellent validity, reliability, and responsiveness. Further high-quality studies are needed to determine responsiveness in populations other than chronic low back pain.
Learn More >Boric acid (BA) has been used in many diseases because it increases the amount of reduced glutathione in the body and reduces oxidative damage. This study aims to investigate the effects of boric acid in cisplatin-induced neuropathy, in which oxidative stress is also effective in its pathophysiology. In this study, 8-10 weeks old, 170-190 g Wistar Albino rats were used. Each group contained seven rats (n = 35). Experimental groups consist of control, sham, neuropathy, treatment, and boric acid groups. For the neuropathy model, a single dose of cisplatin (3 mg/kg, i.p) was administered once a week for five weeks, and for the treatment group, boric acid was administered daily (100 mg/kg, intragastric) for five weeks. After drug administration, the rotarod test to evaluate motor performance, the tail-flick and hot/cold plate tests to evaluate sensory conduction states, the von Frey filament test to evaluate the mechanical allodynia, and the adhesive removal test to assess sensorimotor function were performed. The sciatic nerve's motoric conduction velocity was also assessed electrophysiologically. Oxidative stress parameters were also assessed biochemically in sciatic nerve tissue and serum. Hematoxylin and eosin staining was used to evaluate the sciatic nerve tissue histopathologically. The motor conduction velocity of the sciatic nerve, impaired by cisplatin, was increased considerably by boric acid (p < 0.05). It also reduced the latency time of the compound muscle action potential (CMAP), which was increased by cisplatin. (p < 0.05). The von Frey filament test results demonstrated increased pain sensitivity of the cisplatin group increased, and mechanical allodynia was observed. Boric acid significantly alleviated this condition (p < 0.05). In the cold plate, adhesive removal, and rotarod tests, boric acid attenuated the adverse effects of cisplatin (p < 0.05). Biochemically, BA reduced the level of MDA, which was raised by cisplatin, and significantly increased the level of SOD, which was lowered by cisplatin (p < 0.05). Histopathologically; BA reduced neuronal degeneration and vacuolization caused by cisplatin. As a consequence, it has been determined that boric acid alleviates the adverse effects of cisplatin. BA reduced the destructive effect of cisplatin by reducing oxidative stress, and this effect was verified electrophysiologically, behaviorally, and histopathologically.
Learn More >The aim of this study is to evaluate the preemptive analgesic effects of dexamethasone (DEX) alone or combined with non-steroidal anti-inflammatory drugs (NSAIDs) in third molar surgeries. The subjects were divided into five groups (n = 20 teeth/group); subjects received only 8 mg of dexamethasone 1 h before the surgical procedure (DEX group), or in combination with etodolac (DEX + ETO), ketorolac (DEX + KET), ibuprofen (DEX + IBU), loxoprofen (DEX + LOX). Paracetamol 750 mg was provided as the number of rescue analgesics (NRA). Salivary PGE2 expression was measured preoperatively and at 48 h. Edema and Maximum mouth opening (MMO) were measured postoperatively at 48 h and 7 days. A visual analog scale (VAS) was performed postoperatively at 6, 12, 24, 48, 72 h, and 7 days. Salivary expression of PGE2 showed a decrease only for the DEX group. Edema and MMO and NRA consumption showed no significant differences among the groups (P > 0.05). The VAS showed a significantly lower pain perception at 6 h after the surgery for the DEX + ETO and DEX + KET groups (P < 0.05). The combination of DEX and NSAIDS should be considered for preemptive acute postsurgical pain management in third molar surgery. In some drug associations such as dexamethasone 8 mg + NSAIDS (ETO and KET) in the pre-operative time, only a few rescue analgesics are necessary.
Learn More >The global burden of osteoarthritis (OA) is steadily increasing due to demographic and lifestyle changes. The nervous system can undergo peripheral and central neuroplastic changes (sensitization) in patients with OA impacting the options to manage the pain adequately. As a result of sensitization, patients with OA show lower pressure pain thresholds (PPTs), facilitated temporal summation of pain (TSP), and impaired conditioned pain modulation (CPM). As traditional analgesics (acetaminophen and non-steroidal anti-inflammatory drugs) are not recommended for long-term use in OA, more fundamental knowledge related to other possible management regimes are needed. Duloxetine is a serotonin-noradrenalin reuptake inhibitor, and analgesic effects are documented in patients with OA although the underlying fundamental mechanisms remain unclear. The descending pain inhibitory control system is believed to be dependent on serotonin and noradrenalin. We hypothesized that the analgesic effect of duloxetine could act through these pathways and consequently indirectly reduce pain and sensitization. The aim of this mechanistic study is to investigate if PPTs, TSP, CPM, and clinical pain parameters are modulated by duloxetine.
Learn More >Neuropathic pain symptoms and signs of increased pain sensitisation in osteoarthritis (OA) patients may explain persistent pain after total joint replacement (TJR). Therefore, identifying genetic markers associated with pain sensitisation and neuropathic-like pain phenotypes could be clinically important in identifying targets for early intervention.
Learn More >Chronic abdominal pain is a common symptom of inflammatory bowel diseases (IBD). Peripheral and central mechanisms contribute to the transition from acute to chronic pain during active disease and clinical remission. Lower mechanical threshold and hyperexcitability of visceral afferents induce gliosis in central pain circuits, leading to persistent visceral hypersensitivity (VHS). In the spinal cord, microglia, the immune sentinels of the central nervous system, undergo activation in multiple models of VHS. Here we investigated the mechanisms of microglia activation to identify centrally acting analgesics for chronic IBD pain.
Learn More >The Ad5-nCoV vaccine is a single-dose adenovirus type 5 (Ad5) vectored vaccine expressing the SARS-CoV-2 spike protein that was well-tolerated and immunogenic in phase 1 and 2 studies. In this study, we report results on the final efficacy and interim safety analyses of the phase 3 trial.
Learn More >Whereas human spinal cord injury (SCI) is more common in men, the prevalence is growing in women. However, little is known about the effect of biological sex on brain dysfunction and injury mechanisms. To model the highest per capita rate of injury (ages between 16 and 30 years old) in humans, in the present study, young adult or a young/middle-aged male and female C57BL/6 mice were subjected to moderate contusion SCI. When mice were injured at 10-12-week-old, transcriptomic analysis of inflammation-related genes and flow cytometry revealed a more aggressive neuroinflammatory profile in male than females following 3 d SCI, ostensibly driven by sex-specific changes myeloid cell function rather than cell number. Female mice were generally more active at baseline, as evidenced by greater distance traveled in the open field. After SCI, female mice had more favorable locomotor function than male animals. At 13 weeks post-injury, male mice showed poor performance in cognitive and depressive-like behavioral tests, while injured female mice showed fewer deficits in these tasks. However, when injured at 6 months old followed by 8 months post-injury, male mice had considerably less inflammatory activation compared with female animals despite having similar or worse outcomes in affective, cognitive, and motor tasks. Collectively, these findings indicate that sex differences in functional outcome after SCI are associated with the age at onset of injury, as well as disrupted neuroinflammation not only at the site of injury but also in remote brain regions. Thus, biological sex should be considered when designing new therapeutic agents.
Learn More >Knee osteoarthritis (KOA) is characterized by a degenerative change of knee cartilage and secondary bone hyperplasia, resulting in pain, stiffness, and abnormal walking gait. Long-term chronic pain causes considerable cortical plasticity alternations in patients. However, the brain structural and functional alterations associated with the pathological changes in knee joints of end-stage KOA patients remain unclear. This study aimed to analyze the structural and functional connectivity alterations in end-stage KOA to comprehensively understand the main brain-associated mechanisms underlying its development and progression.
Learn More >Invasive and transcutaneous vagus nerve stimulation [(t)-VNS] have been used to treat epilepsy, depression and migraine and has also shown effects on metabolism and body weight. To what extent this treatment shapes neural networks and how such network changes might be related to treatment effects is currently unclear. Using a pre-post mixed study design, we applied either a tVNS or sham stimulation (5 h/week) in 34 overweight male participants in the context of a study designed to assess effects of tVNS on body weight and metabolic and cognitive parameters resting state (rs) fMRI was measured about 12 h after the last stimulation period. Support vector machine (SVM) classification was applied to fractional amplitude low-frequency fluctuations (fALFF) on established rs-networks. All classification results were controlled for random effects and overfitting. Finally, we calculated multiple regressions between the classification results and reported food craving. We found a classification accuracy (CA) of 79 % in a subset of four brainstem regions suggesting that tVNS leads to lasting changes in brain networks. Five of eight salience network regions yielded 76,5 % CA. Our study shows tVNS' post-stimulation effects on fALFF in the salience rs-network. More detailed investigations of this effect and their relationship with food intake seem reasonable for future studies.
Learn More >This study aimed to examine the N400 effect and event-related potentials (ERPs) elicited from congruent and incongruent stimuli in patients who have migraines with aura (MwA).
Learn More >Placebo and nocebo effects are positive and negative health outcomes that can be elicited by the psychosocial context. They can be mediated by expectations, and may emerge in somatic symptoms even when people are aware of these effects. Interindividual differences (e.g., in personality, affective states) could impact placebo and nocebo responding, but findings are inconsistent. The current work examined expectation as a mediator of the association between verbal placebo and nocebo suggestions (VSs) and histamine-induced itch across three experimental studies. Moreover, we examined whether interindividual differences (e.g., in optimism, neuroticism, behavioral activation system (BAS), body ignorance) modulated: (1) the direct association between VSs and itch (direct moderation), and (2) the indirect, expectation-mediated association between VSs and itch (moderated mediation). Positive VSs were compared to neutral instructions (Study 1; = 92) or negative VSs (Studies 2+3; = 203) in an open-label (i.e., explaining placebo and nocebo effects) or closed-label (concealed) context using PROCESS. First, mediation of VSs effects on itch by expectations was tested. Next, moderation by individual traits was explored using conditional process analyses. The effects of VSs on itch were significantly mediated by expectation in Study 1 and in the open-label (but not closed-label) contexts of Studies 2 and 3. Ignorance of bodily signals marginally moderated the direct effects of VSs on itch when closed-label suggestions were given: at low levels of body ignorance, effects of positive and negative VSs were stronger. Moreover, moderated mediation was observed in the open-label groups of Studies 2 and 3: The expectation-mediated effects of VSs on itch were stronger when BAS drive was lower. Overall, the effects of VSs on itch were mediated by expectations in the open-label, but not the closed-label context. Moreover, the current work suggests that placebo and nocebo effects may be moderated by ignorance of bodily signals and the BAS. There was limited evidence that other interindividual differences modulated placebo and nocebo responding in itch.
Learn More >Pain is known to be socioeconomically patterned and associated with disability. However, knowledge is scarce concerning life-course socioeconomic circumstances and pain among young adults. Our aim was to examine the associations of childhood and current socioeconomic circumstances with acute pain and chronic pain with low and high disability levels among young Finnish municipal employees.
Learn More >Fatigue is a disabling symptom in people with Rheumatoid Arthritis (RA). This study aims to describe the prevalence, risk factors and the longitudinal course of fatigue in early RA.
Learn More >The evaluation and treatment of patients with epilepsy is not limited to the type of epilepsy, but it must incorporate the common comorbid neurologic, psychiatric, and medical disorders, as the latter can bare an impact on the course and response to treatment of the seizure disorder and vice versa. In this article we review the bidirectional relations among epilepsy and two of its most common comorbidities, mood disorders and migraine and examine the implications of these relations on the selection of therapies of these three disorders and their response to treatment. We also review the most salient common pathogenic mechanisms that may explain such relations.
Learn More >Migraine is a medical condition with a severe recursive headache. The activation of the trigeminovascular system is an important mechanism. The neuropeptide calcitonin gene-related peptide (CGRP) plays a crucial role in the pathogenesis of migraine. Several other neuropeptides are also involved; however, their roles in migraine remain unclear. In this study, using a rat model of migraine induced by electrical stimulation of the trigeminal ganglia (TG) and an improved version induced with repeated stimulation, we observed the dynamic changes of these peptides in TG and blood. We demonstrated that the expression of CGRP, pituitary adenylate cyclase activating polypeptide (PACAP), neuropeptide Y (NPY), vasoactive intestinal peptide, and nociceptin in TG was significantly elevated and peaked at different time points after a single stimulation. Their levels in the blood plasma were significantly increased at 12 h after stimulation. The peptides were further elevated with repeated stimulation. The improved rat model of migraine with repeated stimulation of TG resulted in a more pronounced elevation of CGRP, PACAP, and NPY. Thus, the dynamic changes in neuropeptides after stimulation suggest that these neuropeptides may play an important role in the pathogenesis of migraine. Additionally, the migraine model with repetitive stimulation would be a novel model for future research.
Learn More >This study sought to determine whether cannabidiol (CBD) or a CBD derivative, CBD monovalinate monohemisuccinate (CBD-val-HS), could attenuate the development of oxycodone reward while retaining its analgesic effects. To determine the effect on oxycodone reward, animals were enrolled in the conditioned place preference paradigm and received either saline or oxycodone (3.0 mg/kg) in combination with either CBD or CBD-val-HS utilizing three sets of drug-/no drug-conditioning trials. To determine if the doses of CBD or CBD-val-HS that blocked opioid reward would affect nociceptive processes, animals were enrolled in the hot plate and abdominal writhing assays when administered alone or in combination with a subanalgesic (1.0 mg/kg) or analgesic (3.0 mg/kg) dose of oxycodone. Results from condition place preference demonstrated CBD was not able attenuate oxycodone place preference while CBD-val-HS attenuated these rewarding effects at 8.0 mg/kg and was void of rewarding or aversive properties. In contrast to CBD, CBD-val-HS alone produced analgesic effects in both nociceptive assays but was most effective compared with oxycodone against thermal nociception. Of interest, there was a differential interaction of CBD and CBD-val-HS×oxycodone across the two nociceptive assays producing subadditive responses on the hot plate assay, whereas additive responses were observed in the abdominal writhing assay. These findings suggest CBD-val-HS alone, a nonrewarding analgesic compound, could be useful in pain management and addiction treatment settings.
Learn More >Several studies have found evidence of reduced resting-state peak alpha frequency (PAF) in populations with pain. However, the stability of PAF from different analytic pipelines used to study pain has not been determined and underlying neural correlates of PAF have not been validated in humans.
Learn More >The mechanism by which acetaminophen produces its analgesic effects is not fully understood. One possible mechanism is the activation of the spinal 5-hydroxytryptamine (5-HT) receptor, although direct evidence of spinal 5-HT release has not yet been reported. N-arachidonoylphenolamine (AM404), a metabolite of acetaminophen, is believed to be the key substance that contributes to the analgesic effects of acetaminophen. In this study, we examined whether acetaminophen and AM404 induce spinal 5-HT release and the mechanism through which spinal 5-HT receptor activation exerts analgesic effects in a rat formalin test in an inflammatory pain model. Spinal 5-HT release was examined by intrathecal microdialysis in conscious and freely moving rats. Acetaminophen was administered orally, and AM404 was administered intracerebroventricularly. In rat formalin tests, oral acetaminophen and intracerebroventricular AM404 induced significant spinal 5-HT release and produced analgesic effects. The analgesic effect of oral acetaminophen was partially antagonized by intrathecal administration of WAY100135 (a 5-HT receptor antagonist) and SB269970 (a 5-HT receptor antagonist). In contrast, the analgesic effect of intracerebroventricular AM404 was completely antagonized by WAY100135, while SB269970 had no effect. Our data suggest that while oral acetaminophen and intracerebroventricular AM404 activate the spinal 5-HT system, the role of the spinal 5-HT system activated by oral acetaminophen differs from that activated by intracerebroventricular AM404.
Learn More >Complex regional pain syndrome (CRPS) is an orphan disease occurring as a complication after trauma. Due to its acute onset and the typical clinical presentation of the inflammatory and autonomous signs, it is an eye-catching chronic pain disease affecting also young and working people. In social media and the internet, high pain severity and unfavorable prognosis is often empathized.
Learn More >Veterans with chronic pain may be vulnerable during the COVID-19 pandemic. We qualitatively explored the impact of the COVID-19 pandemic on a sample of Veterans receiving brief counseling focused on pain management in an ongoing clinical trial and discuss how the pandemic affected the process of motivating Veterans with chronic pain to engage in interdisciplinary multimodal pain treatment at the Department of Veteran Affairs.
Learn More >Opioids are a class of drugs that are known for their use as pain relievers. They bind to opioid receptors on nerve cells in the brain and the nervous system to mitigate pain. Addiction is one of the chronic and primary adverse events of prolonged usage of opioids. They may also cause psychological disorders, muscle pain, depression, anxiety attacks etc. In this study, we present a collection of predictive models to identify patients at risk of opioid abuse and mortality by using their prescription histories. Also, we discover particularly threatening drug-drug interactions in the context of opioid usage. Using a publicly available dataset from MIMIC-III, two models were trained, Logistic Regression with L2 regularization (baseline) and Extreme Gradient Boosting (enhanced model), to classify the patients of interest into two categories based on their susceptibility to opioid abuse. We've also used K-Means clustering, an unsupervised algorithm, to explore drug-drug interactions that might be of concern. The baseline model for classifying patients susceptible to opioid abuse has an F1 score of 76.64% (accuracy 77.16%) while the enhanced model has an F1 score of 94.45% (accuracy 94.35%). These models can be used as a preliminary step towards inferring the causal effect of opioid usage and can help monitor the prescription practices to minimize the opioid abuse. Results suggest that the enhanced model provides a promising approach in preemptive identification of patients at risk for opioid abuse. By discovering and correlating the patterns contributing to opioid overdose or abuse among a variety of patients, machine learning models can be used as an efficient tool to help uncover the existing gaps and/or fraudulent practices in prescription writing. To quote an example of one such incidental finding, our study discovered that insulin might possibly be interacting with opioids in an unfavourable way leading to complications in diabetic patients. This indicates that diabetic patients under long term opioid usage might need to take increased amounts of insulin to make it more effective. This observation backs up prior research studies done on a similar aspect. To increase the translational value of our work, the predictive models and the associated software code are made available under the MIT License.
Learn More >Pulpitis causes significant changes in the peripheral nervous system, which induce hyperalgesia. However, the relationship between neuronal activity and Nav1.7 expression following pulpal noxious pain has not yet been investigated in the trigeminal ganglion (TG). The aim of our study was to verify whether experimentally induced pulpitis activates the expression of Nav1.7 peripherally and the neuronal activities of the TGs can be affected by Nav1.7 channel inhibition. Acute pulpitis was induced through allyl isothiocyanate (AITC) application to the rat maxillary molar tooth pulp. Three days after AITC application, abnormal pain behaviors were recorded, and the rats were euthanized to allow for immunohistochemical, optical imaging, and western blot analyses of the Nav1.7 expression in the TG. A significant increase in AITC-induced pain-like behaviors and histological evidence of pulpitis were observed. In addition, histological and western blot data showed that Nav1.7 expressions in the TGs were significantly higher in the AITC group than in the naive and saline group rats. Optical imaging showed that the AITC group showed higher neuronal activity after electrical stimulation of the TGs. Additionally, treatment of ProTxII, selective Nav1.7 blocker, on to the TGs in the AITC group effectively suppressed the hyperpolarized activity after electrical stimulation. These findings indicate that the inhibition of the Nav1.7 channel could modulate nociceptive signal processing in the TG following pulp inflammation.
Learn More >Despite high prevalence estimates, chronic low back pain (CLBP) remains poorly understood among older adults. Movement-evoked pain (MeP) is an understudied factor in this patient population that may importantly contribute to disability. This study investigated whether a novel MeP paradigm contributed to self-reported and performance-based function in older adults with CLBP.
Learn More >Chronic migraine is a difficult disease to diagnose, and its pathophysiology remains undefined. Its symptoms affect the quality of life and daily living tasks of the affected person, leading to momentary disability. This is a pilot, randomized, controlled, double-blind clinical trial study with female patients between 18 and 65 years old with chronic migraine. The patients underwent twelve mindfulness sessions paired with anodal transcranial direct-current stimulation (tDCS) over the left dorsolateral prefrontal cortex (DLPFC), with current intensity of 2 mA applied for 20 min, three times a week for 4 weeks. In addition, 20 min of mindfulness home practices were performed by guided meditation audio files. A total of 30 participants were evaluated after the treatment, and these were subdivided into two groups-active tDCS and sham tDCS, both set to mindfulness practice. The FFMQ-BR (Five Facet of Mindfulness Questionnaire), MIDAS (Migraine Disability Assessment), and HIT-6 (Headache Impact Test) questionnaires were used to evaluate the outcomes. After the treatment, the active mindfulness and tDCS group showed better results in all outcomes. The sham group also showed improvements, but with smaller effect sizes compared to the active group. The only significant difference in the intergroup analysis was the outcome evaluated by HIT-6 in the post treatment result. Our results provide the first therapeutic evidence of mindfulness practices associated with left DLPFC anodal tDCS with a consequent increase in the level of full attention and analgesic benefits in the clinical symptoms of patients with chronic migraine.
Learn More >Noxious stimulus and painful experience in early life can induce cognitive deficits and abnormal pain sensitivity. As a major component of the outer membrane of gram-negative bacteria, lipopolysaccharide (LPS) injection mimics clinical symptoms of bacterial infections. Spinal microglial activation and the production of pro-inflammatory cytokines have been implicated in the pathogenesis of LPS-induced hyperalgesia in neonatal rats. Dexmedetomidine (DEX) possesses potent anti-neuroinflammatory and neuroprotective properties through the inhibition of microglial activation and microglial polarization toward pro-inflammatory (M1) phenotype and has been widely used in pediatric clinical practice. However, little is known about the effects of DEX on LPS-induced spinal inflammation and hyperalgesia in neonates. Here, we investigated whether systemic LPS exposure has persistent effects on spinal inflammation and hyperalgesia in neonatal rats and explored the protective role of DEX in adverse effects caused by LPS injection. Systemic LPS injections induced acute mechanical hyperalgesia, increased levels of pro-inflammatory cytokines in serum, and short-term increased expressions of pro-inflammatory cytokines and M1 microglial markers in the spinal cord of neonatal rats. Pretreatment with DEX significantly decreased inflammation and alleviated mechanical hyperalgesia induced by LPS. The inhibition of M1 microglial polarization and microglial pro-inflammatory cytokines expression in the spinal cord may implicate its neuroprotective effect, which highlights a new therapeutic target in the treatment of infection-induced hyperalgesia in neonates and preterm infants.
Learn More >Crotalphine (CRP) is a structural analogue to a peptide that was first identified in the crude venom from the South American rattlesnake . This peptide induces a potent and long-lasting antinociceptive effect that is mediated by the activation of peripheral opioid receptors. The opioid receptor activation regulates a variety of intracellular signaling, including the mitogen-activated protein kinase (MAPK) pathway. Using primary cultures of sensory neurons, it was demonstrated that crotalphine increases the level of activated ERK1/2 and JNK-MAPKs and this increase is dependent on the activation of protein kinase Cζ (PKCζ). However, whether PKCζ-MAPK signaling is critical for crotalphine-induced antinociception is unknown. Here, we biochemically demonstrated that the systemic crotalphine activates ERK1/2 and JNK and decreases the phosphorylation of p38 in the lumbar spinal cord. The in vivo pharmacological inhibition of spinal ERK1/2 and JNK, but not of p38, blocks the antinociceptive effect of crotalphine. Of interest, the administration of a PKCζ pseudosubstrate (PKCζ inhibitor) prevents crotalphine-induced ERK activation in the spinal cord, followed by the abolishment of crotalphine-induced analgesia. Together, our results demonstrate that the PKCζ-ERK signaling pathway is involved in crotalphine-induced analgesia. Our study opens a perspective for the PKCζ-MAPK axis as a target for pain control.
Learn More >Bone marrow lesions (BML) represent areas of deteriorated bone structure and metabolism characterized by pronounced water-equivalent signaling within the trabecular bone on Magnetic Resonance Imaging (MRI). BML are associated with repair mechanisms subsequent to various clinical conditions associated with inflammatory and non-inflammatory injury to the bone. There is no approved treatment for this condition. Bisphosphonates are known to improve bone stability in osteoporosis and other bone disorders and have been used off-label to treat BML. A randomized, triple-blind, placebo-controlled Phase III trial was conducted to assess efficacy and safety of single dose Zoledronic acid (ZOL) 5mg i.v. with Vitamin D 1000 IU/d as opposed to placebo with Vitamin D 1000 IU/d in 48 patients (randomized 2:1) with BML. Primary efficacy endpoint was reduction of edema volume six weeks after treatment as assessed by MRI. Following treatment, mean BML volume decreased by 64.53(±41.92)% in patients receiving Zoledronic acid and increased by 14.43(±150.46)% in the placebo group (p=0.007). A decrease in BML volume was observed in 76.5% of patients receiving ZOL and in 50% of the patients receiving placebo. Pain level (VAS) and all categories of the Pain Disability Index (PDI) improved with ZOL vs placebo after 6 weeks but reconciled after six additional weeks of follow-up. Six SAE occurred in five patients, none of which were classified as related to the study drug. No cases of osteonecrosis or fractures occurred. Therefore single-dose Zoledronic acid 5mg i.v. together with Vitamin D may enhance resolution of bone marrow lesions over 6 weeks along with reduction of pain as compared to Vitamin D supplementation only. This article is protected by copyright. All rights reserved.
Learn More >Trigeminal neuralgia (TN) is a severe facial pain disease with unknown pathogenesis. It has been thought that the familial form of TN is rare with a prevalence of about 1-2% among affected individuals, but emerging evidence suggests a role of genetic factors. This study examined the occurrence of familial TN among patients with classical or idiopathic TN. Patients with TN recruited from a hospital registry received an informed consent form with a questionnaire, and individuals reporting other family members with TN underwent a structured phone-interview. For affected family members, type of TN, available clinical, imaging, management results and available hospital patient records were studied. Pedigrees for all affected families were established. This study included 268 patients with either classical or idiopathic TN. The familial form of TN was present in 41/268 (15.3%) patients, that is, 37/244 (15.2%) patients with classical TN and in 4/24 (16.7%) with idiopathic TN. Total 38 families were identified, with two affected members in 32/38 families (84.2%), three affected family members in 5/38 (13.2%) and four family members in 1/38 (2.6%) families. Comparing the 41 familial TN cases with the 227 sporadic TN patients showed significantly earlier onset of TN and a significantly higher occurrence of right-sided pain in familial cases, while there was no difference in gender distribution, occurrence of arterial hypertension or trigeminal branch involved. Among patients with classical or idiopathic TN, the occurrence of the familial form of the disease is more frequent than traditionally assumed.
Learn More >Mitochondria play an essential role in pathophysiology of both inflammatory and neuropathic pain (NP), but the mechanisms are not yet clear. Dynamin-related protein 1 (Drp1) is broadly expressed in the central nervous system and plays a role in the induction of mitochondrial fission process. Spared nerve injury (SNI), due to the dysfunction of the neurons within the spinal dorsal horn (SDH), is the most common NP model. We explored the neuroprotective role of Drp1 within SDH in SNI. SNI mice showed pain behavior and anxiety-like behavior, which was associated with elevation of Drp1, as well as increased density of mitochondria in SDH. Ultrastructural analysis showed SNI induced damaged mitochondria into smaller perimeter and area, tending to be circular. Characteristics of vacuole in the mitochondria further showed SNI induced the increased number of vacuole, widened vac-perimeter and vac-area. Stable overexpression of Drp1 via AAV under the control of the Drp1 promoter by intraspinal injection (Drp1 OE) attenuated abnormal gait and alleviated pain hypersensitivity of SNI mice. Mitochondrial ultrastructure analysis showed that the increased density of mitochondria induced by SNI was recovered by Drp1 OE which, however, did not change mitochondrial morphology and vacuole parameters within SDH. Contrary to Drp1 OE, down-regulation of Drp1 in the SDH by AAV-Drp1 shRNA (Drp1 RNAi) did not alter painful behavior induced by SNI. Ultrastructural analysis showed the treatment by combination of SNI and Drp1 RNAi (SNI + Drp1 RNAi) amplified the damages of mitochondria with the decreased distribution density, increased perimeter and area, as well as larger circularity tending to be more circular. Vacuole data showed SNI + Drp1 RNAi increased vacuole density, perimeter and area within the SDH mitochondria. Our results illustrate that mitochondria within the SDH are sensitive to NP, and targeted mitochondrial Drp1 overexpression attenuates pain hypersensitivity. Drp1 offers a novel therapeutic target for pain treatment.
Learn More >Neuropathic pain in osteoarthritis is one of the reasons why the pain is difficult to treat, and P2X4R plays an important role in neuropathic pain. In addition, BoNT/A has been proven to have analgesic effects on both neuropathic pain and osteoarthritis, but its exact mechanism is still unknown. This study aims to investigate the relationship between the analgesic effect of BoNT/A on osteoarthritis and the expression of P2X4R in spinal cord microglia. The analgesic effect was compared between BoNT/A and compound betamethasone. Western blot analysis was used to examine the expression of P2X4R and BDNF proteins in the spinal cord. Immunohistochemistry was used to determine the cellular location of P2X4R. Mechanical allodynia and weight asymmetry were identified using the hind paw withdrawal threshold and weight bearing test. The results showed that intra-articular injection of MIA induced persistent mechanical allodynia and weight asymmetry in rats. Both BoNT/A and betamethasone could relieve pain behavior in rats, but BoNT/A had a more obvious effect and lasted longer. Furthermore, BoNT/A could reverse the MIA-induced overexpression of BDNF and P2X4R in the spinal dorsal horn. To sum up, BoNT/A is more effective than betamethasone in relieving MIA-induced osteoarthritis pain in rats, and its analgesic effect may be related to the regulation of P2X4R-mediated BDNF release in spinal microglia and the relief of neuropathic pain in osteoarthritis.
Learn More >TRAAK (KCNK4, K2P4.1) is a mechanosensitive two-pore domain potassium (K2P) channel. Due to its expression within sensory neurons and genetic link to neuropathic pain it represents a promising potential target for novel analgesics. In common with many other channels in the wider K2P sub-family, there remains a paucity of small molecule pharmacological tools. Specifically, there is a lack of molecules selective for TRAAK over the other members of the TREK subfamily of K2P channels. We developed a thallium flux assay to allow high throughput screening of compounds and facilitate the identification of novel TRAAK activators. Using a library of ∼1200 drug like molecules we identified Aprepitant as a small molecule activator of TRAAK. Aprepitant is an NK-1 antagonist used to treat nausea and vomiting. Close structural analogues of Aprepitant and a range of NK-1 antagonists were also selected or designed for purchase or brief chemical synthesis and screened for their ability to activate TRAAK. Electrophysiology experiments confirmed that Aprepitant activates both the 'long' and 'short' transcript variants of TRAAK. We also demonstrated that Aprepitant is selective and does not activate other members of the K2P superfamily. This work describes the development of a high throughput assay to identify potential TRAAK activators and subsequent identification and confirmation of the novel TRAAK activator Aprepitant. This discovery identifies a useful tool compound which can be used to further probe the function of TRAAK K2P channels.
Learn More >Children with autism spectrum disorder (ASD) are frequently diagnosed with co-occurring medical conditions including inflammatory bowel disease (IBD). To investigate the association, we conducted a systematic review registered in PROSPERO (ID:CRD42021236263) with a random-effects meta-analysis. We searched PubMed, Embase, and PsycInfo (last search on January 25, 2021), and manually searched relevant publications. We included observational studies measuring the association between ASD and IBD. The primary outcome was the association (odds ratio, OR) between ASD and later development of IBD. Sensitivity analyses were conducted by quality, confounding adjustment, and study design. We performed meta-regression analyses and assessed heterogeneity, publication bias, and quality of studies with the Newcastle-Ottawa Scale. Overall, we included six studies consisting of eight datasets, including over 11 million participants. We found that ASD was significantly associated with subsequent incident IBD (any IBD, OR = 1.66, 95% confidence interval[CI] = 1.25-2.21, p < 0.001; ulcerative colitis, OR = 1.91, 95%CI = 1.41-2.6, p < 0.001; Crohn's disease, OR = 1.47, 95%CI = 1.15-1.88, p = 0.002). ASD and IBD were also associated regardless of temporal sequence of diagnosis (any IBD, OR = 1.57, 95%CI = 1.28-1.93, p < 0.001; ulcerative colitis, OR = 1.7, 95%CI = 1.36-2.12, p < 0.001; Crohn's disease, OR = 1.37, 95%CI = 1.12-1.69, p = 0.003). Sensitivity analyses confirmed the findings of the main analysis. Meta-regression did not identify any significant moderators. Publication bias was not detected. Quality was high in four datasets and medium in four. In conclusion, our findings highlight the need to screen for IBD in individuals with ASD, and future research should identify who, among those with ASD, has the highest risk of IBD, and elucidate the shared biological mechanisms between ASD and IBD.
Learn More >To systematically review the literature on the relationship between markers of inflammation and pain in patients with knee osteoarthritis (OA).
Learn More >Vaso-occlusive pain leads to high acute care utilization among patients with sickle cell disease (SCD). Data suggest that clinical pathways (CPWs) reduce variation in the management of vaso-occlusive pain and improve clinical outcomes.
Learn More >Chronic pain (CP) commonly presents alongside psychiatric conditions such as depression, PTSD, and generalized anxiety. The current study sought to better understand this complex relationship by determining whether anxiety and depression symptom severity mediated the relationship between DSM-5 PTSD symptom clusters and pain symptoms in a sample of 663 Canadian Armed Forces (CAF) personnel and veterans seeking treatment for mental health conditions.
Learn More >Therapeutic exercise (TE) is recommended in multimodal treatment for patients with non-specific chronic back pain (cLBP).
Learn More >Changes in diagnostic criteria, for example, the various International Classification of Headache Disorders criteria, would lead to changes in the outcomes of epidemiological studies. International Classification of Headache Disorders-1 was based mainly on expert opinion, yet most of the diagnostic criteria were reliable and valid, but it did not include chronic migraine. In its second version, the classification introduced chronic migraine, but this diagnosis resembled more a high-frequency migraine rather than the actual migraine transformation process. It also introduced medication overuse headache, but it necessitated analgesic withdrawal and subsequent headache improvement to be diagnosed as such. Hence patients having medication overuse headache could only be diagnosed in retrospect, which was an awkward situation. Such restrictive criteria for chronic migraine and medication overuse headache omitted a high proportion of patients. International Classification of Headache Disorders-3 allows a diagnosis of medication overuse headache due to combination analgesics if taken for at least 10 days per month for more than three months. Hence the prevalence rate of medication overuse headache and chronic migraine can increase compared to the previous version of the headache classification. Different criteria have been used across studies to identify chronic migraine and medication overuse headache, and therefore the information acquired from previous studies using earlier criteria becomes uncertain. Hence much epidemiological research would need to be interpreted cautiously or repeated with the most updated criteria, since the subjects in studies that apply the latest criteria may be phenotypically different from those in older studies.
Learn More >Patients rarely dispose of left-over opioids after surgery. Disposal serves as a primary prevention against misuse, overdose, and diversion. However, current interventions promoting disposal have mixed efficacy. Increasing disposal in rural communities could prevent or reduce the harms caused by prescription opioids.
Learn More >Misclassification of spondyloarthritis (SpA) as rheumatoid arthritis (RA) may lead to delayed SpA diagnosis and suboptimal therapeutic outcomes. Here, we evaluate the literature on clinical manifestations in patients with SpA and RA, particularly seronegative RA, to understand the potential overlap, distinctions, and most reliable approaches to accurate diagnosis.
Learn More >Various nutritional therapies have been proposed in rheumatoid arthritis, particularly diets rich in ω-3 fatty acids, which may lead to eicosanoid reduction. Our aim was to investigate the effect of potentially anti-inflammatory diets (Mediterranean, vegetarian, vegan, ketogenic) on pain. The primary outcome was pain on a 10 cm visual analogue scale. Secondary outcomes were C-reactive protein levels, erythrocyte sedimentation rate, health assessment questionnaire, disease activity score 28, tender/swollen joint counts, weight, and body mass index. We searched MEDLINE (OVID), Embase (Elsevier), and CINAHL for studies published from database inception to 12 November 2021. Two authors independently assessed studies for inclusion, extracted study data, and assessed the risk of bias. We performed a meta-analysis with all eligible randomized controlled trials using RevMan 5. We used mean differences or standardized mean differences and the inverse variance method of pooling using a random-effects model. The search retrieved 564 unique publications, of which we included 12 in the systematic review and 7 in the meta-analysis. All studies had a high risk of bias and the evidence was very low. The main conclusion is that anti-inflammatory diets resulted in significantly lower pain than ordinary diets (-9.22 mm; 95% CI -14.15 to -4.29; = 0.0002; 7 RCTs, 326 participants).
Learn More >The mechanisms of migraine pathogenesis are not completely clear, but P-nuclear magnetic resonance studies revealed brain energy deficit in migraineurs. As glycolysis is the main process of energy production in the brain, mitochondria may play an important role in migraine pathogenesis. Nutrition is an important aspect of migraine pathogenesis, as many migraineurs report food-related products as migraine triggers. Apart from approved anti-migraine drugs, many vitamins and supplements are considered in migraine prevention and therapy, but without strong supportive evidence. In this review, we summarize and update information about nutrients that may be important for mitochondrial functions, energy production, oxidative stress, and that are related to migraine. Additionally, we present a brief overview of caffeine and alcohol, as they are often reported to have ambiguous effects in migraineurs. The nutrients that can be considered to supplement the diet to prevent and/or ameliorate migraine are riboflavin, thiamine, magnesium ions, niacin, carnitine, coenzyme Q10, melatonin, lipoic acid, pyridoxine, folate, and cobalamin. They can supplement a normal, healthy diet, which should be adjusted to individual needs determined mainly by the physiological constitution of an organism. The intake of caffeine and alcohol should be fine-tuned to the history of their use, as withdrawal of these agents in regular users may become a migraine trigger.
Learn More >Exercise-induced hypoalgesia (EIH) is a decrease in the pain sensitivity after exercise. Individuals with chronic pain show less EIH after one exercise session compared with pain-free individuals possibly due to pain in exercising muscles. The primary aim of this randomized controlled cross-over study was to compare the EIH response at the exercising thigh muscle following exercises performed with painful vs. non-painful muscles. Secondary aims were to explore if a reduced EIH response was confined to the painful muscle, and whether the muscle pain intensity and the EIH responses were negatively associated.
Learn More >Chronic pruritus is a common and debilitating symptom in patients with atopic dermatitis and contributes to impairment of quality of life. Effective treatment of pruritus should therefore be one of the main treatment goals in patients with atopic dermatitis. Pathophysiologically, the histamine-independent pruritogens interleukin-31, interleukin-13, and interleukin-4, have been shown to play a major role in atopic dermatitis. All three cytokines can mediate chronic pruritus via Janus kinase 1/2 signaling pathways. Novel drugs target these pathways and have shown rapid and sustained reduction of pruritus in patients with atopic dermatitis in clinical use and in phase II and III clinical trials. Here we summarize the published data on the effects of these drugs on itch parameters such as overall reduction in pruritus intensity and percent of patients with atopic dermatitis achieving a relevant reduction in itch. Each of the novel drugs shows very good effects on pruritus. These data offer hope for an even better and possibly more specific treatment of pruritus in patients with atopic dermatitis in the future. In addition, the different pharmacological approaches give us the chance to learn more about the pathophysiology of pruritus in atopic dermatitis.
Learn More >Sickle cell disease (SCD) is the most common inherited blood disorder in both Jamaica and the United States and is characterized by poor quality of life and debilitating complications, with the hallmark symptom being pain caused by acute and chronic conditions. Individuals with SCD often experience stigma due to their disease status, opioid use, and race. This study sought to understand the influence of perceived stigma and demographic/clinical characteristics on quality of life in adults with SCD in Jamaica (n = 50) and the United States (n = 50). Participants completed interviewer-administered surveys including demographic/clinical characteristics; the Measure of Sickle Cell Stigma (MoSCS); and the Adult Sickle Cell Quality of Life Measurement System (ASCQ-Me). A set of general linear models for each country was built to examine the influence of explanatory variables on the quality of life outcomes. Overall, stigma scores were low for both countries, with the exception of the MoSCS disclosure concerns and expected discrimination subscales, where scores averaged medium and high, respectively. In both countries, being employed was associated with better quality of life; and reports of stigma (internalized stigma and expected discrimination) was associated with worse quality of life. These findings have several implications for healthcare providers caring for individuals with SCD, policy makers, and researchers. Specifically, findings can be used to advocate for improved access to mental health care for individuals with SCD and inform stigma reduction intervention approaches in SCD.
Learn More >As the principal reason for low back pain, intervertebral disc degeneration (IDD) affects the health of people around the world regardless of race or region. Degenerative discs display a series of characteristic pathological changes, including cell apoptosis, senescence, remodeling of extracellular matrix, oxidative stress and inflammatory local microenvironment. As a serine/threonine-protein kinase in eukaryocytes, AMP-activated protein kinase (AMPK) is involved in various cellular processes through the modulation of cell metabolism and energy balance. Recent studies have shown the abnormal activity of AMPK in degenerative disc cells. Besides, AMPK regulates multiple crucial biological behaviors in IDD. In this review, we summarize the pathophysiologic changes of IDD and activation process of AMPK. We also attempt to generalize the role of AMPK in the pathogenesis of IDD. Moreover, therapies targeting AMPK in alleviating IDD are analyzed, for better insight into the potential of AMPK as a therapeutic target.
Learn More >Hereditary multiple exostoses (HMEs) syndrome, also known as multiple osteochondromas, represents a rare and severe human skeletal disorder. The disease is characterized by multiple benign cartilage-capped bony outgrowths, termed exostoses or osteochondromas, that locate most commonly in the juxta-epiphyseal portions of long bones. Affected individuals usually complain of persistent pain caused by the pressure on neighboring tissues, disturbance of blood circulation, or rarely by spinal cord compression. However, the most severe complication of this condition is malignant transformation into chondrosarcoma, occurring in up to 3.9% of HMEs patients. The disease results mainly from heterozygous loss-of-function alterations in the or genes, encoding Golgi-associated glycosyltransferases, responsible for heparan sulfate biosynthesis. Some of the patients with HMEs do not carry pathogenic variants in those genes, hence the presence of somatic mutations, deep intronic variants, or another genes/loci is suggested. This review presents the systematic analysis of current cellular and molecular concepts of HMEs along with clinical characteristics, clinical and molecular diagnostic methods, differential diagnosis, and potential treatment options.
Learn More >Pain after amputation can be known as residual limb pain (RLP) or phantom limb pain (PLP); however, both can be disabling in daily life with reported incidences of 8% for finger amputations and up to 85% for major limb amputations. The current treatment is focused on reducing the pain after neuropathic pain occurs. However, surgical techniques to prevent neuropathic pain after amputation are available and effective, but they are underutilized. The purpose of the review is to investigate the effects of techniques during amputation to prevent neuropathic pain.
Learn More >Evidence shows that Acceptance and Commitment Therapy (ACT) is an empirically supported psychological approach for chronic pain (CP) management. Although self-compassion is not explicitly a target of ACT, it seems to be one mechanism of change in ACT for CP. However, research is lacking on the benefits of including explicit self-compassionate exercises in ACT for CP. The current study pilot tested a Compassionate ACT 8-session group program (COMP.ACT; n=9), as well as an ACT-only 8-session group program (ACT; n=7), in a sample of women with CP.
Learn More >To analyze the course of symptom-related measures, psychological variables and health-related quality of life (HRQoL) over a 12-month period, and to longitudinally examine symptom-related and psychological factors as predictors for HRQoL in male and female patients with chronic pelvic pain syndrome (CPPS).
Learn More >Disturbances of the gut-brain axis are characterized by complex dysfunctions on peripheral and central nervous system levels, which can contribute to visceral hypervigilance and hyperalgesia and imprint visceral pain. Numerous cognitive, emotional and psychoneurobiological factors are involved in visceral pain modulation, which in the psychosocial treatment concept can have a positive as well as a negative impact on the experience of visceral pain. Nocebo effects induced by negative expectations are of high clinical relevance in acute and especially in chronic visceral pain but the underlying mechanisms remain insufficiently understood. Verbal instructions, previous experiences and learning processes as well as emotional factors, such as fear and stress contribute to the development and maintenance of negative expectation effects. Targeted communication strategies, a sensitive use of information in the clarification and positive environmental context conditions can contribute to establishing an adequate expectation management and minimize negative expectation effects in the clinical practice. At the same time, translational research approaches are required to gain further insights into the mediators and moderators of negative expectation effects and to transfer these into clinical practice. In this way the treatment of patients with disorders of the gut-brain communication can be improved.
Learn More >Patients with back pain comprise a large proportion of the outpatient practice among physiatrists. Diagnostic tools are limited to clinical history, physical examinations and imaging. Non-surgical treatments are largely empirical, encompassing medications, physical therapy, manual treatments and interventional spinal procedures. A body of literature is emerging confirming elevated levels of biomarkers including inflammatory cytokines in patients with back pain and/or radiculopathy, largely because the protein assay sensitivity has increased. These biomarkers may serve as tool to assist diagnosis and assess outcomes.The presence of inflammatory mediators in the intervertebral disc tissues and blood helped confirming the inflammatory underpinnings of back pain related to intervertebral disc degeneration. Literature reviewed here suggests that biomarkers could assist clinical diagnosis and monitor physiological outcomes during and following treatments for spine related pain. Biomarkers must be measured in a large and diverse asymptomatic population, in the context of age and comorbidities to prevent false positive tests. These levels can then be rationally compared to those in patients with back disorders including discogenic back pain, radiculopathy and spinal stenosis. While studies reviewed here used "candidate marker" approaches, future non-biased approaches in clearly defined patient populations could uncover novel biomarkers in clinical management of patients.
Learn More >In this study, we investigated the effects of fosphenytoin (fPHT) a water-soluble prodrug of phenytoin, on the pain responses of a mouse herpes zoster (HZ) pain model. Transdermal herpes simplex virus type 1 (HSV-1) inoculation induced mechanical allodynia and hyperalgesia of the hind paw and spontaneous pain-like behaviors, such as licking the affected skin. Intravenous injection of fPHT (15 and 30 mg/kg) alleviated HSV-1-induced provoked pain (allodynia and hyperalgesia). The suppressive effects of fPHT on provoked pain were weaker than those of diclofenac and pregabalin which were used as positive controls. fPHT, diclofenac, and pregabalin significantly suppressed HSV-1-induced spontaneous pain-like behaviors. Among them, high-dose fPHT (30 mg/kg) showed the strongest suppression. Intravenous fPHT may become a viable option for an acute HZ pain, especially for spontaneous pain.
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