Accepted

Clinical evidence suggests that pain hypersensitivity develops in patients with attention-deficit/hyperactivity disorder (ADHD). However, the mechanisms and neural circuits involved in these interactions remain unknown because of the paucity of studies in animal models. We previously validated a mouse model of ADHD obtained by neonatal 6-hydroxydopamine (6-OHDA) injection. Here, we have demonstrated that 6-OHDA mice exhibit a marked sensitization to thermal and mechanical stimuli, suggesting that phenotypes associated with ADHD include increased nociception. Moreover, sensitization to pathological inflammatory stimulus is amplified in 6-OHDA mice as compared to shams. In this ADHD model, spinal dorsal horn neuron hyperexcitability was observed. Furthermore, ADHD-related hyperactivity and anxiety, but not inattention and impulsivity, are worsened in persistent inflammatory conditions. By combining in vivo electrophysiology, optogenetics, and behavioral analyses, we demonstrated that anterior cingulate cortex (ACC) hyperactivity alters the ACC-posterior insula circuit and triggers changes in spinal networks that underlie nociceptive sensitization. Altogether, our results point to shared mechanisms underlying the comorbidity between ADHD and nociceptive sensitization. This interaction reinforces nociceptive sensitization and hyperactivity, suggesting that overlapping ACC circuits may be targeted to develop better treatments.

Neuropathic pain, characterized by persistent or intermittent spontaneous pain as well as some unpleasant abnormal sensations, is one of the most prevalent health problems in the world. Ectopic nerve activity, central and peripheral nociceptive sensitization and many other potential mechanisms may participate in neuropathic pain. The complexity and ambiguity of neuropathic pain mechanisms result in difficulties in pain management, and existing treatment plans provide less-than-satisfactory relief. In recent years, single-cell RNA sequencing (scRNA-seq) has been increasingly applied and has become a powerful means for biological researchers to explore the complexity of neurobiology. This technique can be used to perform unbiased, high-throughput and high-resolution transcriptional analyses of neuropathic pain-associated cells, improving the understanding of neuropathic pain mechanisms and enabling individualized pain management. To date, scRNA-seq has been preliminarily used in neuropathic pain research for applications such as compiling a dorsal root ganglion (DRG) atlas, identifying new cell types and discovering gene regulatory networks associated with neuropathic pain. Although scRNA-seq is a relatively new technique in the neuropathic pain field, there have been several studies based on animal models. However, because of the various differences between animals and humans, more attention should be given to translational medicine research. With the aid of scRNA-seq, researchers can further explore the mechanism of neuropathic pain to improve the clinical understanding of the diagnosis, treatment and management of neuropathic pain.

Mechanical allodynia has been studied in chronic naltrexone-treated people (N.T.P.) and rats (N.T.R.). After persistent naltrexone administration, patients acquired static and dynamic mechanical allodynia, as measured by von Frey filament (vFf) and brush stimulations. Pregabalin and levodopa administrations in N.T.P. significantly reduced allodynic behaviour, albeit these molecules did not completely stop it. As evidenced by the deployment of the vFf, subchronic treatment with Naltrexone delivered peripherally or intrathecally induced allodynic behaviour in rats. Increased expressions of two pain markers, pERK1/2 and PKCγ, in the spinal dorsal horn laminae were associated with naltrexone-induced allodynic behaviour. After vFf stimulation, pERK1/2 expression was substantially higher (p<0.001) in superficial spinal dorsal horn laminae than in non-stimulated or naive non-stimulated rats. In addition, when compared to control rats, N.T.R. showed a substantial (p<0.001) increase in PKCγ expression. PKCγ expression was found to be strong in lamina IIi and laminae III-IV. A cellular mechanism is proposed for the naltrexone effect. In both people and rats, Naltrexone induces static mechanical allodynia, according to this study.

Brain corticostriatal circuits are important for understanding chronic pain and highly relevant to motivation and cognitive processes. It has been demonstrated that in patients with chronic back pain, altered nucleus accumbens (NAcc)-medial prefrontal cortex (MPFC) circuit fMRI-based activity is predictive of patient outcome. We evaluated the NAcc-MPFC circuit in patients with another chronic pain condition, fibromyalgia, to extend these important findings. First, we compared fMRI-based NAcc-MPFC resting-state functional connectivity in patients with fibromyalgia (N = 32) vs. healthy controls (N = 37). Compared to controls, the NAcc-MPFC circuit's connectivity was significantly reduced in fibromyalgia. In addition, within the fibromyalgia group, NAcc-MPFC connectivity was significantly correlated with trait anxiety. Our expanded connectivity analysis of the NAcc to subcortical brain regions showed reduced connectivity of the right NAcc with mesolimbic circuit regions (putamen, thalamus, and ventral pallidum) in fibromyalgia. Lastly, in an exploratory analysis comparing our fibromyalgia and healthy control cohorts to a separate publicly available dataset from patients with chronic back pain, we identified reduced NAcc-MPFC connectivity across both the patient groups with unique alterations in NAcc-mesolimbic connectivity. Together, expanding upon prior observed alterations in brain corticostriatal circuits, our results provide novel evidence of altered corticostriatal and mesolimbic circuits in chronic pain.

A subset of patients undergoing total knee arthroplasty (TKA) for knee osteoarthritis develop debilitating knee stiffness (reduced range of motion) for poorly understood reasons. Dysregulated inflammatory and immune responses to surgery correlate with reduced surgical outcomes, but the dysregulated gene signatures in patients with stiffness after TKA are poorly defined. As a consequence, we are limited in our ability to identify patients at risk of developing poor surgical outcomes and develop preventative approaches. In this pilot study we aimed to identify perioperative blood gene signatures in patients undergoing TKA for knee osteoarthritis and its association with early surgical outcomes, specifically knee range of motion. To do this, we integrated clinical outcomes collected at 6 weeks after surgery with transcriptomics analyses in blood samples collected immediately before surgery and at 24 h after surgery. We found that patients with stiffness at 6 weeks after surgery have a more variable and attenuated circulating gene expression response immediately after surgery. Our results suggest that patients with stiffness following TKA may have distinct gene expression signatures detectable in peripheral blood in the immediate postoperative period.

The chronification of pain is heterogeneous in rheumatology. Chronic overlapping pain conditions (COPCs) such as fibromyalgia, endometriosis, migraine, and back pain may co-occur with one another and in rheumatic diseases. We describe the sociodemographic and clinical profiles associated with concomitant COPCs among patients with rheumatic diseases.

Chemotherapy induced peripheral neuropathy (CIPN) is a frequent, disabling side effect of anticancer drugs. Oxaliplatin, a platinum compound used in the treatment of advanced colorectal cancer, often leads to a form of CIPN characterized by mechanical and cold hypersensitivity. Current therapies for CIPN are ineffective, often leading to the cessation of treatment. Transient receptor potential ankyrin 1 (TRPA1) is a polymodal, non-selective cation-permeable channel expressed in nociceptors, activated by physical stimuli and cellular stress products. TRPA1 has been linked to the establishment of CIPN and other painful neuropathic conditions. Sigma-1 receptor is an endoplasmic reticulum chaperone known to modulate the function of many ion channels and receptors. S1RA, a highly selective antagonist of Sigma-1 receptor has shown effectiveness in a phase II clinical trial for oxaliplatin CIPN. However, the mechanisms involved in the beneficial effects of S1RA are little understood. We combined biochemical and biophysical (i.e. intermolecular FRET) techniques to demonstrate the interaction between Sigma-1 receptor and human TRPA1. Pharmacological antagonism of Sigma-1R impaired the formation of this molecular complex and the trafficking of functional TRPA1 to the plasma membrane. Using patch-clamp electrophysiological recordings we found that antagonists of Sigma-1 receptor, including S1RA, exert a marked inhibition on plasma membrane expression and function of human TRPA1 channels. In TRPA1-expressing mouse sensory neurons, S1RA reduced inward currents and the firing of actions potentials in response to TRPA1 agonists. Finally, in a mouse experimental model of oxaliplatin neuropathy, systemic treatment with a S1RA prevented the development of painful symptoms by a mechanism involving TRPA1. In summary, the modulation of TRPA1 channels by Sigma-1 receptor antagonists suggests a new strategy for the prevention and treatment of CIPN and could inform the development of novel therapeutics for neuropathic pain.

Polyunsaturated fatty acids (PUFAs) play a role in pain regulation. This study sought to determine whether free PUFAs found in red blood cells also play a role in nociceptive processing. We examined associations between circulating PUFAs and nociceptive thresholds to noxious mechanical stimuli. We also determined whether nociceptive thresholds were associated with nociplastic pain conditions.

There are many surgical operations performed daily in operation rooms worldwide. Adequate anesthesia is needed during an operation. Besides hypnosis, adequate analgesia is critical to prevent autonomic reactions. Clinical experience and vital signs are usually used to adjust the dosage of analgesics. Analgesia nociception index (ANI), which ranges from 0 to 100, is derived from heart rate variability (HRV) via electrocardiogram (ECG) signals, for pain evaluation in a non-invasive manner. It represents parasympathetic activity. In this study, we compared the performance of multilayer perceptron (MLP) and long short-term memory (LSTM) algorithms in predicting expert assessment of pain score (EAPS) based on patient's HRV during surgery. The objective of this study was to analyze how deep learning models differed from the medical doctors' predictions of EAPS. As the input and output features of the deep learning models, the opposites of ANI and EAPS were used. This study included 80 patients who underwent operations at National Taiwan University Hospital. Using MLP and LSTM, a holdout method was first applied to 60 training patients, 10 validation patients, and 10 testing patients. As compared to the LSTM model, which had a testing mean absolute error (MAE) of 2.633 ± 0.542, the MLP model had a testing MAE of 2.490 ± 0.522, with a more appropriate shape of its prediction curves. The model based on MLP was selected as the best. Using MLP, a seven-fold cross validation method was then applied. The first fold had the lowest testing MAE of 2.460 ± 0.634, while the overall MAE for the seven-fold cross validation method was 2.848 ± 0.308. In conclusion, HRV analysis using MLP algorithm had a good correlation with EAPS; therefore, it can play role as a continuous monitor to predict intraoperative pain levels, to assist physicians in adjusting analgesic agent dosage. Further studies may consider obtaining more input features, such as photoplethysmography (PPG) and other kinds of continuous variable, to improve the prediction performance.

Rheumatoid arthritis is the most common autoimmune disease worldwide and requires long-term treatment to suppress inflammation. Currently, treatment is started when arthritis is clinically apparent. We aimed to evaluate whether earlier intervention, in the preceding phase of arthralgia and subclinical joint inflammation, could prevent the development of clinical arthritis or reduce the disease burden.