Papers: 1 Jan 2022 - 7 Jan 2022

Family history of alcohol use disorder (AUD) is frequently endorsed by persons with chronic pain. Although individuals with a family history of AUD have demonstrated enhanced sensitivity to painful stimulation, previous research has not examined endogenous pain modulation in this population. The goal of this study was to test family history of AUD as a predictor of conditioned pain modulation, offset analgesia, and temporal summation among a sample of moderate and heavy drinkers. Adults with no current pain (N = 235; 58.3% male; M = 34.3; 91.9% non-Hispanic; 60% white) were evaluated for family history of AUD at baseline and pain modulatory outcomes were assessed via quantitative sensory testing. Participants with a family history of AUD (relative to those without) evinced a pro-nociceptive pain modulation profile in response to experimental pain. Specifically, family history of AUD was associated with deficits in pain-inhibitory processes. Approximately 4% of the variance in endogenous pain modulation was accounted for by family history, and exploratory analyses suggested these effects may be driven by paternal AUD.

Patients with chronic kidney disease (CKD) frequently experience unpleasant symptoms. These can be gastrointestinal (constipation, nausea, vomiting and diarrhoea), psychological (anxiety and sadness), neurological (lightheadedness, headache and numbness), cardiopulmonary (shortness of breath and oedema), dermatological (pruritus and dry skin), painful (muscle cramps, chest pain and abdominal pain) or involve sexual dysfunction, sleep disorders and fatigue. These symptoms often occur in clusters, with one of them as the lead symptom and others as secondary symptoms. Uraemic toxins (also called uremic toxins) are often considered to be the main cause of CKD-associated symptom burden, but treatment of uraemia by dialysis often fails to resolve them and can engender additional symptoms. Indeed, symptoms can be exacerbated by comorbid conditions, pharmacotherapies, lifestyle and dietary regimens, kidney replacement therapy and ageing. Patients with kidney disease, including those who depend on dialysis or transplantation, should feel actively supported in their symptom management through the identification and targeting of unpleasant symptoms via a tailored palliative care approach. Such an approach may help minimize the burden and consequences of kidney disease, and lead to improved patient outcomes including health-related quality of life and better life participation.

The voltage-gated sodium channel isoform NaV1.7 is a critical player in the transmission of nociceptive information. This channel has been heavily implicated in human genetic pain disorders and is a validated pain target. However, targeting this channel directly has failed, and an indirect approach – disruption of interactions with accessory protein partners – has emerged as a viable alternative strategy. We recently reported that a small-molecule inhibitor of CRMP2 SUMOylation, compound , selectively reduces NaV1.7 currents in DRG neurons across species from mouse to human. This compound also reversed mechanical allodynia in a spared nerve injury and chemotherapy-induced model of neuropathic pain. Here, we show that oral administration of reverses mechanical allodynia in a chronic constriction injury (CCI) model of neuropathic pain. Furthermore, we show that orally administered reverses the increased latency to cross an aversive barrier in a mechanical conflict-avoidance task following CCI. These two findings, in the context of our previous report, support the conclusion that is a robust inhibitor of NaV1.7 function with the ultimate effect of profoundly ameliorating mechanical allodynia associated with nerve injury. The fact that this was observed using both traditional, evoked measures of pain behavior as well as the more recently developed operator-independent mechanical conflict-avoidance assay increases confidence in the efficacy of -induced anti-nociception.

The value of understanding patients' illness experience and social contexts for advancing medicine and clinical care is widely acknowledged. However, methodologies for rigorous and inclusive data gathering and integrative analysis of biomedical, cultural, and social factors are limited. In this paper, we propose a digital strategy for large-scale qualitative health research, using (as a state of being, a communication mode or context, and a set of imaginative, expressive, and game-like activities) as a research method for recursive learning and action planning. Our proposal builds on Gregory Bateson's cybernetic approach to knowledge production. Using chronic pain as an example, we show how pragmatic, structural and cultural constraints that define the relationship of patients to the healthcare system can give rise to conflicted messaging that impedes inclusive health research. We then review existing literature to illustrate how different types of play including games, chatbots, virtual worlds, and creative art making can contribute to research in chronic pain. Inspired by Frederick Steier's application of Bateson's theory to designing a science museum, we propose DiSPORA (Digital Strategy for Play-Oriented Research and Action), a virtual citizen science laboratory which provides a framework for delivering health information, tools for play-based experimentation, and data collection capacity, but is flexible in allowing participants to choose the mode and the extent of their interaction. Combined with other data management platforms used in epidemiological studies of neuropsychiatric illness, DiSPORA offers a tool for large-scale qualitative research, digital phenotyping, and advancing personalized medicine.

It is well known that acute exposure to physical stress produces a transient antinociceptive effect (called stress-induced analgesia [SIA]). One proposed mechanism for SIA involves noradrenaline (NA) in the central nervous system. NA has been reported to activate inhibitory neurons in the spinal dorsal horn (SDH), but its in vivo role in SIA remains unknown. In this study, we found that an antinociceptive effect on noxious heat after acute exposure to restraint stress was impaired in mice with a conditional knockout of α-adrenaline receptors (α-ARs) in inhibitory neurons (Vgat-Cre;Adra1a mice). A similar reduction was also observed in mice treated with N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine, a selective neurotoxin for NAergic neurons in the locus coeruleus (LC). Furthermore, whole-cell patch-clamp recordings using spinal cord slices revealed that NA-induced increase in the frequency of spontaneous inhibitory postsynaptic currents in the substantia gelatinosa neurons was suppressed by silodosin, an α-AR antagonist, and by conditional knockout of α-ARs in inhibitory neurons. Moreover, under unstressed conditions, the antinociceptive effects of intrathecal NA and phenylephrine on noxious heat were lost in Vgat-Cre;Adra1a mice. Our findings suggest that activation of α-ARs in SDH inhibitory neurons, presumably via LC-NAergic neurons, is necessary for SIA to noxious heat.

We reported gender-specific data on the efficacy and safety of erenumab, a monoclonal antibody antagonizing the calcitonin gene-related peptide (CGRP) receptor. Our pooled patient-level analysis of real-world data included patients treated with erenumab and followed up for 12 weeks. We considered the following outcomes at weeks 9-12 of treatment compared with baseline: 0-29%, 30-49%, 50-75%, and ≥75% responder rates, according to the decrease in monthly headache days (MHDs), rate of treatment stopping, change in MHDs, monthly migraine days (MMDs), monthly days of acute medication and triptan use, and Headache Impact Test-6 (HIT-6) score from baseline to weeks 9-12. Outcomes were compared between men and women by the chi-squared test or -test, as appropriate. An analysis of covariance (ANCOVA) was performed to identify factors influencing the efficacy outcomes. We included 1,410 patients from 16 centers, of which 256 (18.2%) were men. Men were older than women and had a lower number of MHDs at baseline. At weeks 9-12, compared with baseline, 46 (18.0%) men had a ≥75% response, 75 (29.3%) had a 50-74% response, 35 (13.7%) had a 30-49% response, and 86 (33.6%) had a 0-29% response, while 14 (5.5%) stopped the treatment. The corresponding numbers for women were 220 (19.1%), 314 (27.2%), 139 (12.0%), 402 (34.8%), and 79 (6.8%). No gender difference was found in any of the outcomes. The ANCOVA showed that gender did not influence the efficacy of outcomes. We found that erenumab is equally safe and effective in men compared with women after 12 weeks.

Neuropathic pain refers to a lesion or disease of peripheral and/or central somatosensory neurons and is an important body response to actual or potential nerve damage. We investigated the therapeutic potential of two thiadiazine-thione [TDT] derivatives, 2-(5-propyl-6-thioxo-1, 3, 5-thiadiazinan-3-yl) acetic acid [TDT1] and 2-(5-propyl-2-thioxo-1, 3, 5-thiadiazinan-3-yl) acetic acid [TDT2] against CCI (chronic constriction injury)-induced neuroinflammation and neuropathic pain. Mice were used for assessment of acute toxicity of TDT derivatives and no major toxic/bizarre responses were observed. Anti-inflammatory activity was assessed using the carrageenan test, and both TDT1 and TDT2 significantly reduced carrageenan-induced inflammation. We also used rats for the induction of CCI and performed allodynia and hyperalgesia-related behavioral tests followed by biochemical and morphological analysis using RT-qPCR, immunoblotting, immunohistochemistry and immunofluorescence. Our findings revealed that CCI induced clear-cut allodynia and hyperalgesia which was reversed by TDT1 and TDT2. To determine the function of TDT1 and TDT2 in glia-mediated neuroinflammation, Iba1 mRNA and protein levels were measured in spinal cord tissue sections from various experimental groups. Interestingly, TDT1 and TDT2 substantially reduced the mRNA expression and protein level of Iba1, implying that TDT1 and TDT2 may mitigate CCI-induced astrogliosis. molecular docking studies predicted that both compounds had an effective binding affinity for TNF-α and COX-2. The compounds interactions with the proteins were dominated by both hydrogen bonding and van der Waals interactions. Overall, these results suggest that TDT1 and TDT2 exert their neuroprotective and analgesic potentials by ameliorating CCI-induced allodynia, hyperalgesia, neuroinflammation and neuronal degeneration in a dose-dependent manner.

The prevalence of Trigeminal Neuralgia (TN) in patients diagnosed with multiple sclerosis (MS) is insufficiently understood and controversially reported. This study focused on providing a better understanding of the prevalence of TN in MS patients.

Pressure pain threshold (PPT) is a widely applied method for measuring the magnitude of increased peripheral and central pain sensitivity causing hyperalgesia in knee osteoarthritis (OA). Although manual therapy techniques effects positively PPT, the effect of end-range Maitland mobilization has not been evaluated in knee OA.

To explore how health care providers in the United States are adapting clinical recommendations and prescriptive practices in response to patient use of medical cannabis (MC) for chronic pain symptoms.

Suitable models are needed to investigate urothelial epithelial to mesenchymal transition (EMT) and pro-fibrogenesis phenotype in bladder pain syndrome/interstitial cystitis (BPS/IC). This study is to establish a novel experimental BPS/IC cell model and explore how different concentrations of tumor necrosis factor (TNF)-α influence the EMT and pro-fibrogenesis phenotype of urothelial cells.

Osteoarthritis (OA) is a common progressively degenerative joint disease that affects more than 300 million people worldwide. OA is manifested by articular cartilage degradation, chronic pain, deformity, functional disability, and decreased quality of life. A real challenge in OA management is the lack of an effective cure because exiting therapeutics often provide symptom control rather than disease modification; therefore, they fail to prevent disease progression. The inadequate treatments for OA management have encouraged researchers to study mesenchymal stem cells (MSCs) as an investigational treatment for OA. MSCs are a promising tool for OA because of their availability; expand cultivation and multi-lineage differentiation capacity as well as well-documented paracrine function have made MSCs a promising tool in this field. Accordingly, MSCs application has been successfully utilized in a broad range of pre-clinical OA animal models as well as clinical studies with the aim of cartilage repair which had not previously been achieved using classical treatments. Here, the brief scientific review of MSC role in the control of OA as well as the proposed mechanisms are discussed. We provide an insight into the last 10 years' studies conducted on preclinical and clinical OA treatment as well as future opportunities in OA management strategies employing MSCs.

Оligoarginines were recently discovered (Lebedev et al., 2019 Nov) [1] as a novel class of nicotinic acetylcholine receptors (nAChRs) inhibitors, octaoligoarginine R8 showing a relatively high affinity (40 nM) for the α9/α10 nAChR. Since the inhibition of α9/α10 nAChR by α-conotoxin RgIA and its analogs is a possible way to drugs against neuropathic pain, here in a mice model we compared R8 with α-conotoxin RgIA in the effects on the chemotherapy-induced peripheral neuropathy (CIPN), namely on the long-term oxaliplatin induced neuropathy. Tests of cold allodynia, hot plate, Von Frey and grip strength analysis revealed for R8 and α-conotoxin RgIA similar positive effects, expressed most prominently after two weeks of administration. Histological analysis of the dorsal root ganglia sections showed for R8 and RgIA a similar partial correction of changes in the nuclear morphology of neurons. Since α9/α10 nAChR might be not the only drug target for R8, we analyzed the R8 action on rat TRPV1 and TRPA1, well-known nociceptive receptors. Against rTRPV1 at 25 μM there was no inhibition, while for rTRPA1 IC was about 20 μM. Thus, involvement of rTRPA1 cannot be excluded, but in view of the R8 much higher affinity for α9/α10 nAChR the latter seems to be the main target and the easily synthesized R8 can be considered as a potential candidate for a drug design.

The assessment and management of urologic chronic pelvic pain syndrome (UCPPS), is controversial. It is classified by voiding symptoms, pelvic pain, and bladder pain, which is weekly treated, weekly understood, and bothersome. In the aspect of clinical efforts and research to help people with this syndrome have been hampered by the deficiency of a widely reliable, accepted, and a valuable tool to evaluate the patient symptoms and quality of life (QoL) impact. However, the etiology comes into sight is multifactorial, and available treatment options have been imprecise considerably in present years. We compiled the published literature on the assessment of the syndrome, a tentative role of pharmacological and non-pharmacological (conservative, alternative, and invasive therapy) interventions in eradicating the disease as well as improving symptoms. The previously published literature on animal models has established the association of immune systems in the etiology, pathogenesis, and progression of the disease. The UPOINT system for clinical phenotyping of UCPPS patients has six predefined domains that direct multimodal therapy, which would lead to significant symptom improvement in the medical field. The narrative review aims to scrutinize the fluctuating scientist's views on the evaluation of patient and multimodal treatment of the UPOINT system.

Pain management is an important priority in the treatment of acute pancreatitis (AP). Current evidence and guideline recommendations are inconsistent on the most effective analgesic protocol. This systematic review and meta-analysis of randomised controlled trials (RCTs) aimed to compare the safety and efficacy of analgesics for pain relief in AP. A literature search was performed to identify all RCTs assessing analgesics in patients with AP. The primary outcome was the number of participants who needed rescue analgesia. Study quality was assessed using Jadad score. Pooled odds ratios (ORs) or weighted mean differences (WMDs) with 95% confidence intervals (CI) were analysed using a random-effects model. Twelve studies comprising 699 patients with AP (83% mild AP) were analysed. The tested analgesics significantly decreased the need for rescue analgesia (3 studies, OR.36, 95% CI 0.21 to 0.60) vs. placebo or conventional treatment. The analgesics also improved the pain score [Visual Analogue Scale (Δ-VAS)] at 24 h (WMD 18.46, 0.84 to 36.07) and by the 3rd to 7th days (WMD 11.57, 0.87 to 22.28). Opioids vs. non-opioids were associated with a decrease in the need for rescue analgesia (6 studies, OR 0.25, 95% CI 0.07 to 0.86, = 0.03) but without significance in pain score. In subgroup analyses, opioids were similar to non-steroidal anti-inflammatory drugs (NSAIDs) regarding the primary outcome (4 studies, OR 0.56, 95% CI 0.24 to 1.32, = 0.18). There were no significant differences in other clinical outcomes and rate of adverse events. Other studies, comparing epidural anaesthesia vs. patient-controlled analgesia and opioid (buprenorphine) vs. opioid (pethidine) did not show significant difference in primary outcome. Study quality issues significantly contributed to overall study heterogeneity. NSAIDs and opioids are equally effective in decreasing the need for rescue analgesia in patients with mild AP. The relative paucity of trials and high-quality data in this setting is notable and the optimal analgesic strategy for patients with moderately severe and severe AP still requires to be determined.

Opioids and alcohol are widely used to relieve pain, with their analgesic efficacy stemming from rapid actions on both spinal and supraspinal nociceptive centers. As an extension of these relationships, both substances can be misused in attempts to manage negative affective symptoms stemming from chronic pain. Moreover, excessive use of opioids or alcohol facilitates the development of substance use disorder (SUD) as well as hyperalgesia, or enhanced pain sensitivity. Shared neurobiological mechanisms that promote hyperalgesia development in the context of SUD represent viable candidates for therapeutic intervention, with the ideal strategy capable of reducing both excessive substance use as well as pain symptoms simultaneously. Neurocognitive symptoms associated with SUD, ranging from poor risk management to the affective dimension of pain, are likely mediated by altered activities of key anatomical elements that modulate executive and interoceptive functions, including contributions from key frontocortical regions. To aid future discoveries, novel and translationally valid animal models of chronic pain and SUD remain under intense development and continued refinement. With these tools, future research strategies targeting severe SUD should focus on the common neurobiology between negative reinforcement and affective elements of pain, possibly by reducing excessive stress hormone and neurotransmitter activity within shared circuitry.

The lungs are constantly exposed to non-sterile air which carries harmful threats, such as particles and pathogens. Nonetheless, this organ is equipped with fast and efficient mechanisms to eliminate these threats from the airways as well as prevent pathogen invasion. The respiratory tract is densely innervated by sensory neurons, also known as nociceptors, which are responsible for the detection of external stimuli and initiation of physiological and immunological responses. Furthermore, expression of functional innate receptors by nociceptors have been reported; however, the influence of these receptors to the lung function and local immune response is poorly described. The COVID-19 pandemic has shown the importance of coordinated and competent pulmonary immunity for the prevention of pathogen spread as well as prevention of excessive tissue injury. New findings suggest that lung nociceptors can be a target of SARS-CoV-2 infection; what remains unclear is whether innate receptor trigger sensory neuron activation during SARS-CoV-2 infection and what is the relevance for the outcomes. Moreover, elderly individuals often present with respiratory, neurological and immunological dysfunction. Whether aging in the context of sensory nerve function and innate receptors contributes to the disorders of these systems is currently unknown. Here we discuss the expression of innate receptors by nociceptors, particularly in the lungs, and the possible impact of their activation on pulmonary immunity. We then demonstrate recent evidence that suggests lung sensory neurons as reservoirs for SARS-CoV-2 and possible viral recognition innate receptors. Lastly, we explore the mechanisms by which lung nociceptors might contribute to disturbance in respiratory and immunological responses during the aging process.

Deep brain stimulation (DBS) is a plausible therapy for various neuropsychiatric disorders, though continuous tonic stimulation without regard to underlying physiology (open-loop) has had variable success. Recently available DBS devices can sense neural signals which, in turn, can be used to control stimulation in a closed-loop mode. Closed-loop DBS strategies may mitigate many drawbacks of open-loop stimulation and provide more personalized therapy. These devices contain many adjustable parameters that control how the closed-loop system operates, which need to be optimized using a combination of empirically and clinically informed decision making. We offer a practical guide for the implementation of a closed-loop DBS system, using examples from patients with chronic pain. Focusing on two research devices from Medtronic, the Activa PC+S and Summit RC+S, we provide pragmatic details on implementing closed- loop programming from a clinician's perspective. Specifically, by combining our understanding of chronic pain with data-driven heuristics, we describe how to tune key parameters to handle feature selection, state thresholding, and stimulation artifacts. Finally, we discuss logistical and practical considerations that clinicians must be aware of when programming closed-loop devices.