Itch and pain are distinct unpleasant sensations that can be triggered from the same receptive fields in the skin, raising the question of how pruriception and nociception are coded and ...discriminated. Here, we tested the multimodal capacity of peripheral first-order neurons, focusing on the genetically defined subpopulation of mouse C-fibers that express the chloroquine receptor MrgprA3. Using optogenetics, chemogenetics, and pharmacology, we assessed the behavioral effects of their selective stimulation in a wide variety of conditions. We show that metabotropic Gq-linked stimulation of these C-afferents, through activation of native MrgprA3 receptors or DREADDs, evokes stereotypical pruriceptive rather than nocifensive behaviors. In contrast, fast ionotropic stimulation of these same neurons through light-gated cation channels or native ATP-gated P2X3 channels predominantly evokes nocifensive rather than pruriceptive responses. We conclude that C-afferents display intrinsic multimodality, and we provide evidence that optogenetic and chemogenetic interventions on the same neuronal populations can drive distinct behavioral outputs.
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•Metabotropic Gq-linked stimulation of MrgprA3 C-afferents triggers itch•Ionotropic stimulation of MrgprA3 C-afferents through ChR2 or native P2X3 evokes pain•Evoked itch and pain responses differentially engage spinal GRPR and opioid pathways•Pruriceptive, but not nociceptive, responses are alleviated by blockade of TRP channels
Sharif et al. present evidence that a subpopulation of peripheral chloroquine-responsive somatosensory afferents can differentially drive itch or pain responses when they are stimulated via metabotropic or fast ionotropic signaling pathways, respectively.
The EGFR belongs to the well-studied ErbB family of receptor tyrosine kinases. EGFR is activated by numerous endogenous ligands that promote cellular growth, proliferation, and tissue regeneration. ...In the present study, we have demonstrated a role for EGFR and its natural ligand, epiregulin (EREG), in pain processing. We show that inhibition of EGFR with clinically available compounds strongly reduced nocifensive behavior in mouse models of inflammatory and chronic pain. EREG-mediated activation of EGFR enhanced nociception through a mechanism involving the PI3K/AKT/mTOR pathway and matrix metalloproteinase-9. Moreover, EREG application potentiated capsaicin-induced calcium influx in a subset of sensory neurons. Both the EGFR and EREG genes displayed a genetic association with the development of chronic pain in several clinical cohorts of temporomandibular disorder. Thus, EGFR and EREG may be suitable therapeutic targets for persistent pain conditions.
Background Congenital heart disease accounts for almost a third of all major congenital anomalies. Congenital heart defects have a significant impact on morbidity, mortality and health costs for ...children and adults. Research regarding the risk of pre-surgical mortality is scarce. Objectives Our goal is to generate a predictive model calculator adapted to the regional reality focused on individual mortality prediction among patients with congenital heart disease undergoing cardiac surgery. Methods Two thousand two hundred forty CHD consecutive patients' data from InCor's heart surgery program was used to develop and validate the preoperative risk-of-death prediction model of congenital patients undergoing heart surgery. There were six artificial intelligence models most cited in medical references used in this study: Multilayer Perceptron (MLP), Random Forest (RF), Extra Trees (ET), Stochastic Gradient Boosting (SGB), Ada Boost Classification (ABC) and Bag Decision Trees (BDT). Results The top performing areas under the curve were achieved using Random Forest (0.902). Most influential predictors included previous admission to ICU, diagnostic group, patient's height, hypoplastic left heart syndrome, body mass, arterial oxygen saturation, and pulmonary atresia. These combined predictor variables represent 67.8% of importance for the risk of mortality in the Random Forest algorithm. Conclusions The representativeness of "hospital death" is greater in patients up to 66 cm in height and body mass index below 13.0 for InCor's patients. The proportion of "hospital death" declines with the increased arterial oxygen saturation index. Patients with prior hospitalization before surgery had higher "hospital death" rates than who did not required such intervention. The diagnoses groups having the higher fatal outcomes probability are aligned with the international literature. A web application is presented where researchers and providers can calculate predicted mortality based on the CgntSCORE on any web browser or smartphone.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Primary C-fiber nociceptors are broadly divided into peptidergic and nonpeptidergic afferents. TRPV1 is a thermosensitive cation channel mainly localized in peptidergic nociceptors, whereas MrgD is a ...sensory G protein-coupled receptor expressed in most nonpeptidergic nociceptive afferents. TRPV1 and MrgD fibers have been reported to be primarily involved in thermal and mechanical nociception, respectively. Yet, their functional assessment in somatosensory transmission relied on ablation strategies that do not account for compensatory mechanisms. To achieve selective activation of these 2 major subsets of C-fibers in vivo in adult mice, we used optogenetics to specifically deliver the excitatory opsin channelrhodopsin-2 (ChR2) to TRPV1 or MrgD primary sensory neurons, as confirmed by histology and electrophysiology. This approach allowed, for the first time, the characterization of behavioral responses triggered by direct noninvasive activation of peptidergic TRPV1 or nonpeptidergic MrgD fibers in freely moving mice. Transdermal blue light stimulation of the hind paws of transgenic mice expressing ChR2 in TRPV1 neurons generated nocifensive behaviors consisting mainly of paw withdrawal and paw licking, whereas paw lifting occurrence was limited. Conversely, optical activation of cutaneous MrgD afferents produced mostly withdrawal and lifting. Of interest, in a conditioned place avoidance assay, blue light induced aversion in TRPV1-ChR2 mice, but not in MrgD-ChR2 mice. In short, we present novel somatosensory transgenic models in which control of specific subsets of peripheral unmyelinated nociceptors with distinct functions can be achieved with high spatiotemporal precision. These new tools will be instrumental in further clarifying the contribution of genetically identified C-fiber subtypes to chronic pain.
Approximately 35 facial transplants have been performed worldwide. Many under-explored aspects of this procedure remain, some emerging as the survivors age. Human-like preclinical trial models, ...including swine, can be explored and developed as a foundation for subsequent studies. A previously described surgical technique for face transplantation in swine carcasses has been employed herein, evaluating its reproducibility in a live pig and the viability of the vascular pedicles.
Flap construction was performed according to the experimental model developed in our service. Under general anesthesia, the structures of the left hemiface of a pig were dissected. Vascular pedicles were the facial artery, caudal auricular artery, and external jugular vein. After dissection, adequate tissue perfusion of the entire explant by those pedicles was documented through vessel filling, observation of the ischemic area, and posterior reperfusion.
A capillary reperfusion test confirmed that the main arterial pedicle irrigating the hemiface flap was the facial artery. The same technique showed that despite divergent literary opinions on the irrigation of the auricular region, the caudal auricular artery provides the arterial supply for the external ear. Performing the surgical technique was more difficult in vivo due to the inherent complications of a live subject.
The methodology for the facial transplant technique in swine carcasses was satisfactorily reproducible in a live animal. The main arterial pedicle responsible for flap irrigation is the facial artery, and the fact that the vessel supplying the outer ear is the caudal atrial artery was confirmed.
Activation of microglia in the spinal cord following peripheral nerve injury is critical for the development of long-lasting pain hypersensitivity. However, it remains unclear whether distinct ...microglia subpopulations or states contribute to different stages of pain development and maintenance. Using single-cell RNA-sequencing, we show that peripheral nerve injury induces the generation of a male-specific inflammatory microglia subtype, and demonstrate increased proliferation of microglia in male as compared to female mice. We also show time- and sex-specific transcriptional changes in different microglial subpopulations following peripheral nerve injury. Apolipoprotein E (Apoe) is the top upregulated gene in spinal cord microglia at chronic time points after peripheral nerve injury in mice. Furthermore, polymorphisms in the APOE gene in humans are associated with chronic pain. Single-cell RNA sequencing analysis of human spinal cord microglia reveals a subpopulation with a disease-related transcriptional signature. Our data provide a detailed analysis of transcriptional states of mouse and human spinal cord microglia, and identify a link between ApoE and chronic pain in humans.
Neuropathic pain is a chronic debilitating disease that results from nerve damage, persists long after the injury has subsided, and is characterized by spontaneous pain and mechanical ...hypersensitivity. Although loss of inhibitory tone in the dorsal horn of the spinal cord is a major contributor to neuropathic pain, the molecular and cellular mechanisms underlying this disinhibition are unclear. Here, we combined pharmacogenetic activation and selective ablation approaches in mice to define the contribution of spinal cord parvalbumin (PV)-expressing inhibitory interneurons in naive and neuropathic pain conditions. Ablating PV neurons in naive mice produce neuropathic pain-like mechanical allodynia via disinhibition of PKCγ excitatory interneurons. Conversely, activating PV neurons in nerve-injured mice alleviates mechanical hypersensitivity. These findings indicate that PV interneurons are modality-specific filters that gate mechanical but not thermal inputs to the dorsal horn and that increasing PV interneuron activity can ameliorate the mechanical hypersensitivity that develops following nerve injury.
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•Parvalbumin (PV) neurons of the dorsal horn synapse onto PKCγ excitatory neurons•After nerve injury, many PV-PKCγ synapses are lost and touch stimuli become painful•Specific activation of PV neurons after nerve injury alleviates mechanical pain
Improved therapy for neuropathic pain requires a better understanding of the spinal cord neuronal networks that process peripheral sensory inputs in health and disease. Petitjean et al. find that a subset of inhibitory interneurons, containing the marker parvalbumin (PV), prevent touch inputs from activating pain circuits. After nerve injury, a decrease is seen in the number of these synapses, and light touch can elicit pain.
Background: Dendritic cells (DCs) form a key link between innate and adaptive immune responses. The aim of this study is to analyze presence and distribution of immature (im) and mature (m) DCs in ...gingival tissue samples obtained from patients diagnosed with aggressive periodontitis (AgP), chronic periodontitis (CP), and clinically healthy periodontium (control group).
Methods: Gingival tissue samples obtained from patients with: 1) AgP (aged <35 years); 2) CP (aged ≥35 years); and 3) control group (aged >18 years) (n = 10 per group) were collected. Two‐way analysis of variance and posterior Fisher least significant difference test were used to observe differences between the means of cells positively marked for imDC (S100, CD1a, and CD207) and mDC (CD208) immunomarkers.
Results: imDCs were more numerous in AgP than CP and control groups, being statistically significant only for S100+ cells. Conversely, mDCs were visualized in higher numbers in CP than AgP and control groups (both P <0.05). Considering frequency of immunostained cells, the number of S100+ cells was greater than CD207+ and CD1a+ cells, followed by a lesser number of CD208+ cells, in all groups.
Conclusions: Considering that the ability of DCs to regulate immunity is dependent on DC maturation, results suggest that predominance of imDCs appears to be involved in AgP pathogenesis, probably due to lack of ability to induce immune cell activation. Further studies are necessary to elucidate the role of DC maturation in regulating immune responses in periodontal disease.
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