Browse by Audience
Ample data support a prominent role of peripheral T-type calcium channels 3.2 (CaV3.2) in generating pain states. Development of primary sensory neuron-specific inhibitors of CaV3.2 channels is an opportunity for achieving effective analgesic therapeutics, but success has been elusive. Small peptides, especially those derived from the natural proteins as inhibitory peptide aptamers (iPAs), can produce highly effective and selective blockade of specific nociceptive molecular pathways to reduce pain with minimal off-target effects. Here, we report the engineering of the potent and selective iPAs of CaV3.2 from the intrinsically disordered regions (IDR) of CaV3.2 intracellular segments. Using established prediction algorithms, we localized the IDRs in CaV3.2 protein and identified several CaV3.2iPA candidates that significantly reduced CaV3.2 current in HEK293 cells stably expressing human wide-type CaV3.2. Two prototype CaV3.2iPAs (iPA1 and iPA2) derived from the IDRs of CaV3.2 intracellular loop 2 and 3 respectively were expressed selectively in the primary sensory neurons of dorsal root ganglia in vivo using recombinant adeno-associated virus (AAV), which produced sustained inhibition of calcium current conducted by CaV3.2/T-type channels and significantly attenuated both evoked and spontaneous pain behavior in rats with neuropathic pain following tibial nerve injury. Recordings from dissociated sensory neurons showed that AAV-mediated CaV3.2iPA expression suppressed neuronal excitability, suggesting that CaV3.2iPA treatment attenuated pain by reversal of injury-induced neuronal hypersensitivity. Collectively, our results indicate that CaV3.2iPAs are promising analgesic leads that, combined with AAV-mediated delivery in anatomically targeted sensory ganglia, have the potential to be a selective peripheral CaV3.2-targeting strategy for clinical treatment of pain.
Learn More >The dual enkephalinase inhibitor PL37, a small molecule that protects enkephalins from their rapid degradation, has demonstrated analgesic properties in animal pain models and in early human clinical trials. This study tested the antimigraine potential of PL37 on cutaneous mechanical hypersensitivity affecting cephalic regions in migraineurs. Using behavioral testing and c-Fos immunoreactivity in male rats, we investigated the effects of single (oral or intravenous) and repeated oral administration of PL37 on changes in cutaneous mechanical sensitivity and sensitization of the trigeminocervical complex induced by repeated administration of the nitric oxide donor, isosorbide dinitrate. In naive rats, single or repeated administration of PL37 or vehicle had no effect on cephalic mechanical sensitivity. However, single oral PL37 treatment effectively inhibited isosorbide dinitrate-induced acute cephalic mechanical hypersensitivity. Single intravenous but not oral PL37 administration inhibited chronic cephalic mechanical hypersensitivity. Daily oral administration of PL37 prevented cephalic mechanical hypersensitivity and decreased touch-induced c-Fos expression in trigeminocervical complex following repeated isosorbide dinitrate administration. These data reveal the therapeutic potential of the dual enkephalinase inhibitor PL37 as an acute and prophylactic treatment for migraine. Protecting enkephalins from their degrading enzymes therefore appears as an innovative approach to treat migraine.
Learn More >Pain has been established as a major public health problem in the United States (U.S.) with 50 million adults experiencing chronic pain and 20 million afflicted with high-impact chronic pain (i.e., chronic pain that interferes with life or work activities). High financial and social costs are associated with chronic pain. Over the past two decades, pain management has been complicated by the marked increase in opioids prescribed to treat chronic non-cancer pain and by the concurrent opioid crisis. Monitoring the prevalence of chronic pain and pain management is especially important because pain management is changing in uncertain ways. We review potential U.S. chronic pain surveillance systems, present potential difficulties of chronic pain surveillance, and explore how to address chronic pain surveillance in the current opioid era. We consider case definitions, severity, anatomic site, and varieties of chronic pain management strategies in reviewing and evaluating national surveys for chronic pain surveillance. Based on the criteria evaluated, the National Health Interview Survey offers the best single source for pain surveillance as the pain-related questions administered are brief, valid, and cover a broad scope of pain-related phenomenon. Perspective: This review article describes data sources that can be leveraged to conduct national chronic pain surveillance in the United States, explores case defining or pain-related questions administered, and evaluates them against eight surveillance attributes.
Learn More >Pain emanating from the female reproductive tract is notoriously difficult to be treated and the prevalence of transient pelvic pain has been placed as high as 70-80% in women surveyed. Although sex hormones, especially estrogen, are thought to underlie enhanced pain perception in females, the underlying molecular and cellular mechanisms are not completely understood. Here we show that the pain-initiating TRPA1 channel is required for pain-related behaviors in a mouse model of estrogen-induced uterine pain in ovariectomized female mice. Surprisingly, 2- and 4-hydroxylated estrogen metabolites (HEMs) in the estrogen hydroxylation pathway, but not estrone, estradiol and 16-HEMs, directly increase nociceptor hyperactivity through TRPA1 and TRPV1 channels, and picomolar concentrations of 2- and 4-hydroxylation estrone (OHE1) can sensitize TRPA1 channel function. Moreover, both TRPA1 and TRPV1 are expressed in uterine-innervating primary nociceptors and their expressions are increased in the estrogen-induced uterine pain model. Importantly, pretreatment of 2- or 4-OHE1 recapitulates estrogen-induced uterine pain-like behaviors and intraplantar injections of 2- and 4-OHE1 directly produce a TRPA1-dependent mechanical hypersensitivity. Our findings demonstrate that TRPA1 is critically involved in estrogen-induced uterine pain-like behaviors, which may provide a potential drug target for treating female reproductive tract pain.
Learn More >Chronic low back pain (CLBP) is one of the leading causes of pain and disability in adults in the United States and disproportionately burdens non-Hispanic Black (NHB) individuals and females. Approximately 90% of CLBP cases are of unknown cause, and it is imperative that potential causes be explored. It has been reported that diet quality can influence pain state via diet-induced inflammation. The present study assessed the relationship between Dietary Inflammatory Index (DII) and movement evoked-pain severity in people with CLBP and investigated whether race/sex moderated the relationship between DII and movement-evoked pain. Results revealed no significant differences in DII scores between males and females, or between NHB and non-Hispanic White (NHW) participants. Participant sex significantly modified the relationship between DII and movement-evoked pain severity (p=0.0155), such that movement-evoked pain severity was significantly impacted by DII scores in females, but not males. Participant race did not significantly moderate the DII – movement-evoked pain severity relationship. These results suggest that diet-induced inflammation may impact the CLBP experiences of females to a greater degree than males. Further research is needed to determine whether dietary interventions that reduce inflammation improve CLBP outcomes and whether these interventions may be differentially-beneficial based on sex. Perspective: This article highlights the impact of diet-induced inflammation in a community-based sample as a whole, as well as stratified in various sociodemographic groups. This work expands our understanding of the influence of diet on pain experience and suggests that modifications to diet may be efficacious treatments for reducing chronic pain.
Learn More >Therapeutics that reduce calcitonin gene-related peptide activity are effective migraine treatments. However, gaps remain in our understanding of the molecular mechanisms that link calcitonin gene-related peptide to migraine. The amylin 1 receptor responds potently to calcitonin gene-related peptide, and to the related peptide amylin, but its role in relation to either peptide or to migraine is unclear. We sought to better understand the expression of the amylin 1 receptor protein subunit, the calcitonin receptor, in the rodent brain.
Learn More >About 1% of children and adolescents worldwide are affected by plaque psoriasis.
Learn More >The current knowledge on the epidemiology and clinical manifestation of airplane headache is mostly derived from case series and small cohort studies without evidence from large populations.
Learn More >Pulsed radiofrequency (PRF) therapy is one of the most common treatment options for neuropathic pain, albeit the underlying mechanism has not been hitherto elucidated. In this study, we investigated the efficacy and mechanism of PRF therapy on resiniferatoxin (RTX)-induced mechanical allodynia, which has been used as a model of postherpetic neuralgia (PHN). Adult male rats were intraperitoneally injected with a vehicle or RTX. Furthermore, PRF current was applied on a unilateral sciatic nerve in all RTX-treated rats. On both ipsilateral and contralateral sides, the paw mechanical withdrawal thresholds were examined and L4-6 dorsal root ganglia (DRG) were harvested. In the DRG of rats with RTX-induced mechanical allodynia, Na1.7, a voltage-gated Na channel, was upregulated following the enhancement of extracellular signal-regulated kinase phosphorylation. Early PRF therapy, which was applied 1 week after RTX exposure, suppressed this Na1.7 upregulation and showed an anti-allodynic effect; however, late PRF therapy, which was applied after 5 weeks of RTX exposure, failed to inhibit allodynia. Interestingly, late PRF therapy became effective after daily tramadol administration for 7 days, starting from 2 weeks after RTX exposure. Both early PRF therapy and late PRF therapy combined with early tramadol treatment suppressed Na1.7 upregulation in the DRG of rats with RTX-induced mechanical allodynia. Therefore, Na1.7 upregulation in DRG is related to the development of RTX-induced neuropathic pain; moreover, PRF therapy may be effective in the clinical management of patients with PHN via Na1.7 upregulation inhibition.
Learn More >Spinal Cord Injury (SCI) results in a permanent or temporary alteration of the motor, sensory and/or autonomic functions, frequently leading to neuropathic pain. To deal with this comorbidity, several non-pharmacological and non-surgical (NP-NS) interventions have been developed. However, their efficacy is still uncertain. The aim of this study was to systematically synthetize the available evidence assessing the efficacy of NP-NS interventions for treating neuropathic pain in people with SCI. Thus, an electronic search was conducted in five databases (Pubmed, Scopus, Cochrane Central, Web of Science and EBSCO) and trials registry databases, in addition to a manual search strategy to retrieve additional records. The review included randomized controlled trials with adults with SCI, in any stage of the condition. Data on the efficacy of the interventions was narratively synthetized. Once the research was completed, of 4853 identified references, 24 were included with a total of 653 participants with SCI and neuropathic pain, mostly male and with paraplegia. These studies investigated the effect of 13 types of NP-NS interventions with different protocols and methodological limitations. Seven different assessment scales were analyzed, with neuropathic pain being the primary outcome in 21 studies. Such high heterogeneity impaired the conduction of meta-analysis for any of the interventions. Although promising results were found regarding analgesic effect of NP-NS on neuropathic pain in people with SCI, it is not yet possible to safely state that these interventions are in fact effective. Further studies with homogeneous protocols and methodological quality are still needed. PERSPECTIVE: : This article presents a review of existing studies on the effectiveness of NP-NS interventions in neuropathic pain in SCI. This synthesis could potentially alert and motivate clinicians to develop studies on this topic, so that interventions can be objectively evaluated and recommendations for an evidence-based practice be created.
Learn More >To assess real-world effectiveness, safety, and usage of erenumab in Canadian patients with episodic and chronic migraine with prior ineffective prophylactic treatments.
Learn More >Noxious pain signals are transduced in the peripheral nervous system as action potentials, which rely on the activities of voltage-gated sodium channels (NaVs). Blocking NaVs is thus a valuable strategy for pain treatment. Here, we report the characterization of a novel NaVs antagonist, 2-(2-(diethylamino)ethyl)indeno[1,2,3-de]phthalazin-3(2H)-one (C65780), and investigation of its action mechanisms. C65780 inhibited the resting NaV1.7, NaV1.8, and NaV1.9 channels with IC50s of 11.3 ± 0.4 μM, 2.7 ± 0.3 μM and 19.2 ± 2.3 μM, respectively. Mechanistic analysis revealed that C65780 quickly bound to its high-affinity receptor site in NaV1.7 as formed by the fast inactivation process and stabilized the channels in a slowly recovering state, for which it facilitated NaV1.7 channels' inactivation by shifting their inactivation-voltage relationship in the hyperpolarizing direction, increasing the plateau proportion of inactivated channels, and blunting their time-dependent recovery. The slow inactivation of NaV1.7, however, is not involved in the action of C65780. In DRG neurons, C65780 also inhibited activity of NaVs, thus dampening neuronal excitability. These effects parlayed into a broad efficacy of orally administrated C65780 in various models of pain, with an efficacy comparable to the antidepressant/neuropathic pain drug Amitriptyline. Excitingly, C65780 demonstrated weaker inactivated state inhibition of related NaV1.4 and NaV1.5 channels compared to amitriptyline, and no toxicity or inhibition of locomotion in a forced-swimming test was observed in mice at pain-relieving doses. These results demonstrate that C65780 acts by trapping NaVs in the inactivated and slowly-recovering state to produce pain relief and may represent an excellent starting compound for developing analgesics.
Learn More >Data are equivocal on the consequences of COVID-19 pandemic on pain and well-being for individuals with chronic pain. Furthermore, little is known regarding its impact on the health of young adults with chronic pain. We conducted a longitudinal study to compare pain, psychological functioning, and substance use before and during the pandemic of 196 young adults with chronic pain. Participants aged 18 to 24 years (M = 21.1 years; 79.6% females) reported on pain, anxiety, depression, and substance use before (October 2018-August 2019) and during the pandemic (October 2020-November 2020), in addition to the assessment of COVID-19 exposure and its impact. Before the pandemic, young adults experienced mild-to-moderate pain intensity (M = 3.75, SD = 2.33) and pain interference (M = 3.44, SD = 2.69). Findings were that pain intensity, pain interference, and depression symptoms remained stable during the pandemic. In contrast, anxiety symptoms increased significantly (M = 8.21, SD = 5.84 vs M = 8.89, SD = 5.95, P = 0.04). Tobacco, alcohol, and cannabis use were unchanged. Mixed linear models revealed that COVID-19 exposure and impact were not associated with changes in pain intensity or interference, with female sex associated with increased pain intensity (β = 0.86, P = 0.02) and pain interference (β = 0.87, P = 0.02). Our findings indicated relative stability of pain symptoms experienced by young adults with chronic pain. However, the increases in anxiety highlight the need to facilitate treatment access for mental health services to mitigate downstream impact.
Learn More >Spinal cord stimulation (SCS) involves electrical stimulation of the dorsal spinal cord to disrupt the transmission of ascending pain signals. SCS has been used successfully to manage a variety of chronic pain conditions, but its efficacy in the treatment of pain syndromes in patients with cancer has not been established because most studies have involved a limited number of patients. The purpose of this study was to assess the efficacy of SCS in a large group of patients with cancer.
Learn More >Spinal cord stimulation (SCS) is known to be an effective long-term treatment option for chronic neuropathic pain. Subcutaneous stimulation (SubQ) is increasingly used to treat chronic back and neck pain, but long-term outcomes are unclear.
Learn More >In 2019, senior leaders within the US Department of Veterans Affairs and the US Department of Defense commissioned the update of a clinical practice guideline for managing chronic multisymptom illness. Clinical experts were assembled across both agencies to systematically review evidence and to develop treatment recommendations based on that evidence. This effort resulted in the development of 29 evidence-based recommendations for providing care for individuals with chronic multisymptom illness.
Learn More >We induced placebo analgesia (PA), a phenomenon explicitly attenuating the self-pain feeling, to assess whether this resulted in reduced empathy pain when witnessing a confederate undergoing such pain experience. We recorded EEG and electrocardiogram during a painful Control and PA treatment in healthy adults who rated their experienced pain and empathy for pain. We derived HRV changes and, using wavelet analysis of non-phase-locked event-related EEG oscillations, EEG spectral power differences for self-pain and other-pain conditions. First-hand PA reduced self-pain and self-unpleasantness, whereas we observed only a slight decrease in other unpleasantness. We derived linear combinations of HRV and EEG band power changes significantly associated with self-pain and empathy for pain changes using PCAs. Lower Behavioral Inhibition System scores predicted self-pain reduction through the mediating effect of a relative HR-slowing and a decreased midline ϑ-band (4-8 Hz) power factor moderated by lower Fight-Flight-Freeze System trait scores. In the other-pain condition, we detected a direct positive influence of Total Empathic Ability on the other-pain decline with a mediating role of the midline β2-band (22-30 Hz) power reduction. These findings suggest that PA modulation of first-hand versus other pain relies on functionally different physiological processes involving different personality traits.
Learn More >According to the Global Burden of Disease (GBD) study, headache disorders are among the most prevalent and disabling conditions worldwide. GBD builds on epidemiological studies (published and unpublished) which are notable for wide variations in both their methodologies and their prevalence estimates. Our first aim was to update the documentation of headache epidemiological studies, summarizing global prevalence estimates for all headache, migraine, tension-type headache (TTH) and headache on ≥15 days/month (H15+), comparing these with GBD estimates and exploring time trends and geographical variations. Our second aim was to analyse how methodological factors influenced prevalence estimates.
Learn More >Rheumatoid arthritis (RA), an autoimmune disease, is characterized by chronic joint inflammation and pain. We previously found that the deletion of T-cell death-associated gene 8 (TDAG8) significantly reduces disease severity and pain in RA mice. Whether it is by modulating gut microbiota remains unclear. In this study, 64 intestinal samples of feces, cecal content, and cecal mucus from the complete Freund's adjuvant-induced arthritis mouse models were compared. The – and -diversity indices of the microbiome were significantly lower in RA mice. Cecal mucus showed a higher ratio of to in RA than healthy mice, suggesting the ratio could serve as an RA indicator. Four core genera, , , , and , were reduced in content in both feces and mucus RA samples, and could serve microbial markers representing RA progression. TDAG8 deficiency decreased the abundance of proinflammation-related , , , , and , which reduced local mucosal inflammation to relieve RA disease severity and pain. The pharmacological block of the TDAG8 function by a salicylanilide derivative partly restored the RA microbiome to a healthy composition. These findings provide a further understanding of specific bacteria interactions with host gut mucus in the RA model. The modulation by TDAG8 on particular bacteria can facilitate microbiota-based therapy.
Learn More >Persistent postsurgical neuropathic pain (PPSNP) can occur after intraoperative damage to somatosensory nerves, with a prevalence of 29-57% in breast cancer surgery. Proteomics is an active research field in neuropathic pain and the first results support its utility for establishing diagnoses or finding therapy strategies.
Learn More >International guidelines recommend diaries in migraine trials for prospective collection of headache symptoms. Studies in other patient populations suggest higher adherence with electronic diaries instead of pen-and-paper. This study examines the feasibility of a text message-based (texting) diary for children and adolescents with headache.
Learn More >We aimed to assess the differences in quantitative sensory testing between chronic migraine and healthy controls and to explore the association between pain sensitivities and outcomes in chronic migraine following preventive treatment.
Learn More >Fremanezumab has demonstrated to be effective, safe, and tolerated in the prevention of episodic or chronic migraine (CM) in randomized, placebo-controlled trials (RCTs). Real-life studies are needed to explore drug effects in unselected patients in routine circumstances and to provide higher generalizability results. This study explores the effectiveness, safety, and tolerability of fremanezumab in a real-life population of individuals affected by high-frequency episodic (HFEM: 8-14 days/month) or CM.
Learn More >NLRP3 is involved in the pathophysiology of several inflammatory diseases. Therefore, there is high current interest in the clinical development of new NLRP3 inflammasome small inhibitors to treat these diseases. Novel -sulfonylureas were obtained by the replacement of the hexahydroindacene moiety of the previously described NLRP3 inhibitor MCC950. These new derivatives show moderate to high potency in inhibiting IL-1β release in vitro. The greatest effect was observed for compound , which was similar to MCC950. Moreover, compound was able to reduce caspase-1 activation, oligomerization of ASC, and therefore, IL-1β processing. Additional in silico predictions confirmed the safety profile of compound , and in vitro studies in AML12 hepatic cells confirmed the absence of toxicological effects. Finally, we evaluated in vivo anti-inflammatory properties of compound , which showed a significant anti-inflammatory effect and reduced mechanical hyperalgesia at 3 and 10 mg/kg (i.p.) in an in vivo mouse model of gout.
Learn More >Irritable bowel syndrome (IBS) is a highly prevalent chronic pain disorder with multiple underlying mechanisms and few treatments that have been demonstrated to be effective in placebo controlled trials. One potential reason may be the use of composite outcomes, such as the IBS Symptom Severity Scale (IBS-SSS) which includes descriptive items related to pain frequency and pain intensity as well as bowel dysfunction and bloating. We investigated if different features of IBS pain have distinct genetic associations and if these may be moderated by sex hormones.
Learn More >The direction and the magnitude of verbal suggestions have been shown to be strong modulators of nocebo hyperalgesia, while little attention has been given to the role of their temporal content. Here, we investigate whether temporal suggestions modulate the timing of nocebo hyperalgesia in an experimental model of sustained pain.
Learn More >Oxytocin (OT) and its receptor are promising targets for the treatment and prevention of the neuropathic pain. In the present study, we compared the effects of a single and continuous intrathecal infusion of OT on nerve injury-induced neuropathic pain behaviours in mice and further explore the mechanisms underlying their analgesic properties. We found that three days of continuous intrathecal OT infusion alleviated subsequent pain behaviours for 14 days, whereas a single OT injection induced a transient analgesia for 30 min, suggesting that only continuous intrathecal OT attenuated the establishment and development of neuropathic pain behaviours. Supporting this behavioural finding, continuous intrathecal infusion, but not short-term incubation of OT, reversed the nerve injury-induced depolarizing shift in Cl reversal potential restoring the function and expression of spinal K-Cl cotransporter 2 (KCC2), which may be caused by OT-induced enhancement of GABA inhibitory transmission. This result suggests that only continuous use of OT may reverse the pathological changes caused by nerve injury, thereby mechanistically blocking the establishment and development of pain. These findings provide novel evidence relevant for advancing understanding of the effects of continuous OT administration on the pathophysiology of pain.
Learn More >Standard opioid tapers tend to be associated with increased patient anxiety and higher pain ratings. Pre-authorized concealed opioid reductions may minimize expectations such as fear of increased pain due to the reduction of opioids and, prolong analgesic benefits in experimental settings. We recently observed that patients and clinicians are open to concealed opioid tapering. However, little is known about the "why" behind their attitudes. Based on this lack of data, we analyzed qualitative responses to survey questions on patients' and clinicians' acceptance of a concealed opioid reduction for chronic pain. Seventy-four patients with a history of high dose opioid therapy and 49 clinicians completed a web-based questionnaire with open-ended questions examining responses to two hypothetical clinical trials comparing a concealed opioid reduction pre-authorized by patients vs. standard tapering. We used content analysis based on qualitative descriptive methodology to analyze comments from the patients and clinicians. Five themes were identified: informed consent; anxiety; safety; support; and ignorance is bliss, or not. These themes highlight the overall positive attitudes toward concealed opioid tapers. Our findings reinforce the importance of patient-centered care and are expected to inform the design of clinical trials from both the patient and clinician perspective. This qualitative study presents patients' and clinicians' attitudes toward hypothetical scenarios for a trial of pre-authorized reduction of opioids. The findings indicate positive attitudes and the relevance of engaging patients with effective decision-making processes.
Learn More >Neuropathic pain is often accompanied by anxiety and depression-like manifestations. Many studies have shown that alterations in synaptic plasticity in the anterior cingulate cortex (ACC) play a critical role, but the specific underlying mechanisms remain unclear. Previously, we showed that cAMP response element-binding protein (CREB) in the dorsal root ganglion (DRG) acts as a transcription factor contributing to neuropathic pain development. At the same time, brain-derived neurotrophic factor (BDNF), as important targets of CREB, is intricate in neuronal growth, differentiation, as well as the establishment of synaptic plasticity. Here, we found that peripheral nerve injury activated the spinal cord and ACC, and silencing the ACC resulted in significant relief of pain sensitivity, anxiety, and depression in SNI rats. In parallel, the CREB/BDNF pathway was activated in the spinal cord and ACC. Central specific knockdown and peripheral non-specific inhibition of CREB reversed pain sensitivity and anxiodepression induced by peripheral nerve injury. Consequently, we identified cingulate CREB/BDNF as an assuring therapeutic method for treating neuropathic pain as well as related anxiodepression.
Learn More >Spinal cord stimulation (SCS)-induced analgesia was characterized, and its underlying mechanisms were examined in a spared nerve injury model of neuropathic pain in rats. The analgesic effect of SCS with moderate mechanical hypersensitivity was increased with increasing stimulation intensity between the 20% and 80% motor thresholds. Various frequencies (2, 15, 50, 100, 10000 Hz, and 2/100 Hz dense-dispersed) of SCS were similarly effective. SCS-induced analgesia was maintained without tolerance within 24 h of continuous stimulation. SCS at 2 Hz significantly increased methionine enkephalin content in the cerebrospinal fluid. The analgesic effect of 2 Hz was abolished by μ or κ opioid receptor antagonist. The effect of 100 Hz was prevented by a κ antagonist, and that of 10 kHz was blocked by any of the μ, δ, or κ receptor antagonists, suggesting that the analgesic effect of SCS at different frequencies is mediated by different endorphins and opioid receptors.
Learn More >Spinal cord injury (SCI) may cause structural alterations in brain due to pathophysiological processes, but the effects of SCI treatment on brain have rarely been reported. Here, voxel-based morphometry is employed to investigate the effects of SCI and neurotrophin-3 (NT3) coupled chitosan-induced regeneration on brain and spinal cord structures in rhesus monkeys. Possible association between brain and spinal cord structural alterations is explored. The pain sensitivity and stepping ability of animals are collected to evaluate sensorimotor functional alterations. Compared with SCI, the unique effects of NT3 treatment on brain structure appear in extensive regions which involved in motor control and neuropathic pain, such as right visual cortex, superior parietal lobule, left superior frontal gyrus (SFG), middle frontal gyrus, inferior frontal gyrus, insula, secondary somatosensory cortex, anterior cingulate cortex, and bilateral caudate nucleus. Particularly, the structure of insula is significantly correlated with the pain sensitivity. Regenerative treatment also shows a protective effect on spinal cord structure. The associations between brain and spinal cord structural alterations are observed in right primary somatosensory cortex, SFG, and other regions. These results help further elucidate secondary effects on brain of SCI and provide a basis for evaluating the effects of NT3 treatment on brain structure.
Learn More >Spinal cord stimulation (SCS) is a surgical treatment modality reserved for a subset of patients with neuropathic pain in which conventional pharmacologic treatment has proven insufficient. Previous studies have suggested a possible negative relationship between opioid use at referral and subsequent success of SCS therapy. The aim of this cohort study was to investigate whether preoperative opioid use was associated with inferior SCS outcomes.
Learn More >Experiencing structural racism over the life course contributes to disproportionate pain-related disability among African American older adults. Positive STEPS, delivered by community health workers, is a culturally congruent chronic pain self-management intervention that incorporates positive psychology principles and gives attention to social determinants of pain and pain management.
Learn More >Osteoarthritis (OA) is a disease with a high negative impact on patient's quality of life and a high financial burden. It is a source of chronic pain and affects all mammals, including humans and dogs. As the dog is a common model for translation research of human OA, and exploring spontaneous dog OA can improve the health and well-being of both humans and dogs. To describe the effect of the intra-articular administration of stanozolol in a naturally occurring canine OA model, forty canine (N = 40) hip joints were randomly assigned to receive stanozolol or saline (control). On treatment day and at 8, 15, 30, 90, and 180 days post-treatment, several evaluations were conducted: weight distribution, joint range of motion, thigh girth, digital thermography, and radiographic signs. Also, synovial fluid C-reactive protein and interleukin-1 levels were evaluated. Results from four Clinical Metrology Instruments was also gathered. Results were compared with Repeated Measures ANOVA, with a Huynh-Feldt correction, paired-samples t-test, or Wilcoxon signed-rank test, with p < 0.05. OA was graded as mild (90%), moderate (5%), and severe (5%), including both sexes. They had a mean age of 6.5 ± 2.4 years and a bodyweight of 26.7 ± 5.2 kg. No differences were found between groups at treatment day in all considered evaluations. Weight distribution showed significant improvements with stanozolol from 15 days (p < 0.05) up to 180 days (p < 0.01). Lower values during thermographic evaluation in both views taken and improved joint extension at 90 (p = 0.02) and 180 days (p < 0.01) were observed. Pain and function scores improved up to 180 days. In the control group, radiographic signs progressed, in contrast with stanozolol. The use of stanozolol was safe and produced significant improvements in weight-bearing, pain score, and clinical evaluations in a naturally occurring canine OA model.
Learn More >Altered pain facilitatory and inhibitory mechanisms have been recognized as an important manifestation in patients with chronic pain, and quantitative sensory testing (QST) can act as a proxy for this process. We have recently developed a simple bedside QST tool kit () for more clinical use. The purpose of this study was to investigate its test-retest reliability and to evaluate its validity compared with the laboratory-based QST protocols in patients with knee osteoarthritis (OA).
Learn More >Osteoarthritis (OA) is one of the leading chronic conditions in the older population. People with OA are more likely to have one or more other chronic conditions than those without. However, the temporal associations, clusters of the comorbidities, role of analgesics and the causality and variation between populations are yet to be investigated. This paper describes the protocol of a multinational study in four European countries (UK, Netherlands, Sweden and Spain) exploring comorbidities in people with OA.
Learn More >CSFL caused by spinal dural defect is a common complication of spinal surgery, which need repair such as suture or sealants. However, low intracranial pressure symptoms, wound infection and prolonged hospital associated with pin-hole leakage or loose seal effect were often occurred after surgical suture or sealants repair. Stable, pressure resistance and high viscosity spinal dural repair patch in wet environment without suture or sealants was highly needed. Herein, a bioactive patch composed of alginate and polyacrylamide hydrogel matrix cross-linked by calcium ions, and chitosan adhesive was proposed. This fabricated patch exhibits the capabilities of promoting defect closure and good tight seal ability with the bursting pressure is more than 790 mm HO in wet environment. In addition, the chitosan adhesive layer of the patch could inhibit the growth of bacterial , which is meaningful for the postoperative infection. Furthermore, the patch also significantly reduced the expression of GFAP, IBA-1, MBP, TNF-α, and COX-2 in early postoperative period study, exerting the effects of anti-inflammatory, analgesic and adhesion prevention. Thus, the bioactive patch expected to be applied in spinal dural repair with the good properties of withstanding high pressure, promoting defect closure and inhibiting postoperative infection.
Learn More >A physician confronts an elusive physical phenomenon.
Learn More >Specific protein 1 (Sp1) is a member of the Sp/Kruppel-like factor family, which regulates cellular processes of neurons in the nervous system. This study was performed to examine the regulatory role and the underlying mechanism of transcription factor Sp1 in neuropathic pain (NP)-like behaviors after spinal nerve ligation (SNL). Sp1 and histone deacetylase 1(HDAC1) expressions were determined in the C57BL6 mouse model with NP-like behaviors after SNL, which demonstrated that Sp1 and HDAC1 elevation occurred in neurons in the spinal dorsal horn of SNL mice. The chromatin immunoprecipitation assay verified that Sp1 was bound to the HDAC1 promoter region and HDAC1 to the SRY-box-containing gene 10 (SOX10) promoter region in the spinal dorsal horn. Immunofluorescence was performed to determine Sp1, HDAC1, and SOX10 in the spinal dorsal horn neurons as well as the neuronal marker (NeuN), microglial marker (Iba-1), and astrocyte marker (GFAP). The nociceptive test was performed to characterize the hindlimb paw withdrawal threshold (PWT) and paw withdrawal latency (PWL) of mice 0-10 days after model establishment. Loss- and gain-of-function assays revealed that Sp1 promoted HDAC1 expression, and HDAC1 in turn promoted SOX10 expression. HDAC1 elevation reversed the effects of Sp1 silencing, and the increased PWT and PWL of SNL mice were negated after SOX10 overexpression. Meanwhile, SOX10 also restored the results by Sp1 knockdown. Collectively, downregulating Sp1 alleviates NP-like behaviors after SNL via the HDAC1/SOX10 axis.
Learn More >Intra-articular injections of human mesenchymal stromal cells (hMSCs) have shown promise in slowing cartilage degradation in posttraumatic osteoarthritis (PTOA). Clinical use of cell therapies for osteoarthritis has accelerated in recent years without sufficient scientific evidence defining best-use practices. Common recommendations advise patients to avoid nonsteroidal anti-inflammatory drug (NSAID) use before and after cell injection over concerns that NSAIDs may affect therapeutic efficacy. Recommendations to restrict NSAID use are challenging for patients, and it is unclear if patients are compliant.
Learn More >People with arthritis, a leading cause of disability, may be prescribed long-term opioid therapy to manage chronic pain. Regular use of opioids can increase risk of overdose and opioid use disorder (OUD).
Learn More >The main aim of this systematic review and meta-analysis (MA) was to assess the effectiveness of online behavior modification techniques (e-BMT) in the management of chronic musculoskeletal pain.
Learn More >Cancer-induced bone pain (CIBP) is a common pain in clinics, which can reduce the quality of life and increase the mortality of patients, but the treatment of CIBP is limited. This study was designed to investigate the analgesic effect of α-cobratoxin on CIBP and further to explore the molecular target and potential signal pathway. As shown by the mechanical allodynia test in a CIBP rat model, administration of α-cobratoxin produced significant analgesia in a dose-dependent manner, and the analgesic effects were blocked by pretreatment with an intrathecal injection of M4 mAChR-siRNA or intraperitoneal injection of tropicamide, an antagonist of M4 muscarinic cholinergic receptor. Whole-cell patch-clamp recording showed that α-cobratoxin can decrease the spontaneous firing and spontaneous excitatory postsynaptic currents of SDH neurons in CIBP rats. In primary lumber SDH neurons, intracellular calcium measurement revealed that α-cobratoxin decreased intracellular calcium concentration, and immunofluorescence demonstrated that M4 muscarinic cholinergic receptor and CaMKII/CREB were co-expressed. In the CIBP model and primary SDH neurons, Western blot showed that the levels of p-CaMKII and p-CREB were increased by α-cobratoxin and the effect of α-cobratoxin was antagonized by M4 mAChR-siRNA. The quantitative polymerase chain reaction (qPCR) results showed that α-cobratoxin downregulated the expression of proinflammatory cytokines through M4 muscarinic cholinergic receptor in SDH. These results suggest that α-cobratoxin may activate M4 muscarinic cholinergic receptor, triggering the inhibition of SDH neuronal excitability via CaMKII signaling pathway, thereby resulting in antagonistic effects in the CIBP rat model.
Learn More >Depression and comorbid chronic back pain (CBP) lead to high personal and economic burden. Internet- and mobile-based interventions (IMI) might be a cost-effective adjunct to established interventions.
Learn More >Nociception refers to the process of encoding and processing noxious stimuli, which allow animals to detect and avoid potentially harmful stimuli. Several types of stimuli can trigger nociceptive sensory transduction, including thermal, noxious chemicals, and harsh mechanical stimulation that depend on the corresponding nociceptors. In view of the high evolutionary conservation of the mechanisms that govern nociception from to mammals, investigation in the fruit fly help us understand how the sensory nervous system works and what happen in nociception. Here, we present an overview of currently identified conserved genetics of nociception, the nociceptive sensory neurons responsible for detecting noxious stimuli, and various assays for evaluating different nociception. Finally, we cover development of anti-pain drug using fly model. These comparisons illustrate the value of using as model for uncovering nociception mechanisms, which are essential for identifying new treatment goals and developing novel analgesics that are applicable to human health.
Learn More >Therapeutic alliance (TA) has been positively correlated to improvements in patient outcomes. This study examined the Working Alliance Inventory (WAI) relationship with changes in disability and pain intensity for patients receiving physical therapy (PT) treatment for acute and chronic musculoskeletal pain conditions.
Learn More >This national postal survey aimed to examine Canadian emergency physicians' practice patterns with respect to drug treatment and perspectives on peripheral nerve blocks.
Learn More >Information on epidural analgesia delivered to parturient women is frequently incomplete, making it difficult for expectant mothers to make an appropriate choice for their delivery. We assessed the impact of a multimodal information session on epidural analgesia delegated to anesthetic nurses on new-mothers' satisfaction.
Learn More >Success rates of spinal surgeries to treat chronic back pain are highly variable and useable prognostic indicators are lacking. We aimed to identify and evaluate preoperative predictors of pain and disability after spinal surgery for chronic low back/leg pain.
Learn More >Rheumatoid arthritis (RA) is an incurable chronic disorder that may induce autoinflammation and serious pain in the joints. Early diagnosis and treatment are important for RA prognosis. However, there is a lack of effective and objective diagnostic approaches. Levels of several immunity cytokines were found to change for patients with early RA, including IL-6, TNF-α, and IL-17 in serum. We assumed a combined change of these cytokines could predict early RA, and a total of 37 outpatients were found. After these patients with early symptoms had been followed for more than one year, 32 clinical cases of RA were diagnosed. The accuracy rate of the current method is >86%. We assumed the symptom relief could be achieved by regulating these cytokines and serum lipid-associated indicators. Thereafter, (R)-dihydrolipoic acid (R-DHLA)-stabilized gold nanoclusters (AuNCs) without (R-DHLA-AuNCs) and with cerium modification (R-DHLA-AuNCs-Ce) were employed for treatment of the RA rat model and . R-DHLA-AuNCs-Ce exhibited extraordinary reactive oxygen species-scavenging and anti-inflammation effects by regulating macrophage polarization, which was found to be more effective than methotrexate. The inflammation response of the joint microenvironment was also reduced with an exciting efficiency. By complex analysis of the pro-inflammatory cytokines and activity period indicators and , we concluded that macrophage-mediated inflammation exacerbated autoimmunity, which fully relieved the symptoms after administration of R-DHLA-AuNCs-Ce to RA rats.
Learn More >Chronic postsurgical pain (CPSP) is common among patients receiving major surgeries. CPSP produces suffering in patients, both physically and mentally. However, the mechanisms underlying CPSP remain elusive. Here, a genome-wide expression profiling of ipsilateral spinal cord dorsal horn (SCDH) was performed to identify potential genes related with CPSP.
Learn More >Chronic pain represents a global health problem with a considerable economic burden. The relation of alcohol intake and chronic pain conditions was assessed in several studies with conflicting results. We used dose-response meta-analysis techniques to answer the question of whether alcohol intake is related to chronic pain occurrence.
Learn More >Disruption of endogenous pain control mechanisms including descending pain inhibition has been linked to several forms of pain including chronic pain after traumatic brain injury (TBI). The locus coeruleus (LC) is the principal noradrenergic (NA) nucleus participating in descending pain inhibition. We therefore hypothesized that selectively stimulating LC neurons would reduce nociception after TBI. All experiments used a well-characterized rat lateral fluid percussion model of TBI. NA neurons were stimulated by administering clozapine N-oxide (CNO) to rats selectively expressing a Designer Receptor Exclusively Activated by Designer Drug (DREADD) viral construct in their LC's. Mechanical nociceptive thresholds were measured using von Frey fibers. The efficacy of diffuse noxious inhibitory control (DNIC), a critical endogenous pain control mechanism, was assessed using the hindpaw administration of capsaicin. Immunohistochemical analyses demonstrated the selective expression of the DREADD construct in LC neurons after stereotactic injection. During the first week after TBI, when rats demonstrated hindlimb nociceptive sensitization, CNO administration provided transient anti-nociception in DREADD-expressing rats but not in rats injected with control virus. Seven weeks after TBI we observed a complete loss of DNIC in response to capsaicin. However, CNO administration largely restored DNIC in TBI DREADD-expressing rats but not those injected with control virus. Unexpectedly, the effects of LC activation in the DREADD-expressing rats were blocked by the α-1 adrenergic receptor antagonist, prazosin but not the α-2 adrenergic receptor antagonist, atipamezole. These results suggest that directly stimulating the LC after TBI can reduce both early and late manifestations of dysfunctional endogenous pain regulation. Clinical approaches to activating descending pain circuits may reduce suffering in those with pain after TBI.
Learn More >The central pathophysiological mechanisms underlying irritable bowel syndrome (IBS), a female-predominant gastrointestinal disorder characterized by abdominal pain and abnormal bowel habits, remain poorly understood. IBS patients often report that chronic stress exacerbates their symptoms. Brain imaging studies have revealed that the amygdala, a stress-responsive brain region, of IBS patients is overactive when compared to healthy controls. Previously, we demonstrated that downregulation of the glucocorticoid receptor (GR) in the central nucleus of the amygdala (CeA) underlies stress-induced visceral hypersensitivity in female rats. In the current study, we aimed to evaluate in the CeA of female rats whether chronic water avoidance stress (WAS) alters DNA methylation of the GR exon 1 promoter region, a region homologous to the human GR promoter. As histone deacetylase (HDAC) inhibitors are able to change DNA methylation, we also evaluated whether administration of the HDAC inhibitor trichostatin A (TSA) directly into the CeA prevented WAS-induced increases in DNA methylation of the GR exon 1 promoter. We found that WAS increased overall and specific CpG methylation of the GR promoter in the CeA of female rats, which persisted for up to 28 days. Administration of the TSA directly into the CeA prevented these stress-induced changes of DNA methylation at the GR promoter. Our results suggest that, in females, changes in DNA methylation are involved in the regulation of GR expression in the CeA. These changes in DNA methylation may contribute to the central mechanisms responsible for stress-induced visceral hypersensitivity.
Learn More >Chronic pain is a substantial personal and societal burden worldwide. Osteoarthritis (OA) is one of the leading causes of chronic pain and is increasing in prevalence in accordance with a global aging population. In addition to affecting patients' physical lives, chronic pain also adversely affects patients' mental wellbeing. However, there remain no pharmacologic interventions to slow down the progression of OA and pain-alleviating therapies are largely unsuccessful. The presence of low-level inflammation in OA has been recognized for many years as a major pathogenic driver of joint damage. Inflammatory mechanisms can occur locally in joint tissues, such as the synovium, within the sensory nervous system, as well as systemically, caused by modifiable and unmodifiable factors. Understanding how inflammation may contribute to, and modify pain in OA will be instrumental in identifying new druggable targets for analgesic therapies. In this narrative review, we discuss recent insights into inflammatory mechanisms in OA pain. We discuss how local inflammation in the joint can contribute to mechanical sensitization and to the structural neuroplasticity of joint nociceptors, through pro-inflammatory factors such as nerve growth factor, cytokines, and chemokines. We consider the role of synovitis, and the amplifying mechanisms of neuroimmune interactions. We then explore emerging evidence around the role of neuroinflammation in the dorsal root ganglia and dorsal horn. Finally, we discuss how systemic inflammation associated with obesity may modify OA pain and suggest future research directions.
Learn More >Radiofrequency thermocoagulation of Gasserian ganglion brings with it the difficult problem of how to provide adequate acesodyne therapy for patients in order to make the treatment more comfortable. In our study, we assess the safety and efficacy of lidocaine local anesthesia in the treatment of trigeminal neuralgia.
Learn More >The efficacy and tolerability of fremanezumab, a fully humanized monoclonal antibody (IgG2Δa) that selectively targets calcitonin gene-related peptide (CGRP) and is approved for the preventive treatment of migraine in adults, have been demonstrated in randomized, double-blind, placebo-controlled trials. Real-world data can further support those clinical trial data and demonstrate the full clinical benefits of fremanezumab. This chart review assessed the effectiveness of fremanezumab for improving clinical outcomes in adult patients with migraine treated according to real-world clinical practice.
Learn More >Antiseizure drugs (ASDs) are commonly used to treat a wide range of nonepileptic conditions, including pain. In this context, the analgesic effect of four pyrrolidine-2,5-dione derivatives (compounds , , , and ), with previously confirmed anticonvulsant and preliminary antinociceptive activity, was assessed in established pain models. Consequently, antinociceptive activity was examined in a mouse model of tonic pain (the formalin test). In turn, antiallodynic and antihyperalgesic activity were examined in the oxaliplatin-induced model of peripheral neuropathy as well as in the streptozotocin-induced model of painful diabetic neuropathy in mice. In order to assess potential sedative properties (drug safety evaluation), the influence on locomotor activity was also investigated. As a result, three compounds, namely , , and , demonstrated a significant antinociceptive effect in the formalin-induced model of tonic pain. Furthermore, these substances also revealed antiallodynic properties in the model of oxaliplatin-induced peripheral neuropathy, while compound attenuated tactile allodynia in the model of diabetic streptozotocin-induced peripheral neuropathy. Apart from favorable analgesic properties, the most active compound did not induce any sedative effects at the active dose of 30 mg/kg after intraperitoneal () injection.
Learn More >Pain transmission at the spinal cord is modulated by noradrenaline (NA)-mediated actions that arise from supraspinal areas. We studied the locus coeruleus (LC) to evaluate the expression of the cathecolamine-synthetizing enzyme tyrosine hydroxylase (TH) and search for local oxidative stress and possible consequences in descending pain modulation in a model of hydrocephalus, a disease characterized by enlargement of the cerebral ventricular system usually due to the obstruction of cerebrospinal fluid flow. Four weeks after kaolin injection into the cisterna magna, immunodetection of the catecholamine-synthetizing enzymes TH and dopamine-β-hydroxylase (DBH) was performed in the LC and spinal cord. Colocalization of the oxidative stress marker 8-OHdG (8-hydroxyguanosine; 8-OHdG), with TH in the LC was performed. Formalin was injected in the hindpaw both for behavioral nociceptive evaluation and the immunodetection of Fos expression in the spinal cord. Hydrocephalic rats presented with a higher expression of TH at the LC, of TH and DBH at the spinal dorsal horn along with decreased nociceptive behavioral responses in the second (inflammatory) phase of the formalin test, and formalin-evoked Fos expression at the spinal dorsal horn. The expression of 8-OHdG was increased in the LC neurons, with higher co-localization in TH-immunoreactive neurons. Collectively, the results indicate increased noradrenergic expression at the LC during hydrocephalus. The strong oxidative stress damage at the LC neurons may lead to local neuroprotective-mediated increases in NA levels. The increased expression of catecholamine-synthetizing enzymes along with the decreased nociception-induced neuronal activation of dorsal horn neurons and behavioral pain signs may indicate that hydrocephalus is associated with alterations in descending pain modulation.
Learn More >Mirogabalin (MGB, Tarlige), an inhibitor of the αδ-1 subunit of voltage-gated Ca (Ca) channels, is used as a way to alleviate peripheral neuropathic pain and diabetic neuropathy. However, to what extent MGB modifies the magnitude, gating, and/or hysteresis of various types of plasmalemmal ionic currents remains largely unexplored. In pituitary tumor (GH) cells, we found that MGB was effective at suppressing the peak (transient, ) and sustained (late, ) components of the voltage-gated Na current () in a concentration-dependent manner, with an effective IC of 19.5 and 7.3 μM, respectively, while the value calculated on the basis of minimum reaction scheme was 8.2 μM. The recovery of inactivation slowed in the presence of MGB, although the overall current-voltage relation of was unaltered; however, there was a leftward shift in the inactivation curve of the current. The magnitude of the window () or resurgent () evoked by the respective ascending or descending ramp pulse (V) was reduced during cell exposure to MGB. MGB-induced attenuation in or was reversed by the further addition of tefluthrin, a pyrethroid insecticide known to stimulate . MGB also effectively lessened the strength of voltage-dependent hysteresis of persistent in response to the isosceles triangular V. The cumulative inhibition of evoked by pulse train stimulation, was enhanced in its presence. Taken together, in addition to the inhibition of Ca channels, the Na channel attenuation produced by MGB might have an impact in its analgesic effects occurring in vivo.
Learn More >G protein-coupled receptors (GPCRs) represent the largest family of human membrane proteins. Four subtypes of adenosine receptors (ARs), the AAR, AAR, AAR and AAR, each with a unique pharmacological profile and distribution within the tissues in the human body, mediate many physiological functions and serve as critical drug targets for treating numerous human diseases including cancer, neuropathic pain, cardiac ischemia, stroke and diabetes. The AAR and AAR preferentially couple to the G proteins, while the AAR and AAR prefer coupling to the G proteins. Adenosine receptors were the first subclass of GPCRs that had experimental structures determined in complex with distinct G proteins. Here, we will review recent studies in molecular simulations and computer-aided drug discovery of the adenosine receptors and also highlight their future research opportunities.
Learn More >Human peripheral neuropathies are poorly understood, and the availability of experimental models limits further research. The PeriTox test uses immature dorsal root ganglia (DRG)-like neurons, derived from induced pluripotent stem cells (iPSC), to assess cell death and neurite damage. Here, we explored the suitability of matured peripheral neuron cultures for the detection of sub-cytotoxic endpoints, such as altered responses of pain-related P2X receptors. A two-step differentiation protocol, involving the transient expression of ectopic neurogenin-1 (NGN1) allowed for the generation of homogeneous cultures of sensory neurons. After >38 days of differentiation, they showed a robust response (Ca-signaling) to the P2X3 ligand α,β-methylene ATP. The clinical proteasome inhibitor bortezomib abolished the P2X3 signal at ≥5 nM, while 50-200 nM was required in the PeriTox test to identify neurite damage and cell death. A 24 h treatment with low nM concentrations of bortezomib led to moderate increases in resting cell intracellular Ca concentration but signaling through transient receptor potential V1 (TRPV1) receptors or depolarization-triggered Ca influx remained unaffected. We interpreted the specific attenuation of purinergic signaling as a functional cell stress response. A reorganization of tubulin to form dense structures around the cell somata confirmed a mild, non-cytotoxic stress triggered by low concentrations of bortezomib. The proteasome inhibitors carfilzomib, delanzomib, epoxomicin, and MG-132 showed similar stress responses. Thus, the model presented here may be used for the profiling of new proteasome inhibitors in regard to their side effect (neuropathy) potential, or for pharmacological studies on the attenuation of their neurotoxicity. P2X3 signaling proved useful as endpoint to assess potential neurotoxicants in peripheral neurons.
Learn More >Neuropathic pain in people with spinal cord injury is thought to be due to altered central neuronal activity. A novel therapeutic intervention using virtual reality (VR) head-mounted devices was investigated in this study for pain relief. Given the potential links to neuronal activity, the aim of the current study was to determine whether use of VR was associated with corresponding changes in electroencephalography (EEG) patterns linked to the presence of neuropathic pain. Using a within-subject, randomised cross-over pilot trial, we compared EEG activity for three conditions: no task eyes open state, 2D screen task and 3D VR task. We found an increase in delta activity in frontal regions for 3D VR with a decrease in theta activity. There was also a consistent decrease in relative alpha band (8-12 Hz) and an increase in low gamma (30-45 Hz) power during 2D screen and 3D VR corresponding, with reduced self-reported pain. Using the nonlinear and non-oscillatory method of extracting fractal dimensions, we found increases in brain complexity during 2D screen and 3D VR. We successfully classified the 3D VR condition from 2D screen and eyes opened no task conditions with an overall accuracy of 80.3%. The findings in this study have implications for using VR applications as a therapeutic intervention for neuropathic pain in people with spinal cord injury.
Learn More >The importance of the dynamic interplay between the opioid and the serotonin neuromodulatory systems in chronic pain is well recognized. In this study, we investigated whether these two signalling pathways can be integrated at the single-cell level via direct interactions between the mu-opioid (MOP) and the serotonin 1A (5-HT) receptors. Using fluorescence cross-correlation spectroscopy (FCCS), a quantitative method with single-molecule sensitivity, we characterized in live cells MOP and 5-HT interactions and the effects of prolonged (18 h) exposure to selected non-peptide opioids: morphine, codeine, oxycodone and fentanyl, on the extent of these interactions. The results indicate that in the plasma membrane, MOP and 5-HT receptors form heterodimers that are characterized with an apparent dissociation constant Kdapp = (440 ± 70) nM). Prolonged exposure to all non-peptide opioids tested facilitated MOP and 5-HT heterodimerization and stabilized the heterodimer complexes, albeit to a different extent: Kd,&nbsp;Fentanylapp = (80 ± 70) nM), Kd,Morphineapp = (200 ± 70) nM, Kd,&nbsp;Codeineapp = (100 ± 70) nM and Kd,&nbsp;Oxycodoneapp = (200 ± 70) nM. The non-peptide opioids differed also in the extent to which they affected the mitogen-activated protein kinases (MAPKs) p38 and the extracellular signal-regulated kinase (Erk1/2), with morphine, codeine and fentanyl activating both pathways, whereas oxycodone activated p38 but not ERK1/2. Acute stimulation with different non-peptide opioids differently affected the intracellular Ca levels and signalling dynamics. Hypothetically, targeting MOP-5-HT heterodimer formation could become a new strategy to counteract opioid induced hyperalgesia and help to preserve the analgesic effects of opioids in chronic pain.
Learn More >Nociceptin and the nociceptin receptor (NOP) have been described as targets for treatment of pain and inflammation, whereas toll-like receptors (TLRs) play key roles in inflammation and impact opioid receptors and endogenous opioids expression. In this study, interactions between the nociceptin and TLR systems were investigated. Human THP-1 cells were cultured with or without phorbol myristate acetate (PMA 5 ng/mL), agonists specific for TLR2 (lipoteichoic acid, LTA 10 µg/mL), TLR4 (lipopolysaccharide, LPS 100 ng/mL), TLR7 (imiquimod, IMQ 10 µg/mL), TLR9 (oligonucleotide (ODN) 2216 1 µM), PMA+TLR agonists, or nociceptin (0.01-100 nM). Prepronociceptin (), , and mRNAs were quantified by RT-qPCR. Proteins were measured using flow cytometry. PMA upregulated mRNA, intracellular nociceptin, and cell membrane NOP proteins (all < 0.05). LTA and LPS prevented PMA's upregulating effects on mRNA and nociceptin protein (both < 0.05). IMQ and ODN 2216 attenuated PMA's effects on mRNA. PMA, LPS, IMQ, and ODN 2216 increased NOP protein levels (all < 0.05). PMA+TLR agonists had no effects on NOP compared to PMA controls. Nociceptin dose-dependently suppressed TLR2, TLR4, TLR7, and TLR9 proteins (all < 0.01). Antagonistic effects observed between the nociceptin and TLR systems suggest that the nociceptin system plays an anti-inflammatory role in monocytes under inflammatory conditions.
Learn More >Chronic tension-type headache (CTTH) is a common disease with no fully defined pathophysiological processes. We designed a study to value electrophysiological responses in these patients and their correlation with possible psychopathological manifestations in order to deepen understanding of central and peripheral mechanisms of CTTH. In 40 patients with CTTH and 40 healthy controls, we used electrical stimulation to determine sensory threshold (SPT) and pain perception threshold (PPT) and the characteristics of the electrophysiological sensory nerve action potential (SNAP): initial sensory response (ISR) and supramaximal response (SMR). We then calculated the intensity differences between thresholds (IDT), namely SPT-PPT, ISR-SMR and SMR-PPT, and correlated these IDTs with psychological characteristics: trait and state anxiety, depression, and emotional regulation. The SPT, together with the ISR and SMR thresholds, were higher ( < 0.01) in CTTH patients. The SMR-PPT IDT was smaller and correlated with significantly higher indicators of depression, state and trait anxiety, and poorer cognitive reappraisal. CTTH patients have less capacity to recognize non-nociceptive sensory stimuli, greater tendency toward pain facilitation, and a poor central pain control requiring higher stimulation intensity thresholds to reach the start and the peak amplitude of the SNAP. This is consistent with relative hypoexcitability of the Aβ nerve fibers in distant regions from the site of pain, and therefore, it could be considered a generalized dysfunction with a focal expression. Pain facilitation is directly associated with psychological comorbidity.
Learn More >Platelets are an essential component of hemostasis, with an increasing role in host inflammatory processes in injured tissues. The reaction between receptors and vascular endothelial cells results in the recruitment of platelets in the immune response pathway. The aim of the present review is to describe the role of platelets in osteoarthritis. Platelets induce secretion of biological substances, many of which are key players in the inflammatory response in osteoarthritis. Molecules involved in cartilage degeneration, or being markers of inflammation in osteoarthritis, are cytokines, such as tumor necrosis factor α (TNFα), interleukins (IL), type II collagen, aggrecan, and metalloproteinases. Surprisingly, platelets may also be used as a treatment modality for osteoarthritis. Multiple randomized controlled trials included in our systematic review and meta-analyses prove the effectiveness of platelet-rich plasma (PRP) as a minimally invasive method of pain alleviation in osteoarthritis treatment.
Learn More >The maladaptive response of the central nervous system (CNS) following nerve injury is primarily linked to the activation of glial cells (reactive gliosis) that produce an inflammatory reaction and a wide cellular morpho-structural and functional/metabolic remodeling. Glial acidic fibrillary protein (GFAP), a major protein constituent of astrocyte intermediate filaments (IFs), is the hallmark of the reactive astrocytes, has pleiotropic functions and is significantly upregulated in the spinal cord after nerve injury. Here, we investigated the specific role of GFAP in glial reaction and maladaptive spinal cord plasticity following sciatic nerve spared nerve injury (SNI) in GFAP KO and wild-type (WT) animals. We evaluated the neuropathic behavior (thermal hyperalgesia, allodynia) and the expression of glial (vimentin, Iba1) and glutamate/GABA system markers (GLAST, GLT1, EAAC1, vGLUT, vGAT, GAD) in lumbar spinal cord sections of KO/WT animals. SNI induced neuropathic behavior in both GFAP KO and WT mice, paralleled by intense microglial reaction (Iba1 expression more pronounced in KO mice), reactive astrocytosis (vimentin increase) and expression remodeling of glial/neuronal glutamate/GABA transporters. In conclusion, it is conceivable that the lack of GFAP could be detrimental to the CNS as it lacks a critical sensor for neuroinflammation and morpho-functional-metabolic rewiring after nerve injury. Understanding the maladaptive morpho-functional changes of glial cells could represent the first step for a new glial-based targeted approach for mechanisms of disease in the CNS.
Learn More >This study aimed to evaluate the expression of cytosine monophosphate kinase 2 (CMPK2) and activation of the NLRP3 inflammasome in rats with spinal cord injury (SCI) and to characterize the effects of electroacupuncture on CMPK2-associated regulation of the NLRP3 inflammasome.
Learn More >To elucidate the mechanisms underlying the antipruritic effect of capsaicin, we investigated how topical application of capsaicin (0.01, 0.1 and 1.0% w/v) affects spontaneous scratching in NC/Nga mice, inerleukin-31 (IL-31) induced in BALB/c mice, and IL-31 receptor A (IL-31RA) and transient receptor potential vanilloid member 1 (TRPV1) mRNA expression in dorsal root ganglia (DRG). Capsaicin concentration-dependently suppressed long-lasting scratching (over 1.0 s, itch-associated scratching) and short-lasting scratching (0.3-1.0 s, locomotor activity) immediately after the application. Total long-lasting scratching and short-lasting scratching counts for 24 h and IL-31RA mRNA expression in the DRG significantly decreased with increasing concentration of capsaicin. Furthermore, 1.0% capsaicin suppressed long-lasting scratching and short-lasting scratching for more than 72 h. At this point, DRG IL-31RAmRNA was significantly decreased, but there was no change in cutaneous IL-31RA and TRPV1 mRNA. Thus capsaicin suppresses long-lasting scratching by inhibiting IL-31RA mRNA expression in the DRG. Next, we examined the effect of capsaicin on IL-31-induced long-lasting scratching in BALB/c mice. Repeated administration of IL-31 (50 μg/kg, subcutaneous) every 12 h for 3 days apparently increased long-lasting scratching counts and IL-31RA mRNA in the DRG. These increases were significantly suppressed by pretreatment with 1.0% capsaicin. TRPV1 mRNA in the DRG was also decreased within 1-24 h after capsaicin application. These results suggest that the strong and prolonged antipruritic action for IL-31-induced itching of capsaicin was caused by desensitization of C-fibers, and, in addition, the long-lasting inhibition of IL-31RA mRNA expression in the DRG.
Learn More >Patients frequently complain of mild, transient, unpleasant skin sensations that cannot be diagnosed as common neuropathies. Dermatologists have termed these symptoms "sensitive skin syndrome." This narrative review was performed for a better knowledge by other specialists.
Learn More >Patients with bone cancer pain (BCP) are more prone to aversion. which not only causes mental distress but also aggravates BCP. However, the mechanism of BCP-related aversion is still unclear. Previous studies have demonstrated that the brain-derived neurotrophic factor (BDNF)-tropomyosin receptor kinase B (TrkB) signaling pathway of the rostral anterior cingulate cortex (rACC) plays an important role in the regulation of emotions related to chronic pain, such as neuropathic pain or inflammatory pain; however, few studies have investigated the role of this pathway in cancer pain. This study explored the role of BDNF in cancer pain-related aversion in the rACC and to determine whether N-methyl D-aspartate receptor subtype 2B (NR2B) and extracellular signal-regulated kinase (ERK)-cAMP response element-binding (CREB) signaling are involved in cancer pain-related aversion. A Sprague-Dawley rat model of BCP (one of the classic BCP models) was established, and the changes in pain aversion were detected by mechanical stimulation-induced conditioned place avoidance. Our findings confirmed that rats with BCP exhibited intense pain aversion accompanied by the up-regulated BDNF expression in the rACC. Additionally, the pain aversion of BCP rats was reduced while blocking the BDNF-TrkB. Furthermore, the expression of NR2B and phosphorylated ERK (pERK)/phosphorylated CREB (pCREB) were up-regulated with the development of pain aversion, whereas the use of NR2B blocker Ro25-6981, or ERK inhibitor U0126 could reduce the pain aversion. The expression of NR2B and pERK/pCREB were up-regulated after exogenous BDNF was injected into the rACC, whereas the expression levels of NR2B and pERK/pCREB were down-regulated after blocking the BDNF-TrkB signaling. In conclusion, the BDNF-TrkB signaling in the rACC mediates the generation of aversion in rats with BCP, which requires the involvement of NR2B and the ERK-CREB signaling pathway.
Learn More >A sucrose downshift causes a temporary suppression of consumption accompanied by psychological pain, a negative emotion triggered by reward loss. When administered systemically before downshift sessions, opioid agonists reduce and opioid antagonists enhance such behavioral suppression. However, little is known about the effects of signals of opioid drugs on behavior during a reward downshift episode. Research showed that morphine administration can induce a direct effect (e.g., hypoalgesia) followed by a compensatory effect (e.g., hyperalgesia). Therefore, a signal for morphine could elicit either a direct or a compensatory effect. Male Wistar rats were exposed to ten 5-min sessions of access to 32% sucrose in context A, followed by three sessions of access to 4% sucrose in context B. In parallel, animals received pairings between context B and morphine (5 mg/kg, sc) occurring each day immediately after sucrose sessions (contexts were counterbalanced). Control conditions included a saline control (no morphine injected), an unpaired control (morphine injected after exposure to B) tested in A (Experiment 1), and an unpaired control tested in B (Experiment 2). In both experiments, behavioral suppression induced by the 32-to-4% sucrose downshift was attenuated when the downshift occurred in a context previously paired with morphine. These data are consistent with the hypothesis that reward downshift is accompanied by an emotion of negative valence that can be counteracted by the conditioned release of endogenous opioids triggered by signals of morphine, much like it is attenuated by systemic morphine administration. Alternative hypotheses are also discussed.
Learn More >Neuropathic pain (NP) is chronic and associated with poor effects of general analgesia. It affects patients' health and quality of life. The apoptotic process of lipid peroxidation caused by iron overload is called ferroptosis, which may be associated with nervous system disease. A recent study has found that sirtuin 2 (SIRT2) achieves a neuroprotective effect by suppressing ferroptosis. Herein, we aimed to examine whether SIRT2 regulated spared nerve injury (SNI)-induced NP by suppressing ferroptosis in rats. A rat model of NP was induced in adult male Sprague-Dawley rats weighing 200-250 g. Mechanical allodynia was observed from the first day after SNI and continued for 14 days. Compared with age-matched control rats, the expression of SIRT2 and ferroportin 1 (FPN1) decreased in the L4-6 spinal cord of the SNI-induced NP rats. In addition, we observed that the levels of both iron and anti-acyl-coenzyme A synthetase long-chain family member 4 (ACSL4) were significantly increased in the spinal cord after SNI, while the expression of glutathione peroxidase 4 (GPX4) was decreased. Furthermore, an intrathecal injection of SIRT2 overexpressed recombinant adenovirus, which upregulated the expression of SIRT2, attenuated mechanical allodynia, enhanced the level of FPN1, inhibited intracellular iron accumulation, and reduced oxidant stress levels, thereby reversing the changes to ACSL4 and GPX4 expression in the SNI rats. This evidence suggests that SIRT2-targeted therapeutics may help relieve the symptoms of chronic NP.
Learn More >Disruption of the inhibitory control provided by the glycinergic system is one of the major mechanisms underlying chronic pain. In line with this concept, recent studies have provided robust proof that pharmacological intervention of glycine receptors (GlyRs) restores the inhibitory function and exerts anti-nociceptive effects on preclinical models of chronic pain. A targeted regulation of the glycinergic system requires the identification of the GlyR subtypes involved in chronic pain states. Nevertheless, the roles of individual GlyR subunits in nociception and in chronic pain are yet not well defined. This review aims to provide a systematic outline on the contribution of GlyR subtypes in chronic pain mechanisms, with a particular focus on molecular pathways of spinal glycinergic dis-inhibition mediated by post-translational modifications at the receptor level. The current experimental evidence has shown that phosphorylation of synaptic α1β and α3β GlyRs are involved in processes of spinal glycinergic dis-inhibition triggered by chronic inflammatory pain. On the other hand, the participation of α2-containing GlyRs and of β subunits in pain signaling have been less studied and remain undefined. Although many questions in the field are still unresolved, future progress in GlyR research may soon open new exciting avenues into understanding and controlling chronic pain.
Learn More >Inflammatory bowel disease (IBD) results in chronic abdominal pain in patients due to the presence of inflammatory responses in the colon. Electroacupuncture (EA) is effective in alleviating visceral pain and colonic inflammation associated with IBD. Cannabinoid CB2 receptor agonists also reduce colonic inflammation in a mouse model of IBD. However, whether EA reduces visceral pain and colonic inflammation the CB2 receptor remains unknown. Here, we determined the mechanism of the antinociceptive effect of EA in a mouse model of IBD induced by rectal perfusion of 2,4,6-trinitrobenzenesulfonic acid solution (TNBS). EA or sham EA was performed at the bilateral Dachangshu (BL25) point for seven consecutive days. The von Frey and colorectal distension tests were performed to measure mechanical referred pain and visceral pain. Western blotting and immunohistochemistry assays were carried out to determine the expression of IL-1β and iNOS and activation of macrophages in the colon tissues. We found that EA, but not sham EA, attenuated visceral hypersensitivity and promoted activation of CB2 receptors, which in turn inhibited macrophage activation and the expression of IL-1β and iNOS. The effects of EA were blocked by AM630, a specific CB2 receptor antagonist, and by CB2 receptor knockout. Our findings suggest that EA attenuates mechanical allodynia and visceral hypersensitivity associated with IBD by activating CB2 receptors and subsequent inhibition of macrophage activation and expression of IL-1β and iNOS.
Learn More >The present study aimed to design and synthesize a series of 2-hydroxy-3-(4-aryl-1-piperazinyl)propyl phthalimide derivatives, which are analogs of 1H-pyrrolo[3,4-c]pyridine-1,3(2H)-dione derivatives with proven analgesic effect. In accordance with the basic principle proposed by Lipinski's rule, the probable bioavailabilities of the F1-F4 phthalimides were assessed. The obtained values indicate good absorption after oral administration and the ability to cross the blood-brain barrier. The four compounds F1-F4 differing in the type of pharmacophore in the phenyl group of the 2-hydroxy-3-(4-aryl-1-piperazinyl)propyl on the imide nitrogen atom (R, F1-F3) and the 4-benzhydryl analog (F4) were selected for in vitro and in vivo studies. Based on the in vitro studies, the effects of compounds F1-F4 on cell viability/proliferation and COX-2 levels were evaluated. Moreover, using in vivo methods, the compounds were tested for antinociceptive activity in models of acute pain (the writhing and the hot-plate tests) in mice. Their influence on the motor coordination effect and locomotor activity was also tested. The obtained results revealed that the compounds F1-F4 strongly suppress the pain of peripheral origin and to a lesser extent (F1-F3) pain of central/supraspinal origin. In the in vitro studies, F1-F4 reduced the COX-2 level in lipopolysaccharide-activated RAW 264.7 cells, which suggests their anti-inflammatory activity.
Learn More >Neuropathic pain (NP) is a complex symptom related to the nerve damage. The discovery of new drugs for treating chronic NP has been continuing for several decades, while more progress is still needed to be made because of the unsatisfactory efficacy and the side effects of the currently available drugs. Among all the approved drugs for chronic NP, voltage-gated calcium channel (VGCC) α2δ subunit ligands, also known as gabapentinoids, are among the first-line treatment and represent a class of efficacious and relatively safe therapeutic agents. However, new strategies are still needed to be explored due to the unsatisfied response rate.
Learn More >Neuropathic pain initiates an interplay of pathways, involving MAP kinases and NFκB-signaling, leading to expression of immune response factors and activation and inactivation of proteins via phosphorylation. Neuropathic pain models demonstrated that spinal cord stimulation (SCS) may provide analgesia by modulating gene and protein expression in neuroinflammatory processes. A differential target multiplexed programming (DTMP) approach was more effective than conventional SCS treatments at modulating these. This work investigated the effect of DTMP and low rate SCS (LR-SCS) on proteins associated with MAP kinases and NFκB-signaling relevant to neuroinflammation.
Learn More >Complex regional pain syndrome (CRPS) is usually triggered by trauma or a surgical procedure, and it typically becomes an established one after an intense inflammatory process with chronic pain and edema as the main symptoms. Available treatments for CRPS have low efficacy. This study aimed to evaluate the clinical and immunoregulatory effects of omega-3 polyunsaturated fatty acid (PUFA) supplementation on paw edema and anti- and pro-inflammatory cytokines and macrophage phenotypes in the chronic post-ischemia pain (CPIP) preclinical model of CRPS-Type I.
Learn More >Paracetamol, or acetaminophen (AAP), is the most commonly used analgesic during pregnancy and early life. While therapeutic doses of AAP are considered harmless during these periods, recent findings in both humans and rodents suggest a link between developmental exposure to AAP and behavioral consequences later in life. The aim of this study is to evaluate the impact of neonatal exposure to clinically relevant doses of AAP on adult spontaneous behavior, habituation, memory, learning, and cognitive flexibility later in life using a mouse model. Markers of oxidative stress, axon outgrowth, and glutamatergic transmission were also investigated in the hippocampus during the first 24 h after exposure. In addition, potential long-term effects on synaptic density in the hippocampus have been investigated. In a home cage setting, mice neonatally exposed to AAP (30 + 30 mg/kg, 4 h apart) on postnatal day 10 displayed altered spontaneous behavior and changed habituation patterns later in life compared to controls. These mice also displayed reduced memory, learning and cognitive flexibility compared to control animals in the Morris water maze. An increase of markers for oxidative stress was observed in the hippocampus 6 h after AAP exposure. As AAP is the first choice treatment for pain and/or fever during pregnancy and early life, these results may be of great importance for risk assessment. Here we show that AAP can have persistent negative effects on brain development and suggest that AAP, despite the relatively low doses, is capable to induce acute oxidative stress in the hippocampus.
Learn More >Expectations of painful sensations constitute a core feature of chronic pain. An important clinical question is whether such expectations are revised when disconfirming experiences are made (e.g., less pain than expected). This study examined how people adjust their pain expectations when the experience of decreasing pain is expected vs. unexpected.
Learn More >This study explored the role of P2X7 receptors in spinal cord astrocytes in the electroacupuncture-induced inhibition of visceral hypersensitivity (VH) in rats with irritable bowel syndrome (IBS). Visceral hypersensitivity of IBS was intracolonically induced by 2,4,6-trinitrobenzene sulfonic acid (TNBS). Visceromotor responses to colorectal distension (CRD-20,40,60,80 mmHg) and abdominal withdrawal reflex scoring (AWRs) were recorded after electroacupuncture at bilateral Zusanli (ST36) and Sanyinjiao (SP6) acupoints to evaluate the analgesic effect of electroacupuncture on visceral pain in rats with IBS. Fluorocitric acid (FCA), an astrocyte activity inhibitor, was injected intrathecally before electroacupuncture intervention and AWRs were recorded. Western blot and real-time qPCR were used to detect the expression of NMDA and P2X7 receptor to observe the regulation effect of electroacupuncture on NMDA receptor in the spinal cord of rats with visceral hypersensitivity. Intrathecal injection of P2X7 agonist or antagonist was administered before electroacupuncture treatment. To observe the effect of P2X7 receptor in spinal astrocytes on the inhibition of visceral hyperalgesia by electroacupuncture, the changes of AWR score, NMDA receptor in the spinal cord, and GFAP expression in astrocytes were detected. Inflammation of the colon had basically subsided at day 21 post-TNBS; persistent visceral hypersensitivity could be suppressed by electroacupuncture. This analgesic effect could be inhibited by FCA. The analgesic effect, downregulation of NMDA receptor NR1 subunit, and P2X7 protein of electroacupuncture were all reversed by FCA. P2X7 receptor antagonist A740003 can cooperate with EA to carry out analgesic effect in rats with visceral pain and downregulate the expression of NR1, NR2B, and GFAP in spinal dorsal horn. However, the P2X7 receptor agonist BzATP could partially reverse the analgesic effect of EA, inhibiting the downregulatory effect of EA on the expression of NR1, NR2B, and GFAP. These results indicate that EA may downregulate the expression of the NMDA receptor by inhibiting the P2X7 receptor in the spinal cord, thereby inhibiting spinal cord sensitization in IBS rats with visceral pain, in which astrocytes are an important medium.
Learn More >To examine the possible bidirectional association between insomnia and comorbid chronic low back pain (LBP) and lower limb pain and to explore whether high-sensitivity C-reactive protein (hsCRP) amplifies these associations.
Learn More >Chronic pain is highly prevalent in treatment-seeking opioid-dependent patients; therefore, this comorbid presentation is an important clinical consideration for both addiction and pain specialists. The objectives of the present study were to examine whether the direction of causal attribution of opioid dependence disorder and chronic pain resulted in two distinct clinical populations, and, if so, to compare treatment received during the 5-year follow-up period.
Learn More >This study aimed to compare the alterations of thalamic nuclei volumes and the intrinsic thalamic network in patients with cluster headache and healthy controls.
Learn More >Although pain management is central to pediatric chronic pancreatitis (CP) care, no evidence-based guidelines exist. In this scoping systematic review, we sought promising strategies for CP pain treatment in children.
Learn More >The deep fascia is a three-dimensional continuum of connective tissue surrounding the bones, muscles, nerves and blood vessels throughout our body. Its importance in chronically debilitating conditions has recently been brought to light. This work investigates changes in these tissues in pathological settings.
Learn More >To compare the effectiveness of pain neuroscience education (PNE) versus biomedical education (BME) in a rehabilitation program following arthroscopic rotator cuff repair (ARCR) in patients with chronic shoulder pain.
Learn More >COVID-19 pandemic containment measures have led to changes in various areas of life, including restrictions on health care. Patients with chronic pain may have faced an increased burden during pandemic and the resources of this vulnerable population are unknown. Therefore, a qualitative study was conducted to understand how people with chronic pain have experienced the course of the pandemic.
Learn More >Interstitial cystitis/bladder pain syndrome (IC/BPS) is a debilitating chronic disorder characterized by suprapubic pain and urinary symptoms such as urgency, nocturia, and frequency. The prevalence of IC/BPS is increasing as diagnostic criteria become more comprehensive. Conventional pharmacotherapy against IC/BPS has shown suboptimal effects, and consequently, patients with end-stage IC/BPS are subjected to surgery. The novel treatment strategies should have two main functions, anti-inflammatory action and the regeneration of glycosaminoglycan and urothelium layers. Stem cell therapy has been shown to have dual functions. Mesenchymal stem cells (MSCs) are a promising therapeutic option for IC/BPS, but they come with several shortcomings, such as immune activation and tumorigenicity. MSC-derived extracellular vesicles (MSC-EVs) hold numerous therapeutic cargos and are thus a viable cell-free therapeutic option. In this review, we provide a brief overview of IC/BPS pathophysiology and limitations of the MSC-based therapies. Then we provide a detailed explanation and discussion of therapeutic applications of EVs in IC/BPS as well as the possible mechanisms. We believe our review will give an insight into the strengths and drawbacks of EV-mediated IC/BPS therapy and will provide a basis for further development.
Learn More >Fibromyalgia (FM) is a prevalent, chronic condition without a cure or reliable therapy. The etiopathogenesis of this syndrome is ambiguous, which has heightened the challenge of discovering treatments to minimize patients' painful symptoms. FM is characterized by diffuse musculoskeletal pain usually accompanied by functional pain syndromes, such as fatigue, sleep disturbances, cognitive difficulties, and mood issues. Currently available treatment options for FM are limited. Recent studies have suggested a potential role for dietary bioactive compounds in FM management. We performed a narrative review to evaluate the existing evidence regarding the dietary bioactive compounds for FM, and we proposed molecular mechanisms on this topic. The inclusion criteria were (i) human, in vivo, or in vitro studies, (ii) studies related to the effect of bioactive compounds on FM-like symptoms, (iii) peer-reviewed literature, and (iv) publications until February 2022 in PubMed and Google Scholar. Exclusion criteria were (i) study designs using CCI, SNI, or SNL models because they are more NP models rather than FM models, and (ii) studies published in a language other than English. Keywords were dietary bioactive compounds, fibromyalgia, cell, animals, humans. Here, we report the effects of commonly consumed bioactive compounds (capsaicin, ginger, curcumin, n-3 PUFA, grape seed extract, naringin, and genistein) on FM-like symptoms in cellular, animal, and human studies. Cellular studies demonstrated that these bioactive compounds reduce pro-inflammatory production and increase antioxidant capacity of neurons or myoblasts that regulate apoptosis/cell survival. Animal studies showed that these regularly consumed bioactive compounds have an effect on FM-like symptoms, as evidenced by decreased pain hypersensitivity and fatigue as well as improved social behaviors. Further studies are warranted to allow meaningful comparison and quantification of the efficacy of these bioactive compounds on FM-like symptoms across studies, in terms of actual changes in antioxidant capacity, pain hypersensitivity, fatigue, and social behaviors. To date, human studies regarding the efficacy of these bioactive compounds on FM-like symptoms are limited and inconclusive. Our review identifies this important knowledge gap and proposes that the development and use of improved preclinical FM models are needed, particularly concerning the usage of female animals to better mimic FM pathophysiology and symptomatology.
Learn More >Virtual reality (VR) is a developing technology that has recently attracted the attention of healthcare practitioners. Recently, VR systems have been used to treat pain symptoms. The present study aims to evaluate the VR effectiveness on chronic pain management. A systematic literature search was performed following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Keywords were used to discover the potentially eligible studies. The primary focus of the present investigation was to evaluate the possible effect of VR-assisted treatments on chronic pain, especially in the commonly occurring low back and neck pain. Nine studies reporting randomized controlled trials were included in the present study. VR-mediated interventions demonstrated significant improvement for pain symptoms in patients experiencing chronic pain. In addition, VR-mediated therapy decreased pain intensity and disability in the case of chronic neck pain compared to control conditions. However, the VR interventions showed a statistically non-significant improvement in chronic low back pain when experimental groups were compared with controls. VR therapy positive effect on chronic pain did not differ from the one reported for other types of interventions for pain management, as physical exercise and laser therapy. Taken together, these findings showed that currently available lines of evidence on the effect of VR-mediated therapy in chronic pain management, despite pointing towards possible therapeutical benefits of the VR-based intervention, are overall inconclusive and that more research on VR-assisted therapy for chronic pain is needed.
Learn More >Trigeminal neuralgia (TN) is a complex orofacial pain syndrome characterized by the paroxysmal onset of pain attacks in the trigeminal distribution. The underlying mechanism for this debilitating condition is still not clearly understood. Decades of basic and clinical evidence support the demyelination hypothesis, where demyelination along the trigeminal afferent pathway is a major driver for TN pathogenesis and pathophysiology. Such pathological demyelination can be triggered by physical compression of the trigeminal ganglion or another primary demyelinating disease, such as multiple sclerosis. Further examination of TN patients and animal models has revealed significant molecular changes, channelopathies, and electrophysiological abnormalities in the affected trigeminal nerve. Interestingly, recent electrophysiological recordings and advanced functional neuroimaging data have shed new light on the global structural changes and the altered connectivity in the central pain-related circuits in TN patients. The current article aims to review the latest findings on the pathophysiology of TN and cross-examining them with the current surgical and pharmacologic management for TN patients. Understanding the underlying biology of TN could help scientists and clinicians to identify novel targets and improve treatments for this complex, debilitating disease.
Learn More >An animal model of voluntary oral morphine consumption would allow for a pre-clinical evaluation of new treatments aimed at reducing opioid intake in humans. However, the main limitation of oral morphine consumption in rodents is its bitter taste, which is strongly aversive. Taste aversion is often overcome by the use of adulterants, such as sweeteners, to conceal morphine taste or bitterants in the alternative bottle to equalize aversion. However, the adulterants' presence is the cause for consumption choice and, upon removal, the preference for morphine is not preserved. Thus, current animal models are not suitable to study treatments aimed at reducing consumption elicited by morphine itself. Since taste preference is a learned behavior, just-weaned rats were trained to accept a bitter taste, adding the bitterant quinine to their drinking water for one week. The latter was followed by allowing the choice of quinine or morphine (0.15 mg/mL) solutions for two weeks. Then, quinine was removed, and the preference for morphine against water was evaluated. Using this paradigm, we show that rats highly preferred the consumption of morphine over water, reaching a voluntary morphine intake of 15 mg/kg/day. Morphine consumption led to significant analgesia and hyperlocomotion, and to a marked deprivation syndrome following the administration of the opioid antagonist naloxone. Voluntary morphine consumption was also shown to generate brain oxidative stress and neuroinflammation, signs associated with opioid dependence development. We present a robust two-bottle choice animal model of oral morphine self-administration for the evaluation of therapeutic interventions for the treatment of morphine dependence.
Learn More >The role of purinergic receptor P2X3 in pathological bladder dysfunction and chronic pelvic pain remains unclear. We aim to investigate the effect of P2X3 on bladder function in interstitial cystitis (IC) through the IC rat model induced by cyclophosphamide (CYP).
Learn More >Chronic pain remains an unresolved problem. Current treatments have limited efficacy. Thus, novel therapeutic targets are urgently required for the development of more effective analgesics. An increasing number of studies have proved that sirtuin 1 (SIRT1) agonists can relieve chronic pain. In this review, we summarize recent progress in understanding the roles and mechanisms of SIRT1 in mediating chronic pain associated with peripheral nerve injury, chemotherapy-induced peripheral neuropathy, spinal cord injury, bone cancer, and complete Freund's adjuvant injection. Emerging studies have indicated that SIRT1 activation may exert positive effects on chronic pain relief by regulating inflammation, oxidative stress, and mitochondrial dysfunction. Therefore, SIRT1 agonists may serve as potential therapeutic drugs for chronic pain.
Learn More >Spinal cord stimulation (SCS) is a recognized intervention for the management of chronic neuropathic pain. The United Kingdom National Institute of Health and Care Excellence has recommended SCS as a management option for chronic neuropathic pain since 2008. The aim of this study is to undertake an assessment of SCS uptake across the National Health Service in England up to 2020.
Learn More >Pain is a common condition in dermatology. The aim of this review is to analyse the characteristics of pain in dermatology. Some skin diseases are conventionally known to cause pain; e.g. ulcers, pyoderma gangrenosum and herpes zoster. Common dermatoses, such as psoriasis or atopic dermatitis, can also cause significant pain. Some conditions are characterized by neuropathic pain and/or pruritus, without visible primary lesions: e.g. the neurocutaneous diseases, including small fibre neuropathies. Patients often fear pain in skin surgery; however, surgical procedures are rather well tolerated and any pain is mainly due to administration of local anaesthetic. Some therapies may also be uncomfortable for the patient, such as photo-dynamic therapy or aesthetic procedures. Thus, pain in dermatology is common, and its aetiology and charac-teristics are very varied. Knowledge of the different situations that cause pain will enable dermatologists to propose suitable analgesic solutions.
Learn More >The human body is constantly under the influence of numerous pathological factors: both external and internal. These factors can be potentially harmful and are perceived as such with a specialized nervous system subunit: the nociceptive system. The functional unit of the nociceptive system is the nociceptor. Recent studies have shown that nociceptors play a crucial role in maintaining of defensive homeostasis (responsive, immune, behavioral). Nociceptors respond to potentially harmful stimuli within viscera, bones, muscles, skin and specialized sensory organs. They function as complex predictors of harm through formation of pain stimulus. Their function and structures vary within different tissues. This variability reflects the anatomical and pathological peculiarities of varying tissues. Nociceptors play a significant role in adaptive, protective and behavioral reactions. Their functional capabilities and vast spread throughout the body make them the main units of the body's defense system, allowing us to interact with the inner and outer environments.
Learn More >Chronic pelvic pain syndrome (CPPS) is defined as the occurrence of chronic pelvic pain (CPP) in the absence of a specific cause. People typically refer to pain associated with urological, gynaecological, and sexual dysfunction, affecting the quality of life. Therefore, we assessed the effectiveness of myofascial manual therapies (MMT) for pain and symptom impact.
Learn More >