Pathological Pain Research Articles

Progress in treatment of pathological neuropathic pain after spinal cord injury

Pathological neuropathic pain is a common complication following spinal cord injury. Due to its high incidence, prolonged duration, tenacity, and limited therapeutic efficacy, it has garnered increasing attention from both basic researchers and clinicians. The pathogenesis of neuropathic pain after spinal cord injury is multifaceted, involving factors such as structural and functional alterations of the central nervous system, pain signal transduction, and inflammatory effects, posing significant challenges to clinical management. Currently, drugs commonly employed in treating spinal cord injury induced neuropathic pain include analgesics, anticonvulsants, antidepressants, and antiepileptics. However, a subset of patients often experiences suboptimal therapeutic responses or severe adverse reactions. Therefore, emerging treatments are emphasizing a combination of pharmacological and non-pharmacological approaches to enhance neuropathic pain management. We provide a comprehensive review of past literature, which aims to aim both the mechanisms and clinical interventions for pathological neuropathic pain following spinal cord injury, offering novel insights for basic science research and clinical practice in spinal cord injury treatment.

Repurposing Aprepitant: Can it protect against doxorubicin-induced Chemobrain beyond its antiemetic role?

The substance P (SP) and neurokinin-1 receptor (NK-1R) axis is crucial in numerous pathological processes, including inflammation, stress responses, pain perception, and vomiting. Consequently, aprepitant, an NK-1R blocker, is used as an antiemetic in chemotherapy, including the use of doxorubicin (DOX), but whether aprepitant can also assuage DOX-mediated chemobrain remains to be unveiled. Here, we scrutinized the potential neuroprotective effect and underlying mechanisms of aprepitant using DOX-induced chemobrain model, where rats were allocated into 4 groups (control, aprepitant, DOX, and DOX+ aprepitant). Cognitive deficits were assessed through behavioral tests and hippocampal structural alterations were determined by H&E and toluidine blue staining. Biochemical measurements were performed using ELISA, real-time quantitative PCR, western blotting, and immunohistochemical methods. Aprepitant improved cognitive responses, and hippocampal morphology, enhancing the presence of intact neurons. At the molecular tier, aprepitant significantly reduced hippocampal contents of SP and the inflammatory markers NF-κB and IL-1β. Additionally, it signified its antioxidant and antiapoptotic capacities by downregulating cleaved caspase-3 protein expression and curbing the content of malondialdehyde but boosted those of glutathione and Bcl-2. Aprepitant also downregulated the expression of miR-146a and turned off the endoplasmic reticulum (ER) stress cascade PERK/eIF-2α/ATF-4/CHOP. To recapitulate, aprepitant demonstrates a neuroprotective effect against DOX-mediated chemobrain by alleviating inflammatory, oxidative, and apoptotic responses, partly by reducing SP, ER stress, and miR-146a. These findings not only underscore the potential of aprepitant as a neuroprotective agent but also offer new understanding of the mechanisms behind chemobrain, leading to better therapeutic strategies for cancer patients.

MiRNA Expression in Long-Distance Runners with Musculoskeletal Pain: Implications for Pain Pathophysiology

Background: miRNAs are short, non-coding RNAs whose deregulation has been shown in painful processes, including musculoskeletal pain. This condition, which causes disability, impacts quality of life, and contributes to substantial healthcare costs, is also a critical issue in sports. In this case-control study, we evaluated the expression of four miRNAs involved in inflammation in runners with musculoskeletal pain and elucidated their functions and pathophysiological implications. Methods: A total of 17 runners with musculoskeletal pain and 17 age- and sex-matched runners without pain participated in this study. The levels of the miRNAs were evaluated by qRT-PCR. Bioinformatic tools were employed to identify the target genes and biological processes regulated by these miRNAs. Results: Compared to the controls, the runners with musculoskeletal pain exhibited significantly higher plasma levels of miR-133b (p = 0.02), miR-155-5p (p = 0.003) and let-7a-5p (p = 0.02). Multivariable regression analysis indicated that these three miRNAs exhibit a positive correlation (p < 0.05) with the presence of musculoskeletal pain, adjusted for age. Bioinformatic analysis suggested that the miRNAs hub genes are involved in regulatory processes, neuroinflammatory pathways, and human diseases that are associated with pain pathology. Conclusions: These results enhance our understanding of the potential role of miR-133b, miR-155-5p and let-7a-5p in pain-associated biological processes. The miRNA-mediated negative regulation of genes identified could explain the inflammatory and tissue repair processes in this population. Further studies are needed to confirm and validate the role of these miRNAs in painful conditions, especially considering the significant public health implications of managing inflammatory pain in sports.

Synergistic effects of human umbilical cord mesenchymal stem cells/neural stem cells and epidural electrical stimulation on spinal cord injury rehabilitation

Spinal cord injury (SCI) is a severe neurological condition marked by a complex pathology leading to irreversible functional loss, which current treatments fail to improve. Epidural electrical stimulation (EES) shows promise in alleviating pathological pain, regulating hemodynamic disturbances, and enhancing motor function by modulating residual interneurons in the lower spinal cord. Cell transplantation (CT), especially using human umbilical cord mesenchymal stem cells (hUCMSCs) and neural stem cells (NSCs), has significantly improved sensory and motor recovery in SCI. However, the limitations of single treatments have driven the exploration of a multifaceted strategy, combining various modalities to optimize recovery at different stages. To comprehensively investigate the effectiveness of in situ transplantation of hUCMSCs/NSCs combined with subacute epidural electrical stimulation in a murine spinal cord crush injury model, providing valuable references for future animal studies and clinical research. In this study, we first examined neural stem cell changes via mRNA sequencing in an in vitro Transwell co-culture model. We then explored cell interaction mechanisms using proliferation assays, differentiation assays, and neuron complexity analysis. For animal experiments, 40 C57BL/6 mice were assigned to four groups (Injury/EES/CT/Combination). Histological evaluations employed HE and immunofluorescence staining, while electrophysiological and behavioral tests assessed motor recovery. Quantitative data were reported as mean ± standard error, with statistical analyses performed using GraphPad Prism and SPSS. Initially, we found that NSCs in the in vitro co-culture model showed a unique expression profile of differentially expressed genes (DEGs) compared to controls. GO/KEGG analysis indicated these DEGs were mainly linked to cell differentiation and growth factor secretion pathways. Neuronal and astrocytic markers further confirmed enhanced NSC differentiation and neuronal maturation in the co-culture model. In vivo, live imaging and human nuclei immunofluorescence staining revealed that transplanted cells persisted for some time post-transplantation. Histological analysis showed that during acute inflammation, both the stem cell and combined therapy groups significantly inhibited microglial polarization. In the chronic phase, these groups reduced fibrotic scar formation and encouraged astrocytic bridging. Behavioral tests, including swimming and gait analysis, demonstrated that combined CT and EES therapy was more effective than either treatment alone. In summary, the combined therapy offers a promising approach for spinal cord injury treatment, providing superior outcomes over individual treatments. Our findings underscore the potential of a combined treatment approach utilizing stem cells transplantation and EES as an effective strategy for the comprehensive management of spinal cord crush injury in mice. This integrated approach holds promise for enhancing functional recovery and improving the quality of life for individuals with spinal cord injury (SCI).

Advancing Pain Understanding and Drug Discovery: Insights from Preclinical Models and Recent Research Findings

Despite major advancements in our understanding of its fundamental causes, pain—both acute and chronic—remains a serious health concern. Various preclinical investigations utilizing diverse animal, cellular, and alternative models are required and frequently demanded by regulatory approval bodies to bridge the gap between the lab and the clinic. Investigating naturally occurring painful disorders can speed up medication development at the preclinical and clinical levels by illuminating molecular pathways. A wide range of animal models related to pain have been developed to elucidate pathophysiological mechanisms and aid in identifying novel targets for treatment. Pain sometimes drugs fail clinically, causing high translational costs due to poor selection and the use of preclinical tools and reporting. To improve the study of pain in a clinical context, researchers have been creating innovative models over the past few decades that better represent pathological pain conditions. In this paper, we provide a summary of traditional animal models, including rodents, cellular models, human volunteers, and alternative models, as well as the specific characteristics of pain diseases they model. However, a more rigorous approach to preclinical research and cutting-edge analgesic technologies may be necessary to successfully create novel analgesics. The research highlights from this review emphasize new opportunities to develop research that includes animals and non-animals using proven methods pertinent to comprehending and treating human suffering. This review highlights the value of using a variety of modern pain models in animals before human trials. These models can help us understand the different mechanisms behind various pain types. This will ultimately lead to the development of more effective pain medications.

Autonomic rehabilitation: Vagal and sympathetic impacts of modified occipitomastoid suture V-spread.

Autonomic rehabilitation using osteopathic manipulative treatment (OMT) to stimulate the vagus nerve may be a good adjunct therapy by physiatrists who treat dysautonomia. Heart rate variability (HRV) may provide quantitative evidence for the benefits of OMT on autonomic nervous system function. Elevated HRV indicates optimal health and reduced mortality risk, whereas low HRV is associated with stress, pain, and chronic disease pathology. To analyze the impact of modified occipitomastoid suture v-spread OMT technique on vagal tone by measuring HRV. Within-participant design with 5-minute HRV measurement pre- and post-OMT treatment. Clinical examination suites. Thirty healthy osteopathic medical students. A modified occipitomastoid suture v-spread treating somatic dysfunction by osteopathic physicians trained in osteopathic neuromusculoskeletal medicine. HRV variables related to vagal tone including root mean square of successive differences (RMSSD), percentage of successive normal sinus RR intervals >50 ms (pNN50), high frequency (HF), Parasympathetic Nervous System Index (PNSI), and Sympathetic Nervous System Index (SNSI). Repeated measures t-test analyzed the difference in mean HRV values after OMT. There were statistically significant increases in each of the HRV measures after OMT. Participants had a mean (95% confidence interval) RMSSD of 50.5 ms (38.3-62.8) at baseline and 55.0 ms (41.2-68.7, p = .013) post-OMT. pNN50 was 24.5% (17.6-31.3, n = 30) at baseline and 28.2% (20.8-35.6, p = .003) post-OMT. HF was 1549.6 ms2 (389.8-2709.4) at baseline and 1901.8 ms2 (618.2-3185.4, p = .103) post-OMT. PNSI was -0.1 (-0.5 to 0.2) at baseline and 0.1 (-0.3 to 1.5, p < .01) post-OMT, and SNSI was 0.2 (-0.1 to 0.6) at baseline and 0.05 (-0.3 to 0.4, p < .01) post-OMT. Normalization, due to high baseline variance, results include RMSSD 1.1 ms (1.0 to 1.1, p = .012), pNN50 1.3 (1.1 to 1.4, p = .011), and HF 1.2 ms2 (1.1 to 1.4, p = .018). Modified occipitomastoid suture v-spread may provide clinical benefit through increased vagal tone and decreased sympathetic activity.

An evaluation of a virtual musculoskeletal podiatry service implemented to address prolonged National Health Service waiting times.

The COVID-19 pandemic had a substantial impact on healthcare systems globally, particularly in the public sector. To address the challenges posed by the pandemic, musculoskeletal (MSK) healthcare providers had to rapidly adopt virtual platforms for delivering care, representing a major shift in how healthcare was delivered. This manuscript aims to retrospectively evaluate a virtual MSK podiatry service offered by a private provider under a National Health Service commission, in terms of patient access, waiting times and patient-reported pain. This service was developed and implemented in response to the COVID-19 pandemic and the extended waiting times. A retrospective clinical service evaluation was conducted on MSK podiatry services delivered via telephone or virtual consultations. The evaluation covered a cohort of 574 referred patients over a 19-month period (July 2021 to January 2023). It analysed demographic data, initial and final visual analogue pain scores, pathology categories, orthoses prescriptions and exercise rehabilitation plans. Data from a total of 492 patients (male=152 and female=340) were analysed, with 82 patients excluded for non-attendance. The average waiting time from referral-to-first appointment and referral-to-discharge was 35 and 91days, respectively. Results showed statistically significant improvement (p<0.001) in the mean visual analogue scale when patients received orthoses with and without a rehabilitation plan (4.12±2.55 and 3.33±2.88, respectively). Most patients (61.5%) were aged 40-69, with "foot pain" being the main reported pathology category. Patients had an average of two appointments. 56.5% of patients remained virtual throughout their journey and were successfully discharged to self-management. 43.9% were discharged to other face-to face services. The study provided evidence that the virtual MSK podiatry service achieved a statistically significant reduction in patient-reported pain for various pathologies with reasonable waiting times. The service delivered favourable outcomes and complemented traditional services at a time with limited access due to the COVID-19 pandemic.

Estrogen receptor α regulates the IKKs/NF-kB activity involved in the development of mechanical allodynia induced by REM sleep deprivation in rats

Several signaling pathways that converge in NF-kB activation have been linked to developing and maintaining different types of pathological pain. In addition, some mechanisms implied in the establishment of chronic pain have been demonstrated to have a sex-dependent correlation. This study aimed to determine if the IKKs/NF-kB signaling pathway is involved in establishing REM sleep deprivation (REMSD) induced mechanical allodynia in rats and its possible regulation depending on estradiol and estrogen receptors. Intrathecal administration of BMS-345541 or minocycline, two drugs that reduce the IKKs/NF-kB activity, avoided the development of mechanical allodynia in female but not in male rats subjected to 48 h of REMSD. Ovariectomy in female rats abolished the effect of BMS-345541 and minocycline. Meanwhile, the 17-β-estradiol restitution restored it. Intrathecal administration of MPP, a selective ERα antagonist, but not PHTPP, a selective ERβ antagonist, avoided the effect of BMS-345541 in female rats without hormonal manipulation. In addition, the transient run-down of ERα in female rats abolished the effect of BMS-345541. All data suggest an important role of ERα as a regulator of the IKKs/NF-kB activity. REMSD increased the ERα protein expression in the dorsal root ganglia and the dorsal spinal cord in females but not in male rats. Interestingly, ERα activation or ERα overexpression allowed the effect of BMS-345541 in male rats. Data suggest an important regulatory role of ERα in the IKKs/NF-kB activity on establishing mechanical allodynia induced by REMSD in female rats.

Cortical kappa opioid receptors integrate negative affect and sleep disturbance

Sleep disruption and negative affect are attendant features of many psychiatric and neurological conditions that are often co-morbid including major depressive disorder, generalized anxiety disorder and chronic pain. Whether there is a causal relationship between negative affect and sleep disruption remains unclear. We therefore asked if mechanisms promoting negative affect can disrupt sleep and whether inhibition of pathological negative affect can normalize disrupted sleep. Signaling at the kappa opioid receptor (KOR) elicits dysphoria in humans and aversive conditioning in animals. We tested the possibility that (a) increased KOR signaling in the anterior cingulate cortex (ACC), a brain region associated with negative emotions, would be sufficient to promote both aversiveness and sleep disruption and (b) inhibition of KOR signaling would normalize pathological negative affect and sleep disruption induced by chronic pain. Chemogenetic Gi-mediated inhibition of KOR-expressing ACC neurons produced conditioned place aversion (CPA) as well as sleep fragmentation in naïve mice. CRISPR/Cas9 editing of ACC KOR normalized both the negative affect and sleep disruption elicited by pathological chronic pain while maintaining the physiologically critical sensory features of pain. These findings suggest therapeutic utility of KOR antagonists for treatment of disease conditions that are associated with both negative affect and sleep disturbances.

Neuromodulation for Neuropathic Pain Syndromes

ABSTRACT OBJECTIVE This article reviews the principles, applications, and emerging trends of neuromodulation as a therapeutic approach for managing painful neuropathic diseases. By parsing evidence for possible mechanisms of action and clinical trial outcomes for various diseases, this article focuses on five common therapy modalities: cutaneous, peripheral nerve, spinal cord, and brain stimulation, and intrathecal drug delivery. LATEST DEVELOPMENTS Recent advances in both invasive and noninvasive neuromodulation for pain have introduced personalized and closed-loop techniques, integrating real-time feedback mechanisms and combining therapies to improve physical and psychosocial function. Novel stimulation waveforms may influence distinct neural tissues to rectify pathologic pain signaling. ESSENTIAL POINTS With appropriate patient selection, peripheral nerve stimulation or epidural stimulation of the spinal cord can provide enduring relief for a variety of chronic pain syndromes. Newer technology using high frequencies, unique waveforms, or closed-loop stimulation may have selective advantages, but our current understanding of therapy mechanisms is very poor. For certain diagnoses and patients who meet clinical criteria, neuromodulation can provide profound, long-lasting relief that significantly improves quality of life. While many therapies are supported by data from large clinical trials, there is a risk of bias as most clinical studies were funded by device manufacturers or insurance companies, which increases the importance of real-world data analysis. Emerging methods like invasive or noninvasive brain stimulation may help us dissect basic mechanisms of pain processing and hold promise for personalized therapies for refractory pain syndromes. Finally, intrathecal delivery of drugs directly to segments of the spinal cord can also modify pain signaling to provide therapy for severe pain syndromes.

CONCEPTUAL STUDY ON THE MANAGEMENT OF GRIDHRASI : A REVIEW ARTICLE

The modern lifestyle has given rise to a number of health-related issues. A growing number of musculoskeletal conditions include sciatica. Sciaticas signs and symptoms are similar to those of Gridhrasi, also known as Shoolpradhan Vatavayadhi in Ayurveda. Given that the patients gait resembles that of a vulture (gridhra) and that his legs are inflexible and slightly bowed, the disease may have derived its name from the bird gridhra. According to Sushruta, the kandara of Gridhrasi is impacted by the vitiated Vata dosha, making it difficult for the patient to extend their leg. Sciatica is an extremely painful ailment where pain radiates along the posteriolateral portion of the leg and thigh from the lumbar area. The quality of life is negatively impacted by low back discomfort, especially during ones prime working years. Since over 75% of people worldwide have had low back pain at some point in their lives, the incidence rate of low back pain is noteworthy. It is the most typical illness that keeps people from working. This illness leaves the victim partially disabled since they may not be able to stand, walk, or sit comfortably. The two basic areas of treatment in modern medicine are surgical pathology repair and pain management. The goal of Ayurvedic treatment is to rectify the underlying functional imbalance in order to restore harmony. The goal of Ayurvedic Gridhrasi treatments is to restore the imbalanced Vata or Vata Kapha to health by bringing it back to equilibrium.

Establishment of a Magnetically Controlled Scalable Nerve Injury Model.

Animal models of peripheral nerve injury (PNI) serve as the fundamental basis for the investigations of nerve injury, regeneration, and neuropathic pain. The injury properties of such models, including the intensity and duration, significantly influence the subsequent pathological changes, pain development, and therapeutic efficacy. However, precise control over the intensity and duration of nerve injury remains challenging within existing animal models, thereby impeding accurate and comparative assessments of relevant cases. Here, a new model that provides quantitative and off-body controllable injury properties via a magnetically controlled clamp, is presented. The clamp can be implanted onto the rat sciatic nerve and exert varying degrees of compression under the control of an external magnetic field. It is demonstrated that this model can accurately simulate various degrees of pathology of human patients by adjusting the magnetic control and reveal specific pathological changes resulting from intensity heterogeneity that are challenging to detect previously. The controllability and quantifiability of this model may significantly reduce the uncertainty of central response and inter-experimenter variability, facilitating precise investigations into nerve injury, regeneration, and pain mechanisms.

Structural reorganization of medullary dorsal horn astrocytes in a rat model of neuropathic pain.

Multiple studies have shown that astrocytes in the medullary dorsal horn (MDH) play an important role in the development of pathologic pain. However, little is known about the structural reorganization of the peripheral astrocytic processes (PAP), the main functional part of the astrocyte, in MDH in neuropathic state. For this, we investigated the structural relationship between PAP and their adjacent presynaptic axon terminals and postsynaptic dendrites in the superficial laminae of the MDH using electron microscopical immunohistochemistry for ezrin, a marker for PAP, and quantitative analysis in a rat model of neuropathic pain following chronic constriction injury of the infraorbital nerve (CCI-ION). We found that, compared to controls, in rats with CCI-ION, (1) the number, % area, surface density, and volume fraction of ezrin-positive (+) PAP, as well as the fraction of synaptic edge apposed by ezrin + PAP and the degree of its coverage of presynaptic axon terminals and postsynaptic dendrites increased significantly, (2) these effects were abolished by administration of the mGluR5 antagonist 2-methyl-6-(phenylethynyl) pyridine (MPEP). These findings indicate that PAP undergoes structural reorganization around the central synapses of sensory afferents following nerve injury, suggest that it may be mediated by mGluR5, and may represent the structural basis for enhancing astrocyte-neuron interaction in neuropathic pain.

Pain pathophysiology and pharmacology of cattle: how improved understanding can enhance pain prevention, mitigation, and welfare.

Globally, humans rely on cattle for food production; however, there is rising societal concern surrounding the welfare of farm animals. From a young age, cattle raised for dairy and beef production experience pain caused by routine management procedures and common disease conditions. The fundamental mechanisms, nociceptive pathways, and central nervous system structures required for pain perception are highly conserved among mammalian species. However, there are limitations to a comparative approach to pain assessment due to interspecies differences in the expression of pain. The stoicism of prey species may impede pain identification and lead to the assumption that cattle lack pain sensitivity. This highlights the importance of establishing validated bovine-specific indicators of pain-a prerequisite for evidence-based pain assessment and mitigation. Our first objective is to provide an overview of pain pathophysiology to illustrate the importance of targeted analgesia in livestock medicine and the negative welfare outcomes associated with unmitigated pain. This is followed by a review of available analgesics, the regulations governing their use, and barriers to implementation of on-farm pain management. We then investigate the current research undertaken to evaluate the pain response in cattle-a critical aspect of the drug approval process. With an emphasis on emerging research in animal cognition and pain pathology, we conclude by discussing the significant influence that pain has on cattle welfare and areas where further research and modified practices are indicated.

Nucleoside Reverse Transcriptase Inhibitors Are the Major Class of HIV Antiretroviral Therapeutics That Induce Neuropathic Pain in Mice.

The development of combination antiretroviral therapy (cART) has transformed human immunodeficiency virus (HIV) infection from a lethal diagnosis into a chronic disease, and people living with HIV on cART can experience an almost normal life expectancy. However, these individuals often develop various complications that lead to a decreased quality of life, some of the most significant of which are neuropathic pain and the development of painful peripheral sensory neuropathy (PSN). Critically, although cART is thought to induce pain pathogenesis, the relative contribution of different classes of antiretrovirals has not been systematically investigated. In this study, we measured the development of pathological pain and peripheral neuropathy in mice orally treated with distinct antiretrovirals at their translational dosages. Our results show that only nucleoside reverse transcriptase inhibitors (NRTIs), not other types of antiretrovirals such as proteinase inhibitors, non-nucleoside reverse transcriptase inhibitors, integrase strand transfer inhibitors, and CCR5 antagonists, induce pathological pain and PSN. Thus, these findings suggest that NRTIs are the major class of antiretrovirals in cART that promote the development of neuropathic pain. As NRTIs form the essential backbone of multiple different current cART regimens, it is of paramount clinical importance to better understand the underlying mechanism to facilitate the design of less toxic forms of these drugs and/or potential mitigation strategies.

The Phytochemical, Quercetin, Attenuates Nociceptive and Pathological Pain: Neurophysiological Mechanisms and Therapeutic Potential.

Although phytochemicals are plant-derived toxins that are primarily produced as a form of defense against insects or microbes, several lines of study have demonstrated that the phytochemical, quercetin, has several beneficial biological actions for human health, including antioxidant and inflammatory effects without side effects. Quercetin is a flavonoid that is widely found in fruits and vegetables. Since recent studies have demonstrated that quercetin can modulate neuronal excitability in the nervous system, including nociceptive sensory transmission via mechanoreceptors and voltage-gated ion channels, and inhibit the cyclooxygenase-2-cascade, it is possible that quercetin could be a complementary alternative medicine candidate; specifically, a therapeutic agent against nociceptive and pathological pain. The focus of this review is to elucidate the neurophysiological mechanisms underlying the modulatory effects of quercetin on nociceptive neuronal activity under nociceptive and pathological conditions, without inducing side effects. Based on the results of our previous research on trigeminal pain, we have confirmed in vivo that the phytochemical, quercetin, demonstrates (i) a local anesthetic effect on nociceptive pain, (ii) a local anesthetic effect on pain related to acute inflammation, and (iii) an anti-inflammatory effect on chronic pain. In addition, we discuss the contribution of quercetin to the relief of nociceptive and inflammatory pain and its potential clinical application.

Sensors and Devices Guided by Artificial Intelligence for Personalized Pain Medicine.

Personalized pain medicine aims to tailor pain treatment strategies for the specific needs and characteristics of an individual patient, holding the potential for improving treatment outcomes, reducing side effects, and enhancing patient satisfaction. Despite existing pain markers and treatments, challenges remain in understanding, detecting, and treating complex pain conditions. Here, we review recent engineering efforts in developing various sensors and devices for addressing challenges in the personalized treatment of pain. We summarize the basics of pain pathology and introduce various sensors and devices for pain monitoring, assessment, and relief. We also discuss advancements taking advantage of rapidly developing medical artificial intelligence (AI), such as AI-based analgesia devices, wearable sensors, and healthcare systems. We believe that these innovative technologies may lead to more precise and responsive personalized medicine, greatly improved patient quality of life, increased efficiency of medical systems, and reducing the incidence of addiction and substance use disorders.

Spinal cord microglia drive sex differences in ethanol-mediated PGE2-induced allodynia

The mechanisms of how long-term alcohol use can lead to persistent pain pathology are unclear. Understanding how earlier events of short-term alcohol use can lower the threshold of non-painful stimuli, described as allodynia could prove prudent to understand important initiating mechanisms. Previously, we observed that short-term low-dose alcohol intake induced female-specific allodynia and increased microglial activation in the spinal cord dorsal horn. Other literature describes how chronic ethanol exposure activates Toll-like receptor 4 (TLR4) to initiate inflammatory responses. TLR4 is expressed on many cell types, and we aimed to investigate whether TLR4 on microglia is sufficient to potentiate allodynia during a short-term/low-dose alcohol paradigm. Our study used a novel genetic model where TLR4 expression is removed from the entire body by introducing a floxed transcriptional blocker (TLR4-null background (TLR4LoxTB)), then restricted to microglia by breeding TLR4LoxTB animals with Cx3CR1:CreERT2 animals. As previously reported, after 14 days of ethanol administration alone, we observed no increased pain behavior. However, we observed significant priming effects 3 hrs post intraplantar injection of a subthreshold dose of prostaglandin E2 (PGE2) in wild-type and microglia-TLR4 restricted female mice. We also observed a significant female-specific shift to pro-inflammatory phenotype and morphological changes in microglia of the lumbar dorsal horn. Investigations in pain priming-associated neuronal subtypes showed an increase of c-Fos and FosB activity in PKCγ interneurons in the dorsal horn of female mice directly corresponding to increased microglial activity. This study uncovers cell- and female-specific roles of TLR4 in sexual dimorphisms in pain induction among non-pathological drinkers.

An approach leveraging radiomics and model checking for the automatic early diagnosis of adhesive capsulitis

Adhesive Capsulitis of the shoulder is a painful pathology limiting shoulder movements, commonly known as “Frozen Shoulder”. Since this pathology limits movement, it is important to make an early diagnosis. Diagnosing capsulitis relies on clinical assessment, although diagnostic imaging, such as Magnetic Resonance Imaging, can provide predictive or supportive information for specific characteristic signs. However, its diagnosis is not so simple nor so immediate, indeed it remains a difficult topic for many general radiologists and expert musculoskeletal radiologists. This study aims to investigate whether it is possible to use disease signs within a medical image to automatically diagnose Adhesive Capsulitis. To this purpose, we propose an automatic Model Checking-based approach to quickly diagnose the Adhesive Capsulitis taking as input the radiomic feature values from the medical images. Furthermore, we compare the performance achieved by our method with diagnostic results obtained by professional radiologists with different levels of experience. To the best of our knowledge, this is the first method for the automatic diagnosis of Adhesive Capsulitis of the Shoulder.

Corticothalamic input derived from corticospinal neurons contributes to chronic neuropathic pain after spinal cord injury

Neuropathic pain is a significant and persistent issue for individuals with spinal cord injuries (SCI), severely impacting their quality of life. While changes at the peripheral and spinal levels are known to contribute to SCI-related pain, whether and how supraspinal centers contribute to post SCI chronic neuropathic pain is poorly understood. Here, we first validated delayed development of chronic neuropathic pain in mice with moderate contusion SCI. To identify supraspinal regions involved in the pathology of neuropathic pain after SCI, we next performed an activity dependent genetic screening and identified multiple cortical and subcortical regions that were activated by innocuous tactile stimuli at a late stage following contusion SCI. Notably, chemogenetic inactivation of pain trapped neurons in the lateral thalamus alleviated neuropathic pain and reduced tactile stimuli evoked cortical overactivation. Retrograde tracing showed that contusion SCI led to enhanced corticothalamic axonal sprouting and over-activation of corticospinal neurons. Mechanistically, ablation or silencing of corticospinal neurons prevented the establishment or maintenance of chronic neuropathic pain following contusion SCI. These results highlighted a corticospinal-lateral thalamic feed-forward loop whose activation is required for the development and maintenance of chronic neuropathic pain after SCI. Our data thus shed lights into the central mechanisms underlying chronic neuropathic pain associated with SCI and the development of novel therapeutic avenues to treat refractory pain caused by traumatic brain or spinal cord injuries.