Pathophysiology Of Pain Research Articles

Navigating through 65years of insights: lessons learned on functional abdominal pain in children.

In 1958, Apley and Naish authored a groundbreaking paper in Archives of Disease in Childhood, elucidating the epidemiology and risk factors of recurrent abdominal pain in children-a subject that had confounded clinicians of their time. Surprisingly, even after 65years, there are several unanswered questions regarding the etiology, pathophysiology, and management of pediatric abdominal pain. Contrary to the prevailing notion that children naturally outgrow functional abdominal pain, compelling evidence suggests it's possible these children develop a number of clinically significant psychological issues that could profoundly impact their quality of life and, consequently, future health and educational outcomes. In this light, we aimed to comprehensively review the current literature to update the knowledge of practicing clinicians on functional abdominal pain, summarizing the evidence from the last 65years.Conclusion: The enduring unanswered questions surrounding childhood abdominal pain continue to challenge clinicians, resulting in unnecessary investigations, thereby contributing to substantial healthcare expenditures. It is also evident that children with long-standing symptoms would progress to adulthood with the potential to develop irritable bowel syndrome and many psychological disturbances. Several key interventions using pharmacological agents, such as amitriptyline, showed that someof these drugs are no more effective than the placebo in clinical trials. Several research during the recent past suggest that psychological interventions such as gut-directed hypnotherapy alleviate symptoms and ensure better prognosis in the long run. Therefore, clinicians and researchers must join hands to explore the pathophysiological mechanisms underpinning functional abdominal pain and novel therapeutic strategies to ensure the well-being of these children. What is Known: • Functional abdominal pain disorders are common among children, with a worldwide prevalence of 13.5% of children suffering from at least one of these disorders • These disorders contribute to a significant reduction in the quality of life of affected children and their families and lead to an array of psychological problems What is New: • The biological basis of functional abdominal pain is becoming more explicit, including complex interactions between altered microbiome, deranged motility, and psychological dysfunction with gut-brain interactions • Novel approaches giving minimal emphasis on pharmacological interventions and exploring psychological interventions are showing promising results.

Radiofrequency ablation of the hip: review.

Radiofrequency ablation (RFA) of the articular branches of the femoral and obturator nerves (the innervation of the anterior capsule of the hip) is an emerging treatment for chronic hip pain. Body mass index (BMI) greater than 30, older age, large acetabular/femoral head bone marrow lesions, chronic widespread pain, depression, and female sex increase the risk of developing hip pain. Chronic hip pain is a common condition with a wide range of etiologies, including hip osteoarthritis (OA), labral tears, osteonecrosis, post total hip arthroplasty (THA), post-operative dislocation/fracture, and cancer. The most common and well studied is hip OA. Management of chronic hip pain includes conservative measures (pharmacotherapy and exercise), surgery, and percutaneous procedures such as RFA. While surgery is effective, those whose medical comorbidities preclude surgery, those who do not wish to have surgery, and those whose pain persists after surgery (11-36% of patients) could benefit from RFA. Because of the aforementioned circumstances, hip RFA is often a palliative intervention. Hip RFA is an effective treatment, one recent retrospective study of 138 patients found 69% had >50% pain relief at 6 months. The most frequent adverse event reported for hip RFA is pain from needle placement. No serious bleeding events have been reported, despite the valid concern of the procedure's proximity to vasculature. This descriptive review details the pathophysiology of hip pain, its etiologies, its clinical presentation, conservative management, the anatomy/technique of hip RFA, hip RFA efficacy, and RFA adverse events.

A novel animal model of symptomatic neuroma for assessing neuropathic pain

IntroductionFollowing amputation, peripheral nerves lack distal targets for regeneration, often resulting in symptomatic neuromas and debilitating neuropathic pain. Animal models can establish a practical method for symptomatic neuroma formation for better understanding of neuropathic pain pathophysiology through behavioral and histological assessments. We created a clinically translatable animal model of symptomatic neuroma to mimic neuropathic pain in patients and assess sexual differences in pain behaviors. MethodsTwenty-two male and female rats were randomly assigned to one of two experimental groups: (1) neuroma surgery, or (2) sham surgery. For the neuroma experimental group, the tibial nerve was transected in the thigh, and the proximal segment was placed under the skin for mechanical testing at the site of neuroma. For the sham surgery, rats underwent tibial nerve isolation without transection. Behavioral testing consisted of neuroma-site pain, mechanical allodynia, cold allodynia, and thermal hyperalgesia at baseline, and then weekly over 8 weeks. ResultsMale and female neuroma rats demonstrated significantly higher neuroma-site pain response compared to sham groups starting at weeks 3 and 4, indicating symptomatic neuroma formation. Weekly assessment of mechanical and cold allodynia among neuroma groups showed a significant difference in pain behavior compared to sham groups (p < 0.001). Overall, males and females did not display significant differences in their pain responses. Histology revealed a characteristic neuroma bulb at week 8, including disorganized axons, fibrotic tissue, Schwann cell displacement, and immune cell infiltration. ConclusionThis novel animal model is a useful tool to investigate underlying mechanisms of neuroma formation and neuropathic pain.

Immune Competence and Pain: A Narrative Review.

This review aims to summarize current knowledge on the pathophysiology of pain and the role of neuro-immune crosstalk in the development of acute and chronic pain (CP). Specifically, the review focuses on the role of immune cells involved in the innate and acquired immune response, emphasizing their bidirectional interactions with the nervous systems and discussing the implications of this crosstalk on acute and CP management. In the last two decades, multiple studies have uncovered the important role of the immune system in initiating, maintaining, and resolving pain stimuli. Furthermore, researchers discovered that the immune system interacts tightly with the nervous system, creating a bidirectional crosstalk in which immune cells influence the response of peripheral and central nerve fibers while neurotransmitters and neuropeptides released by nociceptors directly and indirectly modulate the immune response. The neuro-immune crosstalk in acute and CP is a complex and not fully understood process that comprise the interactions of multiple diverse molecules, bidirectional interferences, and numerous redundant processes. Despite the complexity, important steps have been taken in recent years toward explaining the specific roles of each immune cell type and molecule in the initiation, maintenance and resolution of pain. These findings may set the basis for innovative therapeutic options that target the immune system, overcoming the limitations of current treatments in providing pain relief and the disadvantages associated with opioid therapy.

Mouse models of non-dystrophic and dystrophic myotonia exhibit nociplastic pain-like behaviors.

Pain is a prominent and debilitating symptom in myotonic disorders, yet its physiological mechanisms remain poorly understood. This study assessed preclinical pain-like behavior in murine models of pharmacologically induced myotonia and myotonic dystrophy type 1 (DM1). In both myotonia congenita and DM1, impairment of the CLCN1 gene, which encodes skeletal muscle voltage-gated CLC-1 chloride channels, reduces chloride ion conductance in skeletal muscle cells, leading to prolonged muscle excitability and delayed relaxation after contraction. We used the CLC-1 antagonist anthracene-9-carboxylic acid (9-AC) at intraperitoneal doses of 30 or 60 mg/kg and HSA LR20b DM1 mice to model CLC-1-induced myotonia. Our experimental approach included in vivo pain behavioral testing, ex vivo calcium imaging, and whole-cell current-clamp electrophysiology in mouse dorsal root ganglion (DRG) neurons. A single injection of 9-AC induced myotonia in mice, which persisted for several hours and resulted in long-lasting allodynic pain-like behavior. Similarly, HSA LR20b mice exhibited both allodynia and hyperalgesia. Despite these pain-like behaviors, DRG neurons did not show signs of hyperexcitability in either myotonic model. These findings suggest that myotonia induces nociplastic pain-like behavior in preclinical rodents, likely through central sensitization mechanisms rather than peripheral sensitization. This study provides insights into the pathophysiology of pain in myotonic disorders and highlights the potential of using myotonic mouse models to explore pain mechanisms and assess novel analgesics. Future research should focus on the central mechanisms involved in myotonia-induced pain and develop targeted therapies to alleviate this significant clinical burden.

Protocol for the development of a tool to map systemic sclerosis pain sources, patterns, and management experiences: a Scleroderma Patient-centered Intervention Network patient-researcher partnership

IntroductionSystemic sclerosis (SSc) is a rare, complex autoimmune rheumatic disease with multiple factors that contribute to pain. People with SSc emphasize the effect pain has on their quality of life, but no studies have systematically examined the frequency and relative importance of different SSc pain sources, patterns of pain from different sources, and pain management experiences. Our objectives are to (1) develop a tool, jointly with researchers, health care providers, and patients, to map sources of pain in SSc, determine patterns of pain from different sources, and understand pain management experiences; and (2) administer the final tool version to participants in the large multinational Scleroderma Patient-centered Intervention Network (SPIN) Cohort.MethodsFirst, we will use validated pain assessment tools as templates to develop an initial version of our pain assessment tool, and we will obtain input from patient advisors to adapt it for SSc. The tool will include questions on pain sources, pain patterns, pain intensity, pain management techniques, and barriers to pain management in SSc. Second, we will conduct nominal group technique sessions with people living with SSc and health care providers who care for people with SSc to further refine the tool. Third, we will conduct individual usability testing sessions with SPIN Cohort participants. Once the tool has been finalized, we will administer it to individuals in the multinational SPIN Cohort, which currently includes over 1,300 active participants from 54 sites in 7 countries. We will perform unsupervised clustering using the KAy-Means for MIxed LArge data (KAMILA) method to identify participant subgroups with similar profiles of pain sources (present or absent) and to evaluate predictors of subgroup membership. We will use latent profile analysis to identify subgroups of participants with similar profiles based on pain intensity scores for each pain source and evaluate predictors.DiscussionOnce completed, our pain assessment tool will allow our team and other researchers to map sources of pain in SSc and to understand pain management experiences of people living with SSc. This knowledge will provide avenues for studies on the pathophysiology of pain in SSc and studies of interventions to improve pain management.

Pain in Parkinson's disease: a neuroanatomy-based approach.

Parkinson's disease is a progressive neurodegenerative disorder characterized by the deposition of misfolded alpha-synuclein in different regions of the central and peripheral nervous system. Motor impairment represents the signature clinical expression of Parkinson's disease. Nevertheless, non-motor symptoms are invariably present at different stages of the disease and constitute an important therapeutic challenge with a high impact for the patients' quality of life. Among non-motor symptoms, pain is frequently experienced by patients, being present in a range of 24-85% of Parkinson's disease population. Moreover, in more than 5% of patients, pain represents the first clinical manifestation, preceding by decades the exordium of motor symptoms. Pain implies a complex biopsychosocial experience with a downstream complex anatomical network involved in pain perception, modulation, and processing. Interestingly, all the anatomical areas involved in pain network can be affected by a-synuclein pathology, suggesting that pathophysiology of pain in Parkinson's disease encompasses a 'pain spectrum', involving different anatomical and neurochemical substrates. Here the various anatomical sites recruited in pain perception, modulation and processing are discussed, highlighting the consequences of their possible degeneration in course of Parkinson's disease. Starting from peripheral small fibres neuropathy and pathological alterations at the level of the posterior laminae of the spinal cord, we then describe the multifaceted role of noradrenaline and dopamine loss in driving dysregulated pain perception. Finally, we focus on the possible role of the intertwined circuits between amygdala, nucleus accumbens and habenula in determining the psycho-emotional, autonomic and cognitive experience of pain in Parkinson's disease. This narrative review provides the first anatomically driven comprehension of pain in Parkinson's disease, aiming at fostering new insights for personalized clinical diagnosis and therapeutic interventions.

Development and validation of a mouse model to investigate post surgical pain after laparotomy

BackgroundPostoperative pain following abdominal surgery is a significant obstacle to patient recovery, often necessitating high analgesic doses associated with adverse effects like cognitive impairment and cardiorespiratory depression. Reliable animal models are crucial for understanding the pathophysiology of post surgical pain and developing more effective pain-relieving strategies. MethodsWe developed a mouse model to replicate peritoneal trauma induced by abdominal surgery. 30 C57BL/6 mice underwent laparotomy, with half undergoing standardised peritoneal abrasion and the rest serving as controls. Mouse recovery was assessed using two validated scoring systems of surgical recovery: Post surgery Severity Assessment (PSSA) and Mouse Grimace Score (MGS). Blood samples were taken for cytokine analysis. Adhesions were evaluated on day 6, and peritoneal tissue was examined for healing markers. ResultsAfter laparotomy, all mice exhibited expected pain profiles. Mice with peritoneal abrasion had significantly higher PSSA (7.2 ± 1.2 vs 4.68 ± 0.82, p ≤ 0.001) and MGS scores (3.62 ± 0.74 vs 0.82 ± 0.40, p ≤ 0.05) with slower recovery. Serum inflammatory cytokine levels were significantly elevated in the abraded group, and adhesion formation was higher in this group. Immunohistochemical analysis showed significantly increased expression of α-SMA, CD31, CD68, and F4/80 in peritoneal tissue in the abraded group. DiscussionA mouse model involving laparotomy and standardised peritoneal abrasion replicates the expected pathophysiological changes following abdominal surgery. It will be a useful model for better understanding the mechanisms of post surgical pain and developing improved pain-relief strategies. It also has utility for the study of intra-abdominal adhesion formation. Key messageTo understand the intricate relationship between peritoneal trauma-induced pain, cytokine response, and post-operative adhesion formation in mouse models for advancing therapeutic interventions and enhancing post-operative recovery outcomes.

Regulating neuronal excitability: The role of S-palmitoylation in NaV1.7 activity and voltage sensitivity.

S-palmitoylation, a reversible lipid post-translational modification, regulates the functions of numerous proteins. Voltage-gated sodium channels (NaVs), pivotal in action potential generation and propagation within cardiac cells and sensory neurons, can be directly or indirectly modulated by S-palmitoylation, impacting channel trafficking and function. However, the role of S-palmitoylation in modulating NaV1.7, a significant contributor to pain pathophysiology, has remained unexplored. Here, we addressed this knowledge gap by investigating if S-palmitoylation influences NaV1.7 channel function. Acyl-biotin exchange assays demonstrated that heterologously expressed NaV1.7 channels are modified by S-palmitoylation. Blocking S-palmitoylation with 2-bromopalmitate resulted in reduced NaV1.7 current density and hyperpolarized steady-state inactivation. We identified two S-palmitoylation sites within NaV1.7, both located in the second intracellular loop, which regulated different properties of the channel. Specifically, S-palmitoylation of cysteine 1126 enhanced NaV1.7 current density, while S-palmitoylation of cysteine 1152 modulated voltage-dependent inactivation. Blocking S-palmitoylation altered excitability of rat dorsal root ganglion neurons. Lastly, in human sensory neurons, NaV1.7 undergoes S-palmitoylation, and the attenuation of this post-translational modification results in alterations in the voltage-dependence of activation, leading to decreased neuronal excitability. Our data show, for the first time, that S-palmitoylation affects NaV1.7 channels, exerting regulatory control over their activity and, consequently, impacting rodent and human sensory neuron excitability. These findings provide a foundation for future pharmacological studies, potentially uncovering novel therapeutic avenues in the modulation of S-palmitoylation for NaV1.7 channels.

The Role of Alpha-7 Nicotinic Acetylcholine Receptors in Pain: Potential Therapeutic Implications.

Chronic pain represents a prevalent and costly medical challenge globally. Nicotinic acetylcholine receptors (nAChRs), one type of ligand-gated ion channels found extensively in both the central and peripheral nervous systems, have emerged as promising therapeutic targets for chronic pain. Although there are currently no FDA-approved analgesics specifically targeting nAChRs, accumulating preclinical and clinical evidence suggest that selective ligands for alpha 7 (α7) nAChRs show potential for treating chronic pain, boasting a reduced incidence of side effects compared with other nicotinic receptor types. The recent structural resolution of human α7 nAChRs has confirmed their negative association with heightened pain, providing a valuable foundation for the development of targeted medications. This review presents a comprehensive overview, encompassing insights into the roles of α7 nAChRs derived from structural and functional studies, recent advancements in pharmacology, and investigations into their involvement in the pathophysiology of chronic pain. Moreover, the review addresses the variability in analgesic effects based on the type of receptor agonist and highlights the current research limitations. As such, this review offers potential therapeutic approaches for the development of innovative strategies for chronic pain management.

Optical coherence tomography findings in primary headache disorders: is pain duration a clinical correlate?

Objective Ganglion cell layer thickness (GCLT) may be used as a potential marker for central neural changes. We compared GCLT by using spectral domain optical coherence tomography (SD-OCT) in patients with primary headache disorders and healthy controls. We seek whether there was any difference between the headache groups and whether any clinical parameters correlated to GCLT. Methods Fifty-three primary headache patients, 11 age and sex-matched healthy subjects were included in this cross-sectional study after power analysis. All subjects underwent SD-OCT. The duration of disorder, headache frequency, severity, duration of pain, presence of ocular pain, and accompanying symptoms have been collected. Results Mean GCLT of the headache group was 15.7 ± 3.8 µm (mean ± standard deviation), and the control group was 17.5 ± 2.4. The difference was not statistically significant. When we compared the controls, migraine and tension-type headache patients’ GCLT values, we found a significant difference (ANOVA, p = 0.001). Migraine patients had thinner GCLT compared to all non-migraine headache patients (p = 0.01). Intraocular pressure values of migraine patients and non-migraine patients were not statistically significantly different (p = 0.13). The only clinical parameter that correlated with GCLT was pain duration (r = −0.43 and p = 0.01). The patients with white matter lesions had thinner GCLT (p = 0.046). Conclusion Our results suggest that not long-term suffering from pain but migraine pathophysiology itself seems to affect neuroretinal tissue. Pain duration was moderately and inversely correlated to GCLT, meaning that the longer the headache, the thinner the ganglion cell layer is.

Interactions and Trends of Interleukins, PAI-1, CRP, and TNF-α in Inflammatory Responses during the Perioperative Period of Joint Arthroplasty: Implications for Pain Management-A Narrative Review.

Inflammation during the perioperative period of joint arthroplasty is a critical aspect of patient outcomes, influencing both the pathophysiology of pain and the healing process. This narrative review comprehensively evaluates the roles of specific cytokines and inflammatory biomarkers in this context and their implications for pain management. Inflammatory responses are initiated and propagated by cytokines, which are pivotal in the development of both acute and chronic postoperative pain. Pro-inflammatory cytokines play essential roles in up-regulating the inflammatory response, which, if not adequately controlled, leads to sustained pain and impaired tissue healing. Anti-inflammatory cytokines work to dampen inflammatory responses and promote resolution. Our discussion extends to the genetic and molecular influences on cytokine production, which influence pain perception and recovery rates post-surgery. Furthermore, the role of PAI-1 in modulating inflammation through its impact on the fibrinolytic system highlights its potential as a therapeutic target. The perioperative modulation of these cytokines through various analgesic and anesthetic techniques, including the fascia iliac compartment block, demonstrates a significant reduction in pain and inflammatory markers, thus underscoring the importance of targeted therapeutic strategies. Our analysis suggests that a nuanced understanding of the interplay between pro-inflammatory and anti-inflammatory cytokines is required. Future research should focus on individualized pain management strategies.

Recent developments and challenges in positron emission tomography imaging of gliosis in chronic neuropathic pain.

Understanding the mechanisms that underpin the transition from acute to chronic pain is critical for the development of more effective and targeted treatments. There is growing interest in the contribution of glial cells to this process, with cross-sectional preclinical studies demonstrating specific changes in these cell types capturing targeted timepoints from the acute phase and the chronic phase. In vivo longitudinal assessment of the development and evolution of these changes in experimental animals and humans has presented a significant challenge. Recent technological advances in preclinical and clinical positron emission tomography, including the development of specific radiotracers for gliosis, offer great promise for the field. These advances now permit tracking of glial changes over time and provide the ability to relate these changes to pain-relevant symptomology, comorbid psychiatric conditions, and treatment outcomes at both a group and an individual level. In this article, we summarize evidence for gliosis in the transition from acute to chronic pain and provide an overview of the specific radiotracers available to measure this process, highlighting their potential, particularly when combined with ex vivo / in vitro techniques, to understand the pathophysiology of chronic neuropathic pain. These complementary investigations can be used to bridge the existing gap in the field concerning the contribution of gliosis to neuropathic pain and identify potential targets for interventions.

Pain management in chronic pancreatitis

Pain in chronic pancreatitis (CP) is difficult to manage. Many patients suffer from inadequate pain relief, completely incapacitating them in their daily activities. Historically, despite their well-known adverse effects, opioids have been the pillar of treatment regimens in painful CP. The management is now gradually evolving with a better understanding of the underlying pathophysiology of CP-related pain. Clinicians should follow a holistic approach to the management of CP-associated pain, which must involve lifestyle changes that are coupled with analgesic medications and other pain-relieving interventions. Furthermore, there is no easy cure for vanquishing CP-associated pain. Each patient must be evaluated on a case-by-case basis by a multidisciplinary team to decide which treatment option is best suited for that individual.

Pain in Long-Term Cancer Survivors: Prevalence and Impact in a Cohort Composed Mostly of Breast Cancer Survivors.

Cancer survival is becoming more common which means that there is now a growing population of cancer survivors, in whom pain may be common. However, its prevalence has hardly been addressed systematically. We aimed to assess the prevalence and explore the pathophysiology and impact of pain on health outcomes in cancer survivors. We conducted a retrospective-prospective cohort study in cancer-free patients diagnosed with cancer at least five years before the study start date. We used multivariable regression to establish the association of patients' cancer characteristics with pain, and then the association of patients' pain features with health outcomes and related symptoms. Between March and July 2021, 278 long-term cancer survivors were evaluated. Almost half of them (130/278, 46.8%) had pain, of whom 58.9% had a probable neuropathic component, but only 18 (13.8%) were taking specific drugs for neuropathic pain. A history of surgery-related pain syndrome in breast cancer patients was more than twice as frequent in the pain cohort. Post-chemotherapy and post-radiotherapy pain syndromes were uncommon. Pain was associated with lower QoL, emotional functioning, professional performance, and disability scores. Pain is a frequent health determinant in cancer survivors. Referral to specialised pain services may be a reasonable move in some cases.

Advances in approaches to diagnose endometriosis

Endometriosis is a common, underdiagnosed, systemic inflammatory, and endocrine pain disorder that impacts the quality of life of millions of persons with a uterus globally. It is associated with chronic pelvic pain and an increased risk of subfertility. It has also been associated with cardiovascular disease, depression, thyroid and autoimmune disorders, ovarian and breast cancers, and poor pregnancy outcomes. Treatment of endometriosis-related pain and infertility can be medical and/or surgical, although misdiagnosis due to symptoms that overlap with other conditions and reliance on definitive diagnosis by histologic confirmation of endometriosis at surgery have contributed to a prolonged diagnosis-to-treatment timeline. A paradigm shift in endometriosis diagnosis is underway, with greater reliance on clinical and family history, physical examination, and imaging, without surgical confirmation, and then proceeding with medical and/or surgical therapies, although any one diagnostic approach alone is insufficient. Although there are no validated, specific molecular biomarkers for endometriosis, recent candidates have promise for diagnosing the disease and facilitating symptom management. This review presents current and evolving approaches to diagnose endometriosis with the goal of expediting the diagnosis-to-treatment timeframe, so patients can have confidence in a diagnosis for their symptoms, expectations set about disease management across the lifespan, and a patient-centered treatment plan promptly initiated. To provide context, the review begins with a summary of disease characteristics, followed by genetic and environmental risks for developing endometriosis, the central role of estrogen and inflammation in the pathophysiology of pain and infertility relevant to the disease and biomarker discovery, and nonsurgical approaches that are increasingly being acknowledged by professional organizations across the globe to be of value in the diagnosis of this enigmatic disease with diverse manifestations.

The controllability of pain in palliative medicine as a factor in the medical and social impact on the patients’ quality of life at the end-of-life

Availability and adequacy of analgesia is one of the factors that significantly influence the quality of life of palliative patients. At the current stage of development, the system of palliative and hospice care in Ukraine will not provide clear pain relief for the majority of patients. We conducted a study of PubMed and Google Scholar’s sources and legal acts of Ukraine at the list and content of pain management in palliative patients, which should be considered in their work by medical and social workers providing palliative care, as well as health care managers. We proposed to expand the scientific discussion about types of pain and their corresponding analgesia. The study of regulatory documentation on the palliative care in Ukraine and the protocol for the treatment of chronic pain in palliative patients revealed their compliance with modern protocols and rules of systems with developed systems of palliative care. However, we also found that the practical implementation of the existing rules varies significantly in the direction of their non-enforcement. We came to a conclusion about the need to expand the use of narcotic and non-narcotic pain relievers in Ukrainian palliative medicine, to strengthen the material and technical base of hospices and to eliminate their staff shortage. The article covers a number of issues of the pathophysiology of pain. We determined that both the causes of pain and its perception, which can be evaluated on several scales in points, are important in the issue of pain perception by palliative patients. We came to the conclusion that an adequate reaction of patients to pain simplifies the diagnosis and the appointment of adequate treatment, and an excessive and "stoic" reaction complicates them. We noted that the treatment of chronic pain involves the use of drug therapy, hypnosis, cognitive-behavioral therapy, physical exercises, and physio­therapeutic procedures. Keywords: chronic pain, nociception, pharmacotherapy, narcotic analgesics, non-narcotic analgesics.

Abnormalities of the Descending Inhibitory Nociceptive Pathway in Functional Motor Disorders.

Pain is a common disabling non-motor symptom affecting patients with functional motor disorders (FMD). We aimed to explore ascending and descending nociceptive pathways with laser evoked potentials (LEPs) in FMD. We studied a "bottom-up and top-down" noxious paradigm applying a conditioned pain modulation (CPM) protocol and recorded N2/P2 amplitude in 21 FMD and 20 controls following stimulation of both right arm and leg at baseline (BS) (bottom-up), during heterotopic noxious conditioning stimulation (HNCS) with ice test (top-down) and post-HNCS. We found a normal ascending pathway, but reduced CPM response (lower reduction of the N2/P2 amplitude) in FMD patients, by stimulating both upper and lower limbs. The N2/P2 amplitude ratio*100 (between the HNCS and BS) was significantly higher in patients with FMD than HC. Our results suggest that pain in FMD possibly reflects a descending pain inhibitory control impairment, therefore, providing a novel venue to explore the pathophysiology of pain in FMD. © 2024 International Parkinson and Movement Disorder Society.

Insula→Amygdala and Insula→Thalamus Pathways Are Involved in Comorbid Chronic Pain and Depression-Like Behavior in Mice.

The comorbidity of chronic pain and depression poses tremendous challenges for the treatment of either one because they exacerbate each other with unknown mechanisms. As the posterior insular cortex (PIC) integrates multiple somatosensory and emotional information and is implicated in either chronic pain or depression, we hypothesize that the PIC and its projections may contribute to the pathophysiology of comorbid chronic pain and depression. We show that PIC neurons were readily activated by mechanical, thermal, aversive, and stressful and appetitive stimulation in naive and neuropathic pain male mice subjected to spared nerve injury (SNI). Optogenetic activation of PIC neurons induced hyperalgesia and conditioned place aversion in naive mice, whereas inhibition of these neurons led to analgesia, conditioned place preference (CPP), and antidepressant effect in both naive and SNI mice. Combining neuronal tracing, optogenetics, and electrophysiological techniques, we found that the monosynaptic glutamatergic projections from the PIC to the basolateral amygdala (BLA) and the ventromedial nucleus (VM) of the thalamus mimicked PIC neurons in pain modulation in naive mice; in SNI mice, both projections were enhanced accompanied by hyperactivity of PIC, BLA, and VM neurons and inhibition of these projections led to analgesia, CPP, and antidepressant-like effect. The present study suggests that potentiation of the PIC→BLA and PIC→VM projections may be important pathophysiological bases for hyperalgesia and depression-like behavior in neuropathic pain and reversing the potentiation may be a promising therapeutic strategy for comorbid chronic pain and depression.

A189 INVESTIGATING THE ROLE OF BACTERIAL HISTAMINE METABOLISM IN VISCERAL HYPERALGESIA

Abstract Background Intestinal microbiota have been implicated in the expression of irritable bowel syndrome (IBS) as patients present with altered gut microbial profiles and microbial metabolic activity. We have previously identified bacterial histamine to strongly influence mast cell accumulation through only IBS activation of the H4 receptor, leading to visceral hyperalgesia in a subset of patients with IBS. We hypothesize that a subset of IBS patients with high histamine-producing microbiota exhibit an aberrant histamine metabolism. Investigating the microbiota-driven pathways involved in histamine metabolism is key to understanding abdominal pain pathophysiology in IBS patients. Aims 1. To study whether variations of histamine levels are due to bacterial metabolism using in vitro and in vivo approaches. 2. To identify the prevalence of high histamine-producing and histamine-degrading bacteria in a clinical cohort via in silico analyses. Methods Using in vitro approaches, stool samples from healthy control (HC) donors and IBS patients were inoculated in minimal media in aerobic/anaerobic conditions, with/without excess histidine or added histamine. Bacterial histamine production and degradation were assessed in culture supernatants by ELISA. After identification through Sanger sequencing, individual colony capacity to degrade and produce histamine was assessed. Host and microbial contributions to histamine metabolism will be identified through analyses of germ-free mice colonized with IBS and HC stool samples. Results IBS patients (n=23) tested were found to consistently produce higher levels of histamine compared to HC (n=3). Among the tested isolated colonies from IBS patients (n=179) 61% produced histamine compared to 33% of HC (n=54), and 20% degraded histamine compared to 11% of HC. Of these colonies, 13% of only IBS isolates demonstrated the capacity to both degrade and produce histamine. Facultative anaerobes were found to possess both higher production and degradation capacity. Both pH and histamine concentration determine bacterial ability to produce or degrade histamine. Conclusions Based on these findings, both healthy and IBS individuals exhibit varying levels of histamine production/degradation, most prominently through facultative anaerobes. The intestinal environment and bacterial community composition are major regulators of bacterial histamine metabolism. The observed in vitro capacity to produce/degrade histamine, and its biological implications, will be confirmed with gnotobiotic humanized mice, ultimately aiding in designing microbiota-directed therapies for the management of visceral hypersensitivity. Funding Agencies CIHRFarncombe Innovation Fund