Pain Conditions Research Articles

The Endocannabinoid System of the Nervous and Gastrointestinal Systems Changes after a Subnoxious Cisplatin Dose in Male Rats

Background/Objectives: Cisplatin, a common chemotherapy agent, is well known to cause severe side effects in the gastrointestinal and nervous systems due to its toxic and pro-inflammatory effects. Although pharmacological manipulation of the endocannabinoid system (ECS) can alleviate these side effects, how chemotherapy affects the ECS components in these systems remains poorly understood. Our aim was to evaluate these changes. Methods: Male Wistar rats received cisplatin (5 mg/kg, i.p.) or saline on day 0 (D0). Immediately after, serial X-rays were taken for 24 h (D0). Body weight was recorded (D0, D1, D2 and D7) and behavioural tests were performed on D4. On D7, animals were euthanized, and gastrointestinal tissue, dorsal root ganglia (DRGs) and brain areas were collected. Expression of genes related to the ECS was assessed via Rt-PCR, while LC-MS/MS was used to analyse endocannabinoid and related N-acylethanolamine levels in tissue and plasma. Results: Animals treated with cisplatin showed a reduction in body weight. Cisplatin reduced gastric emptying during D0 and decreased MAGL gene expression in the antrum at D7. Despite cisplatin not causing mechanical or heat sensitivity, we observed ECS alterations in the prefrontal cortex (PFC) and DRGs similar to those seen in other chronic pain conditions, including an increased CB1 gene expression in L4/L5 DRGs and a decreased MAGL expression in PFC. Conclusions: A single dose of cisplatin (5 mg/kg, i.p.), subnoxious, but capable of inducing acute gastrointestinal effects, caused ECS changes in both gastrointestinal and nervous systems. Modulating the ECS could alleviate or potentially prevent chemotherapy-induced toxicity.

Assessing signs of central sensitization: A critical review of physiological measures in experimentally induced secondary hyperalgesia.

Central sensitization (CS) is believed to play a role in many chronic pain conditions. Direct non-invasive recording from single nociceptive neurons is not feasible in humans, complicating CS establishment. This review discusses how secondary hyperalgesia (SHA), considered a manifestation of CS, affects physiological measures in healthy individuals and if these measures could indicate CS. It addresses controversies about heat sensitivity changes, the role of tactile afferents in mechanical hypersensitivity and detecting SHA through electrical stimuli. Additionally, it reviews the potential of neurophysiological measures to indicate CS presence. Four databases, PubMed, ScienceDirect, Scopus and Cochrane Library, were searched using terms linked to 'hyperalgesia'. The search was limited to research articles in English conducted in humans until 2023. Evidence for heat hyperalgesia in the SHA area is sparse and seems to depend on the experimental method used. Minimal or no involvement of tactile afferents in SHA was found. At the spinal level, the threshold of the nociceptive withdrawal reflex (RIII) is consistently reduced during experimentally induced SHA. The RIII area and the spinal somatosensory potential (N13-SEP) amplitude are modulated only with long-lasting nociceptive input. At the brain level, pinprick-evoked potentials within the SHA area are increased. Mechanical pinprick hyperalgesia is the most reliable behavioural readout for SHA, while the RIII threshold is the most sensitive neurophysiological readout. Due to scarce data on reliability, sensitivity and specificity, none of the revised neurophysiological methods is currently suitable for CS identification at the individual level. Gathering evidence for CS in humans is a crucial research focus, especially with the increasing interest in concepts such as 'central sensitization-like pain' or 'nociplastic pain'. This review clarifies which readouts, among the different behavioural and neurophysiological proxies tested in experimental settings, can be used to infer the presence of CS in humans.

A novel opioid/pramipexole combination treatment for the management of acute pain: a pilot study.

Despite their dangerous side effects, opioid drugs remain a standard of care for moderate to severe pain with few alternatives. Strategies to maintain the analgesic effects of opioids while minimizing the associated risks are needed. Pre-clinical studies have shown using a dopamine 3 receptor (D3R) agonist as an adjuvant to morphine provides superior analgesia against painful stimuli compared to morphine alone. Our objective was to test if adjunct treatment with a D3R agonist can lead to a reduction in opioid use while maintaining effective analgesia. This study was set up as a double-blinded, placebo-controlled randomized trial. Enrollment included acute renal colic patients presenting to the emergency department, from which patients were randomized to either the "control" or "study arm". The control group received standard treatment of care (morphine, 0.1 mg/kg; i.v.) and an oral placebo pill. The experimental group received half-dosed morphine and oral pramipexole pill (0.25 mg). Pain measurements including a numerical pain scale and visual analog scale were collected from enrollees at baseline and every subsequent 15 min. A total of 19 patients completed the study, 10 in the experimental arm and 9 in the control arm. During the study period, effective analgesia (50% decrease from baseline) was achieved in 80% of patients in the experimental arm vs. 33.3% in the control arm. Our pilot clinical trial demonstrated that D3R recruitment can serve as an effective adjuvant to low-dose morphine for control of renal colic pain and potentially other acute pain conditions. ClinicalTrials.gov, identifier, (NCT04160520).

Evaluation of Leiomyoma: A Clinicopathological Study in a Tertiary Care Center in Kathmandu

Uterine leiomyoma is one of the common gynecological benign tumors. It is usually observed in female of reproductive age group and often presented with symptoms like abdominal pain, dysmenorrhea and fertility disorders. Hysterectomy and myomectomy are the procedure for management of uterine leiomyoma. The prime objective of our study was to evaluate the demographic distribution and clinicopathological changes in hysterectomy and myomectomy specimens with leiomyomas. A descriptive hospital based cross-sectional study was conducted in the Department of Pathology, Nepal Medical College Teaching Hospital (NMCTH), Nepal from May 2023 to October 2023. A total of 57 uterine leiomyoma samples received in the department of Pathology for histopathological examination were included in the study. Ethical approval for the study was obtained from Institutional Review Committee of NMCTH and informed consent was taken from each patient. The tissue biopsies were routinely processed and stained with Hematoxylin and Eosin (H and E). The observed findings were managed in MS Excel sheet and later analyzed using SPSS 17. The most common age group diagnosed with uterine leiomyoma was 41 to 50 years (64.9%). The leiomyomas were highly prevalent in women from Janajati community (47.4%). Pelvic pain, menorrhagia and bleeding disorders were the most frequent clinical manifestations. Intramural was the commonest site (77.2%) and the hyalinization was the most usual secondary changes (19.2%) found. The correlation between age distribution and site of leiomyoma, age distribution and secondary changes and site of leiomyoma and secondary changes were statistically not significant. However, detailed histopathological examination gives many information related to leiomyoma and it is necessary for the effective management.

Lidocaine-Loaded Iontophoresis-Driven Fiber-Based Microneedle Patch for Controllable and Long-Lasting Transdermal Local Analgesia

AbstractThe acute pain induced by clinical procedures, such as venipuncture, dental operations, and dermatological treatments, as well as postoperative pain, drives the advancement of anesthetic techniques aimed at alleviating discomfort. This situation underscores the ongoing significance of effective pain management strategies within the field of anesthesia. This paper presents an integrated iontophoresis (ITP)-driven fiber-based microneedle patch (IFMP) regulated by a smartphone for controllable, long-lasting lidocaine transdermal delivery. The IFMP integrates pure cotton fiber canvas-based dissolving microneedles (MNs) with ITP into a patch, with the MNs tips and gel layers significantly increasing the drug-loading capacity, achieving a one-step drug administration strategy of “dissolution, diffusion, and ITP.” Lidocaine is released via the microchannels of MNs by passive diffusion. Additionally, an electric current initiates active ITP for lidocaine delivery, creating synergy. User-requirement-based drug release by precisely modulating electrical signals in rat pain models is described herein. A smartphone application enables precise dosage control. It offers three different delivery modes: single-dose, pulse delivery, and sustained-release, ensuring rapid onset, and long-lasting pain relief. This versatility makes the system suitable for various pain conditions. The IFMP represents a promising system for patient-controlled local analgesia treatment, enabling active and long-term local self-controlled pain management in a safe and regulated manner. Graphical Abstract The iontophoresis-driven fiber-based microneedle patch combines fiber-based dissolving microneedles with iontophoresis, facilitating controlled lidocaine release through diffusion and electrical activation for enhanced effect. Precise modulation of electrical signals allows user-requirement-based drug release in rat pain models. A smart application supports precise dosing in single-dose, pulse, or sustained-release modes, ensuring efficient and prolonged pain management.

A Statewide Examination of Medical Cannabis Purchasing Patterns in Arkansas Over the Three Years Immediately Following Legalization.

Introduction: The use of medical cannabis (MC) to treat a host of conditions has expanded considerably in the United States; however, precise quantitative assessments of purchasing characteristics are unknown. This study sought to characterize the trends in MC purchases, US dollars spent, and type and amount purchased by demographic and clinical characteristics. Materials and Methods: This descriptive exploratory association study examined statewide MC registry data in Arkansas linked at the person level with statewide transaction data documenting each MC purchase. MC transaction data (May 11, 2019-August 31, 2022) were assessed to identify persons who could be linked to the registry data and made at least one purchase. Individual demographic characteristics and MC qualifying conditions (QCs) were ascertained. Product types were classified into plant cannabis, cannabis extract for inhalation (vape), edibles, and others. The average daily total delta-9-tetrahydrocannabinol (THC) purchased was calculated based on the concentration and quantity purchased. Purchasing characteristics are described and demographic and clinical factors associated with THC purchased per day and dollars spent per year were estimated by ordinary least square regression and general linear models with a gamma distribution. Results: On average, 89,057 MC purchasers spent $3343 (interquartile range [IQR], $907-$4802), had 33.34 (IQR, 8.32-46.03) transaction days per year, and purchased 162.32 mg (IQR, 30.51-237.69) of THC per day. Most persons predominantly purchased plant cannabis (68.27%), followed by edibles (14.92%) and vape (11.96%). Individuals younger than 18 years of age (β=-78.23; 95% confidence interval [CI], -116.599 to -39.863), persons 70 and older (β = -122.30; 95% CI, -128.18 to -116.422), and women (β=-33.70; 95% CI, -35.95 to -31.446) purchased less THC per day than their counterparts after multivariate adjustment. The most common QCs were pain and post-traumatic stress disorder (PTSD), and compared to those with cancer, persons with pain (β = 26.30; 95% CI, 18.636-33.96) and PTSD (β = 38.34; 95% CI, 30.467-46.222) purchased more THC per day. Conclusion: The average THC purchased per person per day exceeds typically recommended daily doses for therapeutic uses, and further research is warranted to assess the safety and benefits of MC across these conditions.

RNA Interference Unleashed: Current Perspective of Small Interfering RNA (siRNA) Therapeutics in the Treatment of Neuropathic Pain.

Neuropathic pain (NP) is one of the debilitating pain phenotypes that leads to the progressive degeneration of the central as well as peripheral nervous system. NP is often associated with hyperalgesia, allodynia, paresthesia, tingling, and burning sensations leading to disability, motor dysfunction, and compromised psychological state of the patients. Most of the conventional pharmacological agents are unable to improve the devastating conditions of pain because of their limited efficacy, undesirable side effects, and multifaceted pathophysiology of the diseased condition. A rapid rise in new cases of NP warrants further research for identifying the potential novel therapeutic modalities for treating NP. Recently, small interfering RNA (siRNA) approach has shown therapeutic potential in many disease conditions including NP. Delivery of siRNAs led to potential and selective downregulation of target mRNA and abolished the pain-related behaviors/pathophysiological pain response. The crucial role of siRNA in the treatment of NP by considering all of the pathways associated with NP that could be managed by siRNA therapeutics has been discussed. However, their therapeutic use is limited by several hurdles such as instability in systemic circulation due to their negative charge and membrane impermeability, off-target effects, immunogenicity, and inability to reach the intended site of action. This review also emphasizes several strategies and techniques to overcome these hurdles for translating these therapeutic siRNAs from bench to bedside by opening a new avenue for obtaining a potential therapeutic approach for treating NP.

Fibromyalgia progression and association with other diseases and inheritance with management practices in humans

Fibromyalgia is a widespread pain disorder characterized by chronic, diffuse pain, about 1 to 5% around world. While more prevalent in women and adults, it can also manifest in children and adolescents. The specific pathophysiology of fibromyalgia remains unclear, but it is associated with neuronal over sensitization, reduced conditioned pain modulation, cognitive dysfunction, memory loss, and impaired information processing. It has now been categorized as a somatic symptom disorder. This study aimed to investigate fibromyalgia, focusing on its potential hereditary connections and management practices. A key pathophysiological aspect of fibromyalgia is central sensitization, marked by increased functional connectivity with pre-receptive brain areas, decreased connectivity with antinociceptive areas, and alterations in central nervous system neurotransmitters, also in size and shape of specific brain areas. Fibromyalgia is not directly inherited from parents to offspring, it does exhibit a tendency to cluster within families. The serotonin transporter gene, characterized by single nucleotide polymorphism with "S" (short) allele, is more prevalent in individuals with fibromyalgia and psychological distress. In conclusion, fibromyalgia is a widespread pain disorder with a substantial impact on the central nervous system, resulting in significant disability and an elevated risk of chronic diseases. Early diagnosis and intervention can minimize the impact of fibromyalgia. Physical therapy and non-drug therapies should be customized for each patient. The FDA has approved three drugs including pregabalin, duloxetine, and milnacipran for fibromyalgia treatment.

The Impact of Antidepressants on COVID-19 and Post-Acute COVID-19 Syndrome: A Scoping-Review Update

On May 20, 2024, this systematic scoping review in PUBMED identified 1016 articles related to AD and COVID-19, Long COVID and SARS-COV-2. These included 10 retrospective "large scale" studies (> 20000 chart reviews), 8 prospective clinical trials (plus 4 regarding Long COVID), 11 placebo-controlled randomized (RCT) (plus 2 regarding Long COVID) and 15 meta-analyses. COVID-19: Retrospective studies with cohorts taking AD primarily for psychiatric comorbidities or chronic pain conditions directly prior to SARS-COV-2 infection described that this substance class (most studied: Selective Serotonin Re-Uptake Inhibitors (SSRI) and Selective Serotonin Noradrenaline Re-Uptake Inhibitors (SSNRI)) were associated with (i) significantly fewer SARS-COV-2 infections and (ii) a milder course of COVID-19 ("COVID-19 protection"). Ten of the 11 RCTs found regarding COVID-19 tested fluvoxamine, as this old AD appeared suitable as a prophylactic agent against severe COVID-19, taking into account its in vitro potency against the progression of intracellular sepsis cascades. Therefore, most (12 out of 15) meta-analyses also referred to fluvoxamine. They found (iii) a significant (40-70% reduction) in mortality, intubation and hospitalization rates when fluvoxamine was used as an add-on to standard therapy for mild to moderate COVID-19. When this AD was used in the early stages of the disease, it was more successful than when it was given later in advanced, severe COVID-19 (e.g. severe pneumonia, final sepsis stages). A dose dependency was observed: 2x50 mg fluvoxamine over 15 days was less effective than 2x100 or even 3x100 mg with an adverse event profile still at the placebo level. Direct comparisons with drugs approved for COVID-19 do not yet exist. A first indirect meta-analytical comparison showed an advantage of paxlovid or molnupiravir versus fluvoxamine against the development of severe COVID-19: risk reduction of 95% (I2 = N/A, but only one study) or 78% (I2=0) versus 5+-5% (I2=48). However, an add-on of fluvoxamine was still significantly more efficacious than symptom-oriented standard therapy alone. Long COVID: A common Long COVID phenotype with dominant anxiety and depression symptoms, which responds to AD, relaxation therapy and/or psychotherapy, has now been identified. Casuistics report positive effects of AD on fatigue, cognitive and autonomic dysfunctions. A first large prospective open-label RCT has just shown significantly more favourable courses, less viral load and less pro-inflammatory cytokines in the treatment of mild to moderate COVID-19 with fluvoxamine versus standard treatment, also with regard to the subsequent development of neuropsychiatric and pulmonary Long COVID or fatigue. Overall, there is promising evidence of a preventive effect of AD (especially fluvoxamine) against progression to severe COVID-19 and against the development of Long COVID. It is likely, that the entire AD substance class could be effective here. This assumption is based on the results of retrospective large scale studies, but awaits verification by better controlled studies. The potential effectiveness/efficacy (currently low and moderate confidence of the evidence for the entire substance class and specifically fluvoxamine, respectively) of fluvoxamine as an add-on against COVID-19 and possibly also directly against Long COVID could stimulate similar projects in other infectious diseases that also have the potential to pose a lasting threat to the health of those affected. We consider the evidence to date to be sufficient to be able to emphasize a possible positive effect of these substances in the psychoeducation of patients with COVID-19 or Long COVID who are already receiving AD for other conditions - especially also against the symptoms associated with the viral disease or its consequences. In regions where neither vaccines nor antiviral agents currently approved for the prevention or treatment of COVID-19 are available, AD and in particular fluvoxamine would be a cost-effective alternative to protect against a severe course, even if this AD appears to have a smaller effect against COVID-19 than the currently approved antiviral agents, but with presumably better tolerability. A direct comparative clinical trial with approved antiviral agents is still pending and should be positive to further open the door for a guideline-based recommendation of fluvoxamine (or perhaps even AD) for COVID-19 or its aftermath.

Cannabinoids as a Natural Alternative for the Management of Neuropathic Pain: A Systematic Review of Randomized Placebo-Controlled Trials.

Dysfunction or damage to the nervous system may develop into and result in a chronic pain condition known as neuropathic pain. Neuropathic painis defined as the structural and functional alteration of the somatosensory component of the nervous system. The treatment of neuropathic pain is a complex endeavor, which often requires specialist care and intensive drug therapy. Recently, cannabinoids have emerged as an alternative and natural option for the treatment of chronic pain, with tetrahydrocannabinol (THC) and cannabidiol (CBD) being the most extensively studied neuroactive components. The therapeutic potential of cannabis remains largely underexplored, primarily due to its social stigma and the restrictions that are in place on its cultivation. The primary aim of this systematic review was to explore the therapeutic value of cannabinoids in the management of chronic pain and thus achieve an improved quality of life for those patients. A systematic review of the literature published over the last two decades was performed usingthe following databases: PubMed, Cochrane Central Register of Controlled Trials (CENTRAL), Turning research into practice (Trip), and Google Scholar. Studies that were completed and published between January 01, 2000 and August 31, 2024, in English language, were extracted and appraised. A combination of keywords and Boolean operators Cannabis OR Chronic Pain OR End of life OR Pain Management AND Drug therapywas employed for data extraction. The Cochrane risk-of-bias tool for randomized trials (RoB 2) was used for risk-of-bias assessment. The initial search resulted in 125282 articles; 86,781 of the articles were identified as duplicates and were removed from the primary analysis, and 38,501 abstracts were thus screened. Abstracts, case studies, reports, editorials, viewpoints, cross-sectional studies, cohort studies, case-control studies, case series, and letters to the editor/correspondence manuscripts (n =38,492) were furthermore excluded. Nine full-text articles were critically assessed and tested against the inclusion and exclusion criteria, and a further four articles were excluded with a total of five placebo-controlled randomized control studies being ultimately included in the final systematic review. Compared to placebo, cannabinoids provided significant relief from chronic pain(33% vs 15%) as measured by the visual analog scale. The transdermal application of CBD led to a more pronounced reduction in sharp pain, according to the neuropathic pain scale. Minimal to no side effects were recorded, further highlighting the potential benefits of cannabinoids.

Increased behavioural inhibition and decreased behavioural activation in whiplash‐associated disorders: Associations with health outcomes

AbstractBackgroundMotivation can be investigated with the BIS (Behavioural Inhibition System)/BAS (Behavioural Activation System) scale. BAS regulates the motivation to approach goal‐oriented outcomes, particularly rewarding stimuli and situations, while BIS regulates escape and avoidance of unpleasant outcomes. Chronic whiplash‐associated disorders (WAD) is a heterogenous pain condition with known alterations in motivated behaviour. The study aimed (1) to investigate the relationship between BIS/BAS, and pain and disability with quality of life and psychological measures in chronic WAD; (2) to determine if BIS and/or BAS mediate the relationships between pain, disability, and psychological symptoms and quality of life.Methods254 chronic WAD patients participated in the study. Outcome measures were assessed using self‐report questionnaires. BIS/BAS scores were compared to published normative data. Differences in health outcomes for participants within/outside normative 95% confidence intervals were compared and correlations with health measures tested. Mediation models explored bi‐directional associations between stress, anxiety, depression, post‐traumatic stress severity, pain catastrophizing, and quality of life with pain and disability.ResultsParticipants who exceeded normative 95% confidence intervals for BIS demonstrated higher scores for pain interference, disability and all mental health measures. No mediating role of BIS/BAS on the relation between pain and disability with quality of life and health outcomes could be confirmed.ConclusionsA comparatively large proportion of the sample exceeded the 95% confidence interval for BIS and BAS scores with associations of these scores with health outcomes, but altered motivation to approach goal‐oriented outcomes appears to play only a subordinate role in chronic WAD.Significance statementIn line with current theories, we found a large proportion (30%–50%) of patients with whiplash‐associated disorders (WAD) showing signs of altered function in the Behavioural Inhibition System (BIS) and Behavioural Activation System (BAS) suggesting altered reward processing and motivation in these patients. While such altered functions showed associations with pain interference, disability and all mental health measures, reward processing could no be demonstrated as a pathogenetically relevant factor in chronic WAD patients.

Safety analysis of fluoroquinolone drugs in elderly patients over 65 based on FAERS

ABSTRACT Objective This study investigates adverse drug event (ADE) reports from the FAERS related to FQs drugs in patients aged 65 and older. The findings aim to guide the rational clinical use of these drugs in elderly patients. Methods We employed Reporting Odds Ratio (ROR) and Proportional Reporting Ratio (PRR) methods to analyze ADE reports for the representative FQ drugs from Q1 2015 to Q4 2023, covering 36 quarters. Results The analysis identified 6883 ADE cases for ciprofloxacin, 5866 for levofloxacin, 1498 for moxifloxacin, and 317 for ofloxacin. Moxifloxacin showed higher incidences of Cardiac disorders and Psychiatric disorders ADEs (4.01%, 23.11%). Ciprofloxacin and levofloxacin showed higher ADE rates in musculoskeletal and connective tissue diseases (20.18% and 26.97%) compared to moxifloxacin (3.62%) and ofloxacin (9.25%). Additionally, moxifloxacin and ofloxacin showed higher ADE rates for eye disorders (10.61% and 15.03%). Conclusion Different FQs exhibit varying ADE profiles across cardiovascular, vascular and lymphatic, renal and urinary, psychiatric, musculoskeletal and connective tissue, and ocular systems. Patients with underlying systemic diseases should avoid FQs with higher ADE risks for their conditions. Personalized medication plans for elderly patients should also be strengthened.

A novel Project ECHO curriculum on older adult pain management and opioid use disorder for outpatient clinicians

ABSTRACT Chronic pain, opioid use, and opioid use disorder (OUD) are increasingly common in older adults. Outpatient clinician education may improve outcomes. Our aim was to create and evaluate a novel curriculum for outpatient clinicians on older adult pain management, opioid prescribing, and OUD leveraging Project ECHO®, a model for delivering subspecialized medical knowledge to community outpatient clinicians via videoconferencing. The series is comprised of 8-hour-long sessions, each with an expert-led interactive lectures followed by participant-led case discussions. Topics include pain assessment & treatment, considerations in older adults (e.g. cognition, caregiver support), shared decision-making, behavioral health, and OUD diagnosis and treatment. Sixty-nine clinicians attended the series and completed the pre-series survey; 78% (n = 54) completed the post-series survey. Clinicians reported a significant increase in self-efficacy in 14/14 queried competencies and greater frequency of performing 7/10 practice behaviors regarding older adult pain management, opioid prescribing, and OUD management. The most liked curricular components were opportunities to learn with subspecialists and discussions with other community clinicians. Qualitative analysis suggests that clinicians may benefit from education on specific geriatrics-related content areas. This novel curriculum has potential to improve management of older adult chronic pain, opioid prescribing, and OUD in a virtual and scalable format.

Targeting IGF1/IGF1r signaling relieve pain and autophagic dysfunction in NTG-induced chronic migraine model of mice

BackgroundChronic migraine is a severe and common neurological disorder, yet its precise physiological mechanisms remain unclear. The IGF1/IGF1r signaling pathway plays a crucial role in pain modulation. Studies have shown that IGF1, by binding to its receptor IGF1r, activates a series of downstream signaling cascades involved in neuronal survival, proliferation, autophagy and functional regulation. The activation of these pathways can influence nociceptive transmission. Furthermore, alterations in IGF1/IGF1r signaling are closely associated with the development of various chronic pain conditions. Therefore, understanding the specific mechanisms by which this pathway contributes to pain is of significant importance for the development of novel pain treatment strategies. In this study, we investigated the role of IGF1/IGF1r and its potential mechanisms in a mouse model of chronic migraine.MethodsChronic migraine was induced in mice by repeated intraperitoneal injections of nitroglycerin. Mechanical and thermal hypersensitivity responses were assessed using Von Frey filaments and radiant heat, respectively. To determine the role of IGF1/IGF1r in chronic migraine (CM), we examined the effects of the IGF1 receptor antagonist ppp (Picropodophyllin) on pain behaviors and the expression of calcitonin gene-related peptide (CGRP) and c-Fos.ResultIn the nitroglycerin-induced chronic migraine model in mice, neuronal secretion of IGF1 is elevated within the trigeminal nucleus caudalis (TNC). Increased phosphorylation of the IGF1 receptor occurs, predominantly co-localizing with neurons. Treatment with ppp alleviated basal mechanical hypersensitivity and acute mechanical allodynia. Furthermore, ppp ameliorated autophagic dysfunction and reduced the expression of CGRP and c-Fos.ConclusionOur findings demonstrate that in the chronic migraine (CM) model in mice, there is a significant increase in IGF1 expression in the TNC region. This upregulation of IGF1 leads to enhanced phosphorylation of IGF1 receptors on neurons. Targeting and inhibiting this signaling pathway may offer potential preventive strategies for mitigating the progression of chronic migraine.

Low Magnetic Field Exposure Alters Prostate Cancer Cell Properties.

Prostate cancer is the second most common neoplasia and fifth-leading cause of cancer death in men worldwide. Electromagnetic and magnetic fields have been classified as possible human carcinogens, but current understanding of molecular and cellular pathways involved is very limited. Effects due to extremely low magnetic/hypomagnetic fields (LMF) are furthermore poorly understood. Extracellular vesicles (EVs) are crucial mediators of cellular communication with multifaceted roles in cancer progression, including via transport and uptake of various protein and microRNA (miRNA) EV-cargoes. miRNAs regulate gene expression and are implicated in cancer-related processes such as proliferation, metastasis, and chemoresistance. This study investigated the effects of LMF exposure (20 nT) by magnetic shielding on the prostate cancer cell line PC3 compared to the prostate epithelial cell line PNT2 under short-term (4 h) conditions. We examined EV profiles following a 4 h LMF exposure alongside associated functional enrichment KEGG and GO pathways for the EV proteomes. The 4 h LMF exposure significantly reduced cellular EV release and modified PC3 EV cargoes to a more inflammatory and metastatic profile, with 16 Disease Pathways and 95 Human Phenotypes associated specifically with the LMF-treated PC3 EV proteomes. These included cancerous, metabolic, blood, skin, cardiac and skeletal Disease Pathways, as well as pain and developmental disorders. In the normal PNT2 cells, less EV protein cargo was observed following LMF exposure compared with cells not exposed to LMF, and fewer associated functional enrichment pathways were identified. This pointed to some differences in various cellular functions, ageing, defence responses, oxidative stress, and disease phenotypes, including respiratory, digestive, immune, and developmental pathways. Furthermore, we analysed alterations in matrix metalloproteinases (MMPs) and miRNAs linked to metastasis, as this is crucial in cancer aggressiveness. The 4 h LMF exposure caused a significant increase in MMP2 and MMP9, as well as in onco-miRs miR-155, miR-210, miR-21, but a significant reduction in tumour-suppressor miRs (miR-200c and miR-126) in the metastatic PC3 cells, compared with normal PNT2 cells. In addition, 4 h LMF exposure significantly induced cellular invasion of PC3 cells. Overall, our findings suggest that changes in magnetic field exposures modulate EV-mediated and miR-regulatory processes in PCa metastasis, providing a basis for exploring novel therapeutic strategies.

A nationwide analysis of 350 million patient encounters reveals a high volume of mental-health conditions in primary care

How many primary-care encounters are devoted to mental-health conditions compared with physical-health conditions? Here we analyzed Norway’s nationwide administrative primary-care records, extracting all doctor–patient encounters occurring during 14 years (2006–2019) for the population aged 0–100 years. Encounters were recorded according to the International Classification of Primary Care. We compared the volume of mental-health encounters against volumes for conditions in multiple different body systems. A total of 4,875,722 patients generated 354,516,291 encounters. One in 9 encounters (11.7%) involved a mental-health condition. Only musculoskeletal conditions accounted for a greater share of primary-care physicians’ attention. The volume of mental-health encounters in primary care equaled encounters for infections, cardiovascular and respiratory conditions and exceeded encounters for pain, injuries, metabolic, digestive, skin, urological, reproductive and sensory conditions. Primary-care physicians frequently treat complex mental-health conditions in patients of every age. These physicians may have a more important role in preventing the escalation of mental-health problems than heretofore appreciated.

Purine nucleoside phosphorylase as a target for the treatment of interstitial cystitis/bladder pain syndrome with and without Hunner lesions

Chronic visceral pain disorders, such as interstitial cystitis/bladder pain syndrome (IC/BPS), are difficult to treat, and therapies are limited in number and efficacy. Emerging evidence suggests that alterations in the enzyme purine nucleoside phosphorylase (PNPase) may participate in oxidative injury and cellular damage. PNPase is important for the metabolism of ‘tissue-protective’ purine metabolites to ‘tissue-damaging’ purines that generate free radicals. The aim of this study is to test whether patients living with IC/BPS without or with Hunner lesions and irrespective of any therapies exhibit purine dysregulation with higher levels of tissue-damaging purine metabolites as measured by liquid chromatography-tandem mass spectrometry. Our results demonstrate that levels of urotoxic purine metabolites (hypoxanthine and xanthine) in IC/BPS patients with and without Hunner lesions are elevated compared to healthy controls. These findings suggest there may be pathophysiologic commonalities between patient subtypes. Furthermore, the accumulation of uroprotective purines and depletion of urodamaging purines by PNPase inhibition may be therapeutically effective in both groups of patients.

Development of Machine Learning Algorithms Using EEG Data to Detect the Presence of Chronic Pain.

Chronic pain impacts more than one in five adults in the United States (US) and the costs associated with the condition amount to hundreds of billions of dollars annually. Despite the tremendous impact of chronic pain in the US and worldwide, the standard of care for diagnosis depends on subjective self-reporting of pain state, with no effective objective assessment procedure available. This study investigated the application of signal processing and machine learning to electroencephalography (EEG) data for the development of classification algorithms capable of differentiating subjects in pain from pain free subjects. In this study, nineteen (19) channels of EEG data were obtained from subjects in an eyes closed resting state, and ultimately data from 186 participants were used for algorithm development, including 35 healthy controls and 151 chronic pain patients. Signal processing was applied to identify noise free segments of EEG data and 6375 quantitative EEG (qEEG) measures were calculated for each subject. Various machine learning methodologies were applied to the data, with Elastic Net chosen as the optimal methodology. The final classifier developed using Elastic Net contained 34 qEEG features with non-zero weights. The classifier was able to differentiate pain versus no pain subjects with an accuracy of 79.6%, sensitivity of 82.2%, and specificity of 66.7%. The features used in the classifier were evaluated and found to align well with contemporary literature regarding changes in neurological characteristics associated with chronic pain.

The conotoxin Contulakin-G reverses hypersensitivity observed in rodent models of cancer-induced bone pain without inducing tolerance or motor disturbance

Abstract As the incidence and survival rates of patients with cancer continues to grow, an increasing number of people are living with comorbidities, which often manifests as cancer-induced bone pain (CIBP). The majority of patients with CIBP report poor pain control from currently available analgesics. A conotoxin, Contulakin-G (CGX), has been demonstrated to be an antinociceptive agent in postsurgical and neuropathic pain states via a neurotensin receptor 2 (NTSR2)-mediated pathway. However, the efficacy and side effect profile of CGX have never been assessed in CIBP. Here, we evaluated CGX's antinociceptive potential in a rodent model of CIBP. We hypothesized that CGX engages the NTSR2 pathway, providing pain relief with minimal tolerance and motor side effects. Our results demonstrated that CGX intrathecal injection in mice with CIBP attenuated both spontaneous pain behaviors and evoked mechanical hypersensitivity, regardless of their sex. Furthermore, the antinociceptive effect of CGX was dependent upon expression of NTSR2 and the R-type voltage-gated calcium channel (Cav2.3); gene editing of these targets abolished CGX antinociception without affecting morphine antinociception. Examination of the side effect profile of CGX demonstrated that, unlike morphine, chronic intrathecal infusion maintained antinociception with reduced tolerance in rats with CIBP. Moreover, at antinociceptive doses, CGX had no impact on motor behavior in rodents with CIBP. Finally, RNAScope and immunoblotting analysis revealed expression of NTSR2 in both dorsal and ventral horns, while Cav2.3 was minimally expressed in the ventral horn, possibly explaining the sensory selectivity of CGX. Together, these findings support advancing CGX as a potential therapeutic for cancer pain.

Exploring Sleep Architecture in Polish Patients with Multiple Sclerosis: A Polysomnography Study.

Sleep disturbances are a prevalent phenomenon in patients with multiple sclerosis (PwMS). The present study employs polysomnography (PSG) to quantify sleep efficiency and architecture in PwMS, aiming to elucidate the relationships between PSG parameters and factors including gender, disability level, brain lesion location, and subjective measures of insomnia, excessive daytime sleepiness (EDS), fatigue, pain, and mood disorders. The study cohort comprised 51 adult PwMS, of whom 31 underwent overnight PSG. The demographic and clinical characteristics, including age, gender, and Expanded Disability Status Scale (EDSS), were collated. The Athens Insomnia Scale, the Epworth Sleepiness Scale, the Fatigue Severity Scale, the Modified Fatigue Impact Scale (MFIS), the Numerical Pain Rating Scale, and the Hospital Anxiety and Depression Scale were employed for the assessment of insomnia, EDS, fatigue, pain, and mood disorders. The brain and spinal cord magnetic resonance imaging (MRI) were evaluated. A reduced sleep efficiency was observed among 30 PwMS (aged 38.9 ± 12.9), with a mean of 80 ± 12%, especially in those with brainstem demyelinating lesions. In those PwMS aberrant sleep onset latency (SOL) and wake after sleep onset were also noted (p < 0.05). The prevalence of sleep fragmentation, as measured by the total arousal index, was greater in male PwMS than in female (p < 0.05). Higher disability according to the EDSS correlated with longer SOL (ρ = 0.48, p < 0.05), and reduced N2 sleep stage correlated with cognitive fatigue according to MFIS (ρ = -0.46, p < 0.05). Age, disease duration, insomnia, EDS, physical fatigue, and mood disorders did not impact PSG parameters. The study demonstrated the disruption of sleep architecture in PwMS, and highlighted the importance of a comprehensive PSG assessment of sleep disturbances in this population.