Pathogenesis Of Pain Research Articles

Brain network functional connectivity changes in patients with anterior knee pain: a resting-state fMRI exploratory study

BackgroundThis study investigates the functional brain connectivity in patients with anterior knee pain (AKP). While biomechanical models are frequently employed to investigate AKP, it is important to recognize that pain can manifest even in the absence of structural abnormalities. Leveraging the capabilities of functional magnetic resonance imaging (fMRI), this research aims to investigate the brain mechanisms present in AKP patients.MethodsForty-five female subjects (24 AKP patients, 21 controls) underwent resting-state fMRI and T1-weighted structural MRI. Functional brain connectivity patterns were analyzed, focusing on pain network areas, and the influence of catastrophizing thoughts was evaluated.ResultsComparing patients and controls, several findings emerged. First, patients with AKP exhibited increased correlation between the right supplementary motor area and cerebellum I, as well as decreased correlation between the right insula and the left rostral prefrontal cortex and superior frontal gyrus. Second, in AKP patients with catastrophizing thoughts, there was increased correlation of the left lateral parietal cortex with two regions of the right cerebellum (II and VII) and the right pallidum, and decreased correlation between the left medial frontal gyrus and the right thalamus. Furthermore, the correlation between these regions showed promising results for discriminating AKP patients from controls, achieving a cross-validation accuracy of 80.5%.ConclusionsResting-state fMRI revealed correlation differences in AKP patients compared to controls and based on catastrophizing thoughts levels. These findings shed light on neural correlates of chronic pain in AKP, suggesting that functional brain connectivity alterations may be linked to pain experience in this population.Relevance statementEtiopathogenesis of pain in anterior knee pain patients might not be limited to the knee, but also to underlying alterations in the central nervous system: cortical changes might lead a perpetuation of pain.Key points• Anterior knee pain patients exhibit distinct functional brain connectivity compared to controls, and among catastrophizing subgroups.• Resting-state fMRI reveals potential for discriminating anterior knee pain patients with 80.5% accuracy.• Functional brain connectivity differences improve understanding of pain pathogenesis and objective anterior knee pain identification.Graphical

Modern concepts of treatment of phantom limb pain

Phantom limb pain is a specific entity of neuropathic pain that develops in 30%85% of patients with amputated limbs and leads to considerable worsening of the quality of life. The number of such cases increases during military conflicts. It can be caused by a traumatic amputation due to mine blast injury, peculiarities of provided medical assistance, and the special psychological state of casualties being in extremely stressful situations at the moment of wounding. Phantom limb pain development is accompanied by multiple functional and structural changes at different levels of the peripheral and central nervous systems. As a result, different theories of pathogenesis are proposed. However, at present, no final opinion concerns mechanisms of phantom limb pain development. Although different versions of drug and non-drug therapy have been suggested, none of them turned out to be universal and fully effective. Many medications were found to be linked to phantom limb pain pathogenesis; however, even first-line therapy drugs (non-steroidal anti-inflammatory drugs, tricyclic antidepressants, narcotic analgesics, and anticonvulsants) often fail to provide adequate analgesia. Long-term prescription of narcotic analgesics is at risk of the development of addictive disorders. Surgical interventions have not demonstrated their effectiveness as well. Thus, their use is justified only in the case of ineffective conservative treatment. Poor efficacy of conventional concepts of phantom limb pain treatment led to the use of new means such as botulinum toxin therapy, non-drug methods (psychotherapy, mirror therapy, biological feedback, virtual reality, acupuncture, massage, hypnosis, etc.). Thus, the search for original methods based on the development and introduction of new drug therapy schemes is imperative. A possible solution to this problem is not only creating absolutely new non-opioid analgesics but also using adjuvant therapeutic means in the multimodality schemes of analgesia. The latter promotes neurotransmission in the antinociceptive system and potentiates the effect of traditional analgesics.

IL-33/ST2 Signaling in the Pathogenesis of Chronic Pain and Itch.

Interleukin-33 (IL-33) is an inflammatory factor with an extensive range of biological effects and pleiotropic roles in diseases. Evidence suggests that IL-33 and its receptor ST2 play a pivotal role in chronic pain and itch at the level of primary sensory neurons, the spinal cord, and the brain. In this review, we outline an evolving understanding of the roles and mechanisms of IL-33 in chronic pathological pain, including inflammatory, neuropathic, and cancer, and chronic pruritus, such as allergic contact dermatitis, atopic dermatitis, and dry skin. Understanding the key roles of IL-33/ST2 signaling may provide exciting insights into the mechanisms of chronic pain and itch and lead to new clues for therapeutic approaches to the resolution of chronic pain and itch.

Burning mouth syndrome (BMS) - possible pathogenesis related to pain pathways

Burning mouth syndrome (BMS) has been admitted relatively recently as a condition/syndrome within oral pathology, bordering various other medical specialities, which may collaborate to determine the diagnosis and especially to achieve therapeutic success. From a clinical point of view, BMS can present itself in 2 forms: the primary/essential form, whose etiopathogenesis is unexplained, justifying the permanent concern as a topic of research at the international level, and the secondary form, in which the causes of the syndrome can be identified and treated/ removed, allowing healing. Particular to the primary form of BMS is the discrepancy between the extent of subjective pain felt by the patient as “burning” and the lack of any objective (clinical) signs in the oral mucosa. In this form of BMS, the pathogenesis of pain can be explained by invoking the role and importance of the field and some favourable factors. In recent years it has been noticed that changes in taste perception and pain tolerance could be possible causes of the “burning” sensation. Thus, the involvement of the field allowed the following hypothesis to be issued, namely that taste is generated mainly at the level of the fungiform lingual papillae.

The Effect of Probiotic Consumption Status and Quality of Life in Patients with Fibromyalgia

Aim: Recent studies have suggested that disruptions in the gut microbiota could potentially contribute to the pathogenesis of chronic pain and fibromyalgia syndrome (FMS) by affecting the gut microbiota-brain axis. The increasing prevalence of fibromyalgia syndrome has prompted investigations into the impact of probiotic food consumption, which regulates the microbiota, on quality of life.
 Material and Methods: The study included 99 patients diagnosed with fibromyalgia syndrome who presented to our Physical Medicine and Rehabilitation outpatient clinic. A questionnaire was administered to assess the patients' knowledge and consumption of probiotic foods, and the Short Form-12 Health Survey(SF-12) was used to gather data and assess health-related quality of life.
 Results: Of the 99 patients who completed the questionnaire, 89 were female and 10 were male. In response to the question, "Do you know what probiotics are?"7.4% of primary school graduates,64.7% of high school graduates, and 78.6% of university graduates answered affirmatively. When asked, "Have you experienced any benefits from probiotic foods?" 21.2% responded positively, and among those who experienced benefits, the most common accompanying issue (37.04%) was Irritable Bowel Syndrome(IBS). Fibromyalgia syndrome patients who consumed yogurt as a probiotic had higher physical function subdomain scores on the SF-12 Health Survey.
 Conclusion: The high level of education in FMS patients increased the awareness of probiotics. Probiotic consumption may have a improving effect on irritable bowel syndrome and constipation associated with FMS.Training on probiotics and increasing the frequency of use of probiotics, the quality of life of FMS patients can be increased and accompanying symptoms can be reduced.

Exercise, Spinal Microglia and Neuropathic Pain: Potential Molecular Mechanisms.

As one of the most common neuropathic disorders, neuropathic pain often has a negative impact on patients with persistent pain, mood disorders and sleep disturbances. Currently, neuropathic pain is not treated with any specific drug, instead, drugs for other diseases are used as replacements in clinics, but most have adverse effects. In recent years, the role of spinal cord microglia in the pathogenesis of neuropathic pain has been widely recognized, and they are being explored as potential therapeutic targets. Spinal microglia are known to be involved in the pathogenic mechanisms of neuropathic pain through purine signaling, fractalkine signaling, and p38 MAPK signaling. Exercise is a safe and effective treatment, and numerous studies have demonstrated its effectiveness in improving neurological symptoms. Nevertheless, it remains unclear what the exact molecular mechanism is. This review summarized the specific molecular mechanisms of exercise in alleviating neuropathic pain by mediating the activity of spinal microglia and maintaining the phenotypic homeostasis of spinal microglia through purine signaling, fractalkine signaling and p38 MAPK signaling. In addition, it has been proposed that different intensities and types of exercise affect the regulation of the above-mentioned signaling pathways differently, providing a theoretical basis for the improvement of neuropathic pain through exercise.

Levo-tetrahydropalmatine ameliorates neuropathic pain by inhibiting the activation of the Clec7a-MAPK/NF-κB-NLRP3 inflammasome axis

BackgroundBecause of the complex pathogenesis of neuropathic pain (NP), the therapeutic efficacy of existing drugs is not satisfactory. Accumulating studies have indicated that neuroinflammation may play a key role in NP onset and progression. Levo-tetrahydropalmatine (l-THP) has been extensively used for relieving chronic pain for decades. However, its potential mechanisms against NP have not yet been fully elucidated. PurposeExploring and elucidating the therapeutic effect and pharmacological mechanism of l-THP in treating NP. MethodsRNA-seq and bioinformatics analyses were carried out to identify effective target profiling of I-THP in chronic constrictive injury (CCI) rats. The I-THP related hub targets and signaling pathways were obtained via bioinformatics analysis, then subjected to in-depth analyses through experiments in vivo. A gain-of-function study further confirmed the role of Clec7a in l-THP-mediated pain relief. Finally, the interaction between l-THP and Clec7a was verified through molecular docking and surface plasmon resonance (SPR). Resultsl-THP treatment effectively alleviated mechanical and thermal allodynia in NP model rats. Functionally, the I-THP effective targets were mainly enriched in inflammatory response-related pathways. Furthermore, Clec7a-MAPK/NF-κB-NLRP3 inflammasome axis was selected as one of the potential pathways of l-THP against NP. Mechanically, l-THP markedly reduced CCI-induced Clec7a overexpression, significantly inhibited the Clec7a-triggered phosphorylation of MAPK and NF-κB-p65, and decreased the expression of pyroptosis-related protein NLRP3 and Caspase-1-p20. The analgesic effect of l-THP on NP was partly eliminated when transfecting the overexpression vector virus pLVSO5Clec7a. Importantly, molecular docking and SPR data revealed that l-THP directly binds with the Clec7a protein. ConclusionThis study is the first to indicate that l-THP may exert an analgesic effect through inhibiting neuroinflammation via the Clec7a-MAPK/NF-κB-NLRP3 inflammasome axis, supporting the clinical utility of l-THP in NP therapy.

Neuralized1-Mediated CPEB3 Ubiquitination in the Spinal Dorsal Horn Contributes to the Pathogenesis of Neuropathic Pain in Rats.

Compelling evidence has shown that Neuralized1 (Neurl1) facilitates hippocampal-dependent memory storage by modulating cytoplasmic polyadenylation element-binding protein 3 (CPEB3)-dependent protein synthesis. In the current study, we investigated the role of Neurl1 in the pathogenesis of neuropathic pain and the underlying mechanisms. The neuropathic pain was evaluated by lumbar 5 spinal nerve ligation (SNL) in rats. Immunofluorescence staining, Western blotting, qRT-PCR, and coimmunoprecipitation (Co-IP) were performed to investigate the underlying mechanisms. Our results showed that SNL led to an increase of Neurl1 in the spinal dorsal horn. Spinal microinjection of AAV-EGFP-Neurl1 shRNA alleviated mechanical allodynia; decreased the level of CPEB3 ubiquitination; inhibited the production of GluA1, GluA2, and PSD95; and reduced GluA1-containing AMPA receptors in the membrane of the dorsal horn following SNL. Knockdown of spinal CPEB3 decreased the production of GluA1, GluA2, and PSD95 in the dorsal horn and attenuated abnormal pain after SNL. Overexpression of Neurl1 in the dorsal horn resulted in pain-related hypersensitivity in naïve rats; raised the level of CPEB3 ubiquitination; increased the production of GluA1, GluA2, and PSD95; and augmented GluA1-containing AMPA receptors in the membrane in the dorsal horn. Moreover, spinal Neurl1 overexpression-induced mechanical allodynia in naïve rats was partially reversed by repeated intrathecal injections of CPEB3 siRNA. Collectively, our results suggest that SNL-induced upregulation of Neurl1 through CPEB3 ubiquitination-dependent production of GluA1, GluA2, and PSD95 in the dorsal horn contributes to the pathogenesis of neuropathic pain in rats. Targeting spinal Neurl1 might be a promising therapeutic strategy for the treatment of neuropathic pain.

M2 macrophage polarization: a potential target in pain relief.

Pain imposes a significant urden on patients, affecting them physically, psychologically, and economically. Despite numerous studies on the pathogenesis of pain, its clinical management remains suboptimal, leading to the under-treatment of many pain patients. Recently, research on the role of macrophages in pain processes has been increasing, offering potential for novel therapeutic approaches. Macrophages, being indispensable immune cells in the innate immune system, exhibit remarkable diversity and plasticity. However, the majority of research has primarily focused on the contributions of M1 macrophages in promoting pain. During the late stage of tissue damage or inflammatory invasion, M1 macrophages typically transition into M2 macrophages. In recent years, growing evidence has highlighted the role of M2 macrophages in pain relief. In this review, we summarize the mechanisms involved in M2 macrophage polarization and discuss their emerging roles in pain relief. Notably, M2 macrophages appear to be key players in multiple endogenous pathways that promote pain relief. We further analyze potential pathways through which M2 macrophages may alleviate pain.

Improved Sleep Affects Epigastric Pain in Functional Dyspepsia by Reducing the Levels of Inflammatory Mediators

Introduction: The pathogenesis of epigastric pain in functional dyspepsia (FD) is complex. The study aims to explore the effect of sleep improvement on this symptom. Methods: In total, 120 patients with FD-associated epigastric pain and insomnia were randomly divided into experimental and control groups using the envelope method. After applying the exclusion criteria, 107 patients were enrolled in the experimental (56 patients) and control (51 patients) groups. Insomnia was graded according to the Pittsburgh Sleep Quality Index (PSQI). In the experimental group, eszopiclone 3 mg, eszopiclone 3 mg + estazolam 1 mg, and eszopiclone 3 mg + estazolam 2 mg were given to patients with mild, moderate, and severe insomnia, respectively. In the control group, patients were given 1, 2, or 3 tablets of vitamin B complex. Patient sleep quality was monitored with Sleepthing. Epigastric pain was evaluated with a Numeric Rating Scale. The serum levels of IL-1β, IL-6, IL-8, and tumor necrosis factor-α (TNF-α) were measured by enzyme-linked immunosorbent assay. Pain scores, sleep parameters, and serum levels of inflammatory mediators were compared before and after treatment. Results: After treatment, the pain scores, sleep parameters, and TNF-α and IL-6 levels in the experimental group were significantly lower than those in the control group (p < 0.05). PSQI insomnia scores were significantly associated with pain scores, IL-6, and TNF-α (p < 0.05) but not in IL-8 and IL-1β levels (p > 0.05) among the three groups. Conclusions: Improving sleep with eszopiclone and/or estazolam alleviates FD-associated epigastric pain, possibly by inhibiting related downstream transmission pathways and reducing the release of inflammatory mediators.

ThTP6.8 Incidence and management of non-resolution of Biliary Colic or Right Upper Quadrant pain Post Laparoscopic Cholecystectomy

Abstract Background The pathogenesis and risk of chronic pain after laparoscopic cholecystectomy are not well understood. Post-cholecystectomy syndrome describes persistence of biliary colic or right upper quadrant pain with a variety of GI symptoms, similar to features prior to cholecystectomy. It is attributed to biliary (retained stone, biliary stricture), extra-biliary (pancreatitis, gastritis, IBS) and psychiatric or neurological disorders. Aim To find out (1) the incidence of post laparoscopic cholecystectomy pain. (2) if patients were counselled on non-resolution of pain during consenting for surgery. (3) if patients were investigated for non-resolution of pain. Methodology Retrospective cohort study was performed by interviewing patients undergoing laparoscopic cholecystectomy from April2022-October2022. Direct telephone consultation to enquire about non-resolution of pain. Digital case notes were reviewed for subsequent admissions. Results A total of 50 cases met the audit inclusion criteria over the period of 7months. Mean age of the selected population was 47.98 years (SD 15.47). Male:female ratio was 11:39. 24%(n=12) patients were reported non-resolution of pain post-op. 48%(n=24) patients were counselled on non-resolution of pain while consenting for surgery. Discussion The study suggested a significant number of patients experience non-resolution of pain post-cholecystectomy. However, less than half of the study population were counselled during consenting. Limitations include low number of patients and risk factors like urgent surgery like ‘hot gallbladders’ and choledochotomy could not be assessed. To improve clinical practice, non-resolution of pain should be mentioned during consenting. Additionally, a potential follow-up system should be introduced to review non-resolution of pain and guidelines on investigation of the residual pain should be produced.

Microglia and p38 MAPK Inhibitors Suppress Development of Mechanical Allodynia in Both Sexes in a Mouse Model of Antiretroviral-Induced Neuropathic Pain.

Microglia activation in the spinal cord play a major role in the pathogenesis of neuropathic pain. The p38 mitogen-activated protein kinase (MAPK) regulates microglia activation. Previously, 2',3'-dideoxycytidine (ddC), a nucleoside reverse transcriptase inhibitor (NRTI), was found to induce mechanical allodynia and microglia activation in the spinal cords of male and female mice. In this study, we investigated the role of spinal microglia and p38 MAPK signaling in the development of mechanical allodynia using immunofluorescence staining and treatment with microglia and p38 MAPK inhibitors in both sexes. Male and female mice (BALB/c strain) treated intraperitoneally once daily with ddC 25 mg/kg for five consecutive days developed mechanical allodynia, assessed using the dynamic plantar aesthesiometer. Treatment with ddC increased microglia markers CD11b and ionized calcium-binding adapter molecule 1 (Iba1) staining intensity in male mice, while only CD11b was increased in female mice. Both sexes had increased phosphorylated p38 MAPK staining intensity. The administration of minocycline, an inhibitor of microglia activation, and adezmapimod, a selective p38 MAPK inhibitor, suppressed mechanical allodynia in both sexes at day 7 after ddC treatment. Therefore, microglia activation and p38 MAPK signaling are important for the development of antiretroviral drug-induced mechanical allodynia.

Chronic thoracic pain after cardiac surgery: role of inflammation and biomechanical sternal stability.

The pathogenesis of chronic chest pain after cardiac surgery has not been determinate. If left untreated, postoperative sternal pain reduces the quality of life and patient satisfaction with cardiac surgery. The purpose of the study was to examine the effect of chest inflammation on postoperative pain, risk factors for chronic pain after cardiac surgery and to explore how chest reconstruction was associated with the intensity of pain. The authors performed a study of acute and chronic thoracic pain after cardiac surgery in patients with and without sternal infection and compared different techniques for chest reconstruction. 42 high-risk patients for the development of mediastinitis were included. Patients with mediastinitis received chest reconstruction (group 1). Their demographics and risk factors were matched with no-infection patients with chest reconstruction (group 2) and subjects who underwent conventional sternal closure (group 3). Chronic pain was assessed by the numeric rating scale after surgery. The assessment of the incidence and intensity of chest pain at 3 months post-surgery demonstrated that 14 out of 42 patients across all groups still experienced chronic pain. Specifically, in group 1 with sternal infection five patients had mild pain, while one patient experienced mild pain in group 2, and eight patients in group 3. Also, follow-up results indicated that the highest pain score was in group 3. While baseline levels of cytokines were increased among patients with sternal infection, at discharge only the level of interleukin 6 remained high compared to no infection groups. Compared to conventional closure, after chest reconstruction, we found better healing scores at 3-month follow-up and a higher percentage of patients with the complete sternal union. Overall, 14 out of 42 patients have chronic pain after cardiac surgery. The intensity of the pain in mediastinitis patients significantly decreased at 3 months follow-up after chest reconstruction. Thus, post-surgery mediastinitis is not a determining factor for development the chronic chest pain. There is no correlation between cytokines levels and pain score except interleukin 6 which remains elevated for a long time after treatment. Correlation between sternal healing score and chronic chest pain was demonstrated.

Chemokine CCL7 mediates trigeminal neuropathic pain via CCR2/CCR3-ERK pathway in the trigeminal ganglion of mice.

Chemokine-mediated neuroinflammation plays an important role in the pathogenesis of neuropathic pain. The chemokine CC motif ligand 7 (CCL7) and its receptor CCR2 have been reported to contribute to neuropathic pain via astrocyte-microglial interaction in the spinal cord. Whether CCL7 in the trigeminal ganglion (TG) involves in trigeminal neuropathic pain and the involved mechanism remain largely unknown. The partial infraorbital nerve transection (pIONT) was used to induce trigeminal neuropathic pain in mice. The expression of Ccl7, Ccr1, Ccr2, and Ccr3 was examined by real-time quantitative polymerase chain reaction. The distribution of CCL7, CCR2, and CCR3 was detected by immunofluorescence double-staining. The activation of extracellular signal-regulated kinase (ERK) was examined by Western blot and immunofluorescence. The effect of CCL7 on neuronal excitability was tested by whole-cell patch clamp recording. The effect of selective antagonists for CCR1, CCR2, and CCR3 on pain hypersensitivity was checked by behavioral testing. Ccl7 was persistently increased in neurons of TG after pIONT, and specific inhibition of CCL7 in the TG effectively relieved pIONT-induced orofacial mechanical allodynia. Intra-TG injection of recombinant CCL7 induced mechanical allodynia and increased the phosphorylation of ERK in the TG. Incubation of CCL7 with TG neurons also dose-dependently enhanced the neuronal excitability. Furthermore, pIONT increased the expression of CCL7 receptors Ccr1, Ccr2, and Ccr3. The intra-TG injection of the specific antagonist of CCR2 or CCR3 but not of CCR1 alleviated pIONT-induced orofacial mechanical allodynia and reduced ERK activation. Immunostaining showed that CCR2 and CCR3 are expressed in TG neurons, and CCL7-induced hyperexcitability of TG neurons was decreased by antagonists of CCR2 or CCR3. CCL7 activates ERK in TG neurons via CCR2 and CCR3 to enhance neuronal excitability, which contributes to the maintenance of trigeminal neuropathic pain. CCL7-CCR2/CCR3-ERK pathway may be potential targets for treating trigeminal neuropathic pain.

Sodium Leak Channel in Glutamatergic Neurons of the Lateral Parabrachial Nucleus Modulates Inflammatory Pain in Mice.

Elevated excitability of glutamatergic neurons in the lateral parabrachial nucleus (PBL) is associated with the pathogenesis of inflammatory pain, but the underlying molecular mechanisms are not fully understood. Sodium leak channel (NALCN) is widely expressed in the central nervous system and regulates neuronal excitability. In this study, chemogenetic manipulation was used to explore the association between the activity of PBL glutamatergic neurons and pain thresholds. Complete Freund's adjuvant (CFA) was used to construct an inflammatory pain model in mice. Pain behaviour was tested using von Frey filaments and Hargreaves tests. Local field potential (LFP) was used to record the activity of PBL glutamatergic neurons. Gene knockdown techniques were used to investigate the role of NALCN in inflammatory pain. We further explored the downstream projections of PBL using cis-trans-synaptic tracer virus. The results showed that chemogenetic inhibition of PBL glutamatergic neurons increased pain thresholds in mice, whereas chemogenetic activation produced the opposite results. CFA plantar modelling increased the number of C-Fos protein and NALCN expression in PBL glutamatergic neurons. Knockdown of NALCN in PBL glutamatergic neurons alleviated CFA-induced pain. CFA injection induced C-Fos protein expression in central nucleus amygdala (CeA) neurons, which was suppressed by NALCN knockdown in PBL glutamatergic neurons. Therefore, elevated expression of NALCN in PBL glutamatergic neurons contributes to the development of inflammatory pain via PBL-CeA projections.

Stress-Induced Changes in the Endogenous Opioid System Cause Dysfunction of Pain and Emotion Regulation.

Early life stress, such as child abuse and neglect, and psychosocial stress in adulthood are risk factors for psychiatric disorders, including depression and anxiety. Furthermore, exposure to these stresses affects the sensitivity to pain stimuli and is associated with the development of chronic pain. However, the mechanisms underlying the pathogenesis of stress-induced depression, anxiety, and pain control remain unclear. Endogenous opioid signaling is reportedly associated with analgesia, reward, addiction, and the regulation of stress responses and anxiety. Stress alters the expression of various opioid receptors in the central nervous system and sensitivity to opioid receptor agonists and antagonists. μ-opioid receptor-deficient mice exhibit attachment disorders and autism-like behavioral expression patterns, while those with δ-opioid receptor deficiency exhibit anxiety-like behavior. In contrast, deficiency and antagonists of the κ-opioid receptor suppress the stress response. These findings strongly suggest that the expression and dysfunction of the endogenous opioid signaling pathways are involved in the pathogenesis of stress-induced psychiatric disorders and chronic pain. In this review, we summarize the latest basic and clinical research studies on the effects of endogenous opioid signaling on early-life stress, psychosocial stress-induced psychiatric disorders, and chronic pain.

Combined use of non-steroidal anti-inflammatory drugs and symptomatic slow-acting drugs in musculoskeletal diseases

Musculoskeletal diseases, such as osteoarthritis (OA), nonspecific back pain (NBP), and periarticular soft tissue pathology (PSTP – tendinitis, enthesitis, bursitis, etc.) are one of the most common reasons for visiting general practitioners. The treatment of this pathology is based on the complex use of drugs and non-drug methods for maximum pain control and lost function restoration. Considering the common pathogenesis of musculoskeletal pain in OA, NBP, and PSTP, it is advisable to base the therapy of these diseases on a single algorithm. Of course, when prescribing treatment, one should take into account "red flags" (symptoms of life threatening diseases), features of the clinical course, patient's psycho-emotional condition, and comorbid diseases.Development of a unified tactic for the treatment of musculoskeletal pain will significantly reduce the time spent on a diagnostic search and the choice of adequate therapy, which will facilitate the work of a general practitioner. Thus, non-drug approaches (patient education, kinesiotherapy, psychotherapeutic methods, etc.), non-steroidal anti-inflammatory drugs (NSAIDs) and symptomatic slow-acting drugs (SYSADOA) seem to be the most rational approach in the debut of the treatment of OA, NBP and PSTP. Among NSAIDs, celecoxib seems to be one of the optimal drugs in terms of efficacy and safety, and among SYSADOAs – diacerein. There is evidence that the combined use of these drugs may increase their analgesic and anti-inflammatory potential.

POSTСOLITIS ALTERATIONS IN NOCICEPTIVE PROPERTIES OF NEURONS IN THE RAT RAPHE MAGNUS AND DORSAL RAPHE NUCLEI

Dysfunction of the brain serotonergic system is thought to play a leading role in the pathogenesis of chronic abdominal pain and comorbid somatic hyperalgesia, which disturb a significant proportion of patients with digestive tract diseases, even in remission. However, the specific changes in the serotonergic structures nociceptive properties that can be initiated by organic pathology and persist after its resolution remain unclear. The aim of our neurophysiological study on anesthetized rats – healthy and recovered from colitis – was to identify the alterations in the raphe magnus (RMg) and dorsal raphe (DR) nuclei neuronal responses to visceral (colorectal distension) and somatic (squeezing of the tail) noxious stimulations that persist after resolution of intestinal inflammation. It has been shown that both nuclei contain different groups of nociceptive neurons: 1) responding with activation only to colorectal distension (visceral); 2) excited only by tail squeezing (somatic); 3) reacting with excitation to the both irritations (general); 4) responding with discharge inhibition to any of the stimulations (inhibited). Compared with healthy animals, in RMg of colitis-exposed rats the number of the inhibited cells was increased and the total proportion of excited nociceptive neurons was reduced. Distension of the inflammation-undergone intestine caused enhanced RMg neuronal inhibition, whereas squeezing of the pathology-unaffected tail led to increased excitation of the RMg selective somatic and general nociceptive cells. In turn, in the DR of postcolitis rats the inhibited neuron proportion was reduced, while the increased population of excited neurons included fewer visceral and more somatic selective cells. This was accompanied by an increase in the selective reactions of the latter to somatic pain stimuli and by an increase in non-selective DR neuron excitation by visceral and somatic pain signals. The identified neuronal alterations can contribute to the postcolitis impairment of the studied raphe nuclei functions in the endogenous control of visceral and somatic pain sensitivity.

Artemin sensitizes nociceptors that innervate the osteoarthritic joint to produce pain

There have been significant developments in understanding artemin/GFRα3 signaling in recent years, and there is now accumulating evidence that artemin has important roles to play in pain signaling, including that derived from joint and bone, and that associated with OA. A total of 163 Sprague Dawley rats were used in this study. We used an animal model of mono-iodoacetate (MIA)-induced OA, in combination with electrophysiology, behavioral testing, Western blot analysis, and retrograde tracing and immunohistochemistry, to identify roles for artemin/GFRα3 signaling in the pathogenesis of OA pain. We have found that: 1) GFRα3 is expressed in a substantial proportion of knee joint afferent neurons; 2) exogenous artemin sensitizes knee joint afferent neurons in naïve rats; 3) artemin is expressed in articular tissues of the joint, but not surrounding bone, early in MIA-induced OA; 4) artemin expression increases in bone later in MIA-induced OA when pathology involves subchondral bone; and 5) sequestration of artemin reverses MIA-induced sensitization of both knee joint and bone afferent neurons late in disease when there is inflammation of knee joint tissues and damage to the subchondral bone. Our findings show that artemin/GFRα3 signaling has a role to play in the pathogenesis of OA pain, through effects on both knee joint and bone afferent neurons, and suggest that targeted manipulation of artemin/GFRα3 signaling may provide therapeutic benefit for the management of OA pain.

MAKO robot-assisted total knee arthroplasty cannot reduce the aggravation of ankle varus incongruence after genu varus correction ≥ 10°: a radiographic assessment

IntroductionThe objective of this study was to investigate the ankle alignment alterations after the correction of knee varus deformity in MAKO robot-assisted total knee arthroplasty (MA-TKA).MethodsA retrospective analysis was conducted for 108 patients with TKA from February 2021 to February 2022. Patients were divided into two groups based on MAKO robot involvement during the procedure: the MA-TKA group (n = 36) and the conventional manual total knee arthroplasty (CM-TKA) group (n = 72). The patients were divided into four subgroups according to the degree of surgical correction of the knee varus deformity. Seven radiological measurements were evaluated pre and post-surgery: mechanical tibiofemoral angle (mTFA), mechanical lateral distal femoral angle (mLDFA), medial proximal tibial angle (MPTA), lateral distal tibial angle (LDTA), tibial plafond inclination angle (TPIA), talar inclination angle (TIA), and tibiotalar tilt angle (TTTA). TTTA is a quantitative representation of the extent of ankle incongruence.ResultsThe number of mTFA, mLDFA, and MPTA outliers in the MA-TKA group was significantly lower compared to the CM-TKA group (P<0.05). Knee varus deformity was properly corrected and the mechanical axis was restored in all patients, regardless of the treatment group. Only for varus corrections ≥ 10° did TTTA change significantly (p < 0.01) and ankle varus incongruence aggravate post-operation. The ΔTTTA correlated negatively with ΔTFA (r=-0.310,P = 0.001) and correlated positively with ΔTPIA (r = 0.490,P = 0.000). When the varus correction was ≥ 7.55°, the probability of ankle varus incongruence exacerbation increased 4.86-fold.ConclusionCompared with CM-TKA, MA-TKA osteotomy showed more precision but was unable to reduce post-operation ankle varus incongruence. When the varus correction ≥ 10°, ankle varus incongruence aggravated, while when the varus correction ≥ 7.55°, the probability of ankle varus incongruence increased 4.86-fold. This may occasion the pathogenesis of ankle pain following TKA.