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Chronic prostatitis and chronic pelvic pain syndrome (CP/CPPS) is a complicated syndrome characterized by genitourinary pain in the absence of bacterial infection. Th17 cell-driven autoimmunity has been proposed as a cause of CP/CPPS. However, the factors that promote Th17-driven autoimmunity in experimental autoimmune prostatitis (EAP) and the molecular mechanisms are still largely unknown. Here, we showed that Th17 cells were excessively activated, and blockade of IL-17A could effectively ameliorate various symptoms in EAP. Furthermore, we revealed that calcium/calmodulin-dependent kinase Ⅳ (CaMK4), especially Thr p-CaMK4 was increased in the Th17 cells of the EAP group, which were activated by intracellular cytosolic Ca . Pharmacologic and genetic inhibition of CaMK4 decreased the proportion of Th17 cells, and the protein and mRNA level of IL-17A, IL-22, and RORγt. The phosphorylation of CaMK4 was dependent on the increase in intracellular cytosolic Ca concentration in Th17 cells. A mechanistic study demonstrated that inhibition of CaMK4 reduced IL-17A production by decreasing the phosphorylation of Akt-mTOR, which was well accepted to positively regulate Th17 differentiation. Collectively, our results demonstrated that Ca -CaMK4-Akt/mTOR-IL-17A axis inhibition may serve as a promising therapeutic strategy for CP/CPPS.
Learn More >Small dorsal root ganglion (DRG) neurons are primary nociceptors which are responsible for sensing pain. Elucidation of their dynamics is essential for understanding and controlling pain. To this end, we present a numerical bifurcation analysis of a small DRG neuron model in this paper. The model is of Hodgkin-Huxley type and has 9 state variables. It consists of a Na1.7 and a Na1.8 sodium channel, a leak channel, a delayed rectifier potassium, and an A-type transient potassium channel. The dynamics of this model strongly depend on the maximal conductances of the voltage-gated ion channels and the external current, which can be adjusted experimentally. We show that the neuron dynamics are most sensitive to the Na1.8 channel maximal conductance ([Formula: see text]). Numerical bifurcation analysis shows that depending on [Formula: see text] and the external current, different parameter regions can be identified with stable steady states, periodic firing of action potentials, mixed-mode oscillations (MMOs), and bistability between stable steady states and stable periodic firing of action potentials. We illustrate and discuss the transitions between these different regimes. We further analyze the behavior of MMOs. As the external current is decreased, we find that MMOs appear after a cyclic limit point. Within this region, bifurcation analysis shows a sequence of isolated periodic solution branches with one large action potential and a number of small amplitude peaks per period. For decreasing external current, the number of small amplitude peaks is increasing and the distance between the large amplitude action potentials is growing, finally tending to infinity and thereby leading to a stable steady state. A closer inspection reveals more complex concatenated MMOs in between these periodic MMO branches, forming Farey sequences. Lastly, we also find small solution windows with aperiodic oscillations which seem to be chaotic. The dynamical patterns found here-as consequences of bifurcation points regulated by different parameters-have potential translational significance as repetitive firing of action potentials imply pain of some form and intensity; manipulating these patterns by regulating the different parameters could aid in investigating pain dynamics.
Learn More >This study was designed to investigate painless and painful subsets of pediatric restless legs syndrome (RLS) for genetic influence and for associations with iron deficiency and common pediatric pain disorders.
Learn More >Acute inflammation is a protective reaction by the immune system in response to invading pathogens or tissue damage. Ideally, the response should be localized, self-limited, and returning to homeostasis. If not resolved, acute inflammation can result in organ pathologies leading to chronic inflammatory phenotypes. Acute inflammation and inflammation resolution are complex coordinated processes, involving a number of cell types, interacting in space and time. The biomolecular complexity and the fact that several biomedical fields are involved, make a multi- and interdisciplinary approach necessary. The Atlas of Inflammation Resolution (AIR) is a web-based resource capturing an essential part of the state-of-the-art in acute inflammation and inflammation resolution research. The AIR provides an interface for users to search thousands of interactions, arranged in inter-connected multi-layers of process diagrams, covering a wide range of clinically relevant phenotypes. By mapping experimental data onto the AIR, it can be used to elucidate drug action as well as molecular mechanisms underlying different disease phenotypes. For the visualization and exploration of information, the AIR uses the Minerva platform, which is a well-established tool for the presentation of disease maps. The molecular details of the AIR are encoded using international standards. The AIR was created as a freely accessible resource, supporting research and education in the fields of acute inflammation and inflammation resolution. The AIR connects research communities, facilitates clinical decision making, and supports research scientists in the formulation and validation of hypotheses. The AIR is accessible through https://air.bio.informatik.uni-rostock.de.
Learn More >Chronic pain is a leading cause of disability globally. Interdisciplinary multimodal pain rehabilitation (IMPR) targets pain with a bio-psycho-social approach, often delivered as composite programs. However, evidence of optimal program duration for the rehabilitation to succeed remains scarce. This study evaluated the effectiveness of different duration IMPR-programs-using within- and between-effects analyses in a pragmatic multicenter register-based controlled design. Using the Swedish Quality Registry for Pain Rehabilitation, data from fifteen clinics specialized in chronic pain rehabilitation across Sweden were retrieved. Participants were patients with chronic musculoskeletal pain who had taken part in short (4-9 weeks; = 924), moderate (10 weeks; = 1379), or long (11-18 weeks; = 395) IMPR programs. Longitudinal patient-reported outcome data were assessed at baseline, post-intervention, and at a 12-month follow-up. Primary outcomes were health-related quality of life, presented as perceived physical and mental health (SF-36). Secondary outcomes included the Hospital Anxiety and Depression Scale (HADS), pain intensity (NRS 0-10), the Multidimensional Pain Inventory (MPI), and perceived health (EQ-5D). Overall, all groups showed improvements. No clinically important effect emerged for different duration IMPR. In conclusion, while our results showed that patients following IMPR report improvement across a bio-psycho-social specter, a longer program duration was no more effective than a shorter one.
Learn More >Pain is a multidimensional experience mediated by distributed neural networks in the brain. To study this phenomenon, EEGs were collected from 20 subjects with chronic lumbar radiculopathy, 20 age and gender matched healthy subjects, and 17 subjects with chronic lumbar pain scheduled to receive an implanted spinal cord stimulator. Analysis of power spectral density, coherence, and phase-amplitude coupling using conventional statistics showed that there were no significant differences between the radiculopathy and control groups after correcting for multiple comparisons. However, analysis of transient spectral events showed that there were differences between these two groups in terms of the number, power, and frequency-span of events in a low gamma band. Finally, we trained a binary support vector machine to classify radiculopathy versus healthy subjects, as well as a 3-way classifier for subjects in the 3 groups. Both classifiers performed significantly better than chance, indicating that EEG features contain relevant information pertaining to sensory states, and may be used to help distinguish between pain states when other clinical signs are inconclusive.
Learn More >The US Food and Drug Administration has approved orally administered 100-mg and 200-mg doses of lasmiditan for the acute treatment of migraine, with or without aura. Having a unique mechanism of action, lasmiditan is the first and only Food and Drug Administration-approved serotonin 5-HT receptor agonist.
Learn More >Opioid drugs are a first-line treatment for severe acute pain and other chronic pain conditions, but long-term opioid drug use produces opioid-induced hyperalgesia (OIH). Co-administration of cannabinoids with opioid receptor agonists produce anti-nociceptive synergy, but cannabinoid receptor agonists may also produce undesirable side effects. Therefore, positive allosteric modulators (PAM) of cannabinoid type-1 receptors (CB1R) may provide an option reducing pain and/or enhancing the anti-hyperalgesic effects of opioids without the side effects, tolerance, and dependence observed with the use of ligands that target the orthosteric binding sites. This study tested GAT211, a PAM of cannabinoid type-1 receptors (CB1R), for its ability to enhance the anti-hyperalgesic effects of the mu-opioid receptor (MOR) agonist DAMGO in rats treated chronically with morphine (or saline) and tested during withdrawal. We tested the effects of intra-periaqueductal gray (PAG) injections of (1) DAMGO, (2) GAT211, or (3) DAMGO + GAT211 on thermal nociception in chronic morphine-treated rats that were hyperalgesic and also in saline-treated control rats. We used slice electrophysiology to test the effects of DAMGO/GAT211 bath application on synaptic transmission in the vlPAG. Intra-PAG DAMGO infusions dose-dependently reversed chronic morphine-induced hyperalgesia, but intra-PAG GAT211 did not alter nociception at the doses we tested. When co-administered into the PAG, GAT211 antagonized the anti-nociceptive effects of DAMGO in morphine-withdrawn rats. DAMGO suppressed synaptic inhibition in the vlPAG of brain slices taken from saline- and morphine-treated rats, and GAT211 attenuated DAMGO-induced suppression of synaptic inhibition in vlPAG neurons via actions at CB1R. These findings show that positive allosteric modulation of CB1R antagonizes the behavioral and cellular effects of a MOR agonist in the PAG of rats.
Learn More >The current study aimed to investigate the clinical significance of European Society for the Study of Interstitial Cystitis (ESSIC) bladder histopathological classification and its impact on treatment outcomes among patients with interstitial cystitis/bladder pain syndrome (IC/BPS).
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