An Analysis of the Influence of a Patient's Sex on Quality of Life in Liver and Kidney Transplantation.

Background: Renal and liver transplantation influences the quality of life of the patients who undergo these procedures. Therefore, the aim of the present study was to analyze possible differences in liver and kidney transplantation in relation to the patient's sex and to determine their impact on quality of life.

Methodology: An observational study was carried out with 147 patients with liver ( = 70) and kidney ( = 77) failure on the transplantation waiting list.

Piezo2 channels and tactile pain: an intriguing voltage connection.

This scientific commentary refers to ‘Piezo2 voltage-block regulates mechanical pain sensitivity’ by Sánchez-Carranza (https://doi.org/10.1093/brain/awae227).

Proper Frequency of Perinatal Retinal Waves Is Essential for the Precise Wiring of Visual Axons in Nonimage-Forming Nuclei.

The development of the visual system is a complex and multistep process characterized by the precise wiring of retinal ganglion cell (RGC) axon terminals with their corresponding neurons in the visual nuclei of the brain. Upon reaching primary image-forming nuclei (IFN), such as the superior colliculus and the lateral geniculate nucleus, RGC axons undergo extensive arborization that refines over the first few postnatal weeks. The molecular mechanisms driving this activity-dependent remodeling process, which is influenced by waves of spontaneous activity in the developing retina, are still not well understood.

The ion channel TRPM8 is a direct target of the immunosuppressant rapamycin in primary sensory neurons.

Background And Purpose: The mechanistic target of rapamycin (mTOR) signalling pathway is a key regulator of cell growth and metabolism. Its deregulation is implicated in several diseases. The macrolide rapamycin, a specific inhibitor of mTOR, has immunosuppressive, anti-inflammatory and antiproliferative properties.

TRPA1 modulation by Sigma-1 receptor prevents oxaliplatin-induced painful peripheral neuropathy.

Chemotherapy-induced peripheral neuropathy 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 chemotherapy-induced peripheral neuropathy characterized by mechanical and cold hypersensitivity. Current therapies for chemotherapy-induced peripheral neuropathy are ineffective, often leading to the cessation of treatment.

Generation of hiPSC-derived low threshold mechanoreceptors containing axonal termini resembling bulbous sensory nerve endings and expressing Piezo1 and Piezo2.

Somatosensory low threshold mechanoreceptors (LTMRs) sense innocuous mechanical forces, largely through specialized axon termini termed sensory nerve endings, where the mechanotransduction process initiates upon activation of mechanotransducers. In humans, a subset of sensory nerve endings is enlarged, forming bulb-like expansions, termed bulbous nerve endings. There is no in vitro human model to study these neuronal endings.

Piezo2 Mediates Low-Threshold Mechanically Evoked Pain in the Cornea.

Mammalian Piezo2 channels are essential for transduction of innocuous mechanical forces by proprioceptors and cutaneous touch receptors. In contrast, mechanical responses of somatosensory nociceptor neurons evoking pain, remain intact or are only partially reduced in Piezo2-deficient mice. In the eye cornea, comparatively low mechanical forces are detected by polymodal and pure mechanosensory trigeminal ganglion neurons.

Characterization of TRPC Channels in a Heterologous System Using Calcium Imaging and the Patch-Clamp Technique.

The family of transient receptor potential (TRPs) channels contains 28 mammalian members, each a unique cellular sensor that responds to a wide variety of external and internal signals. TRP channels are expressed by most mammalian cells, where they are involved in many different physiological functions. Canonical TRP channels (TRPCs) form a family of nonselective cationic channels, although with greater selectivity for Ca.

Expression of the cold thermoreceptor TRPM8 in rodent brain thermoregulatory circuits.

The cold- and menthol-activated ion channel transient receptor potential channel subfamily M member 8 (TRPM8) is the principal detector of environmental cold in mammalian sensory nerve endings. Although it is mainly expressed in a subpopulation of peripheral sensory neurons, it has also been identified in non-neuronal tissues. Here, we show, by in situ hybridization (ISH) and by the analysis of transgenic reporter expression in two different reporter mouse strains, that TRPM8 is also expressed in the central nervous system.

The Immunosuppressant Macrolide Tacrolimus Activates Cold-Sensing TRPM8 Channels.

TRPM8 is a polymodal, nonselective cation channel activated by cold temperature and cooling agents that plays a critical role in the detection of environmental cold. We found that TRPM8 is a pharmacological target of tacrolimus (FK506), a macrolide immunosuppressant with several clinical uses, including the treatment of organ rejection following transplants, treatment of atopic dermatitis, and dry eye disease. Tacrolimus is an inhibitor of the phosphatase calcineurin, an action shared with cyclosporine.

Joint nociceptor nerve activity and pain in an animal model of acute gout and its modulation by intra-articular hyaluronan.

The mechanisms whereby deposition of monosodium urate (MSU) crystals in gout activates nociceptors to induce joint pain are incompletely understood. We tried to reproduce the signs of painful gouty arthritis, injecting into the knee joint of rats suspensions containing amorphous or triclinic, needle MSU crystals. The magnitude of MSU-induced inflammation and pain behavior signs were correlated with the changes in firing frequency of spontaneous and movement-evoked nerve impulse activity recorded in single knee joint nociceptor saphenous nerve fibers.

A critical role for Piezo2 channels in the mechanotransduction of mouse proprioceptive neurons.

Proprioceptors are responsible for the conscious sensation of limb position and movement, muscle tension or force, and balance. Recent evidence suggests that Piezo2 is a low threshold mechanosensory receptor in the peripheral nervous system, acting as a transducer for touch sensation and proprioception. Thus, we characterized proprioceptive neurons in the mesencephalic trigeminal nucleus that are involved in processing proprioceptive information from the face and oral cavity.

Hyaluronan modulates TRPV1 channel opening, reducing peripheral nociceptor activity and pain.

Hyaluronan (HA) is present in the extracellular matrix of all body tissues, including synovial fluid in joints, in which it behaves as a filter that buffers transmission of mechanical forces to nociceptor nerve endings thereby reducing pain. Using recombinant systems, mouse-cultured dorsal root ganglia (DRG) neurons and in vivo experiments, we found that HA also modulates polymodal transient receptor potential vanilloid subtype 1 (TRPV1) channels. HA diminishes heat, pH and capsaicin (CAP) responses, thus reducing the opening probability of the channel by stabilizing its closed state.

Monoacylglycerols activate TRPV1--a link between phospholipase C and TRPV1.

Phospholipase C-mediated hydrolysis of phosphatidylinositol 4,5-bisphosphate generates diacylglycerol, inositol 1,4,5-trisphosphate and protons, all of which can regulate TRPV1 activity via different mechanisms. Here we explored the possibility that the diacylglycerol metabolites 2-arachidonoylglycerol and 1-arachidonoylglycerol, and not metabolites of these monoacylglycerols, activate TRPV1 and contribute to this signaling cascade. 2-Arachidonoylglycerol and 1-arachidonoylglycerol activated native TRPV1 on vascular sensory nerve fibers and heterologously expressed TRPV1 in whole cells and inside-out membrane patches.

G protein-coupled receptor signalling potentiates the osmo-mechanical activation of TRPC5 channels.

TRPC5 is an ion channel permeable to monovalent and divalent cations that is widely expressed in different tissues. Although implicated in the control of neurite extension and in the growth cone morphology of hippocampal neurons, as well as in fear-related behaviour, the mechanisms by which TRPC5 is activated remain poorly understood. TRPC5 is known to be activated downstream of Gq-coupled receptors and by membrane stretch, and since there is evidence that mechanical stress may directly activate Gq-coupled receptors, we examined the relationship between the activation of TRPC5 by the type 1 histamine receptor and osmotic stress.

Membrane-tethered peptides patterned after the TRP domain (TRPducins) selectively inhibit TRPV1 channel activity.

The transient receptor potential vanilloid 1 (TRPV1) channel is a thermosensory receptor implicated in diverse physiological and pathological processes. The TRP domain, a highly conserved region in the C terminus adjacent to the internal channel gate, is critical for subunit tetramerization and channel gating. Here, we show that cell-penetrating, membrane-anchored peptides patterned after this protein domain are moderate and selective TRPV1 antagonists both in vitro and in vivo, blocking receptor activity in intact rat primary sensory neurons and their peripheral axons with mean decline time of 30 min.

Hypoosmotic- and pressure-induced membrane stretch activate TRPC5 channels.

Transient receptor potential (TRP) channels mediate a wide array of sensory functions. We investigated the role of TRPC5, a poorly characterized channel widely expressed in the central and peripheral nervous system, as a potential osmosensory protein. Here we show that hypoosmotic stimulation activates TRPC5 channels resulting in a large calcium influx.

Identification of molecular determinants of channel gating in the transient receptor potential box of vanilloid receptor I.

Transient receptor potential vanilloid receptor subtype I (TRPV1) is an ion channel gated by physical and chemical stimuli that belongs to the TRPV protein family. TRPV receptors contain a highly conserved, 6-mer segment near the channel gate, known as the TRP box, whose function remains unknown. Here, we performed an alanine scanning mutagenesis of the TRP box of TRPV1 (IWKLQR) and found that mutation of this motif affected channel gating by raising the free energy of channel activation.

A role of the transient receptor potential domain of vanilloid receptor I in channel gating.

Transient receptor potential vanilloid receptor subtype 1 (TRPV1) is an ionotropic receptor activated by temperature and chemical stimuli. The C-terminal region that is adjacent to the channel gate, recognized as the TRP domain, is a molecular determinant of receptor assembly. However, the role of this intracellular domain in channel function remains elusive.

Nociceptive nerve activity in an experimental model of knee joint osteoarthritis of the guinea pig: effect of intra-articular hyaluronan application.

Nociceptive impulse activity was recorded extracellularly from single A delta and C primary afferents of the guinea pig's medial articular nerve after induction of an experimental osteoarthritis in the knee joint by partial medial menisectomy and transection of the anterior cruciate ligament (PMM+TACL). Also, the analgesic effects of intra-articular hyaluronan solutions were evaluated. Healthy, PMM+TACL operated, sham-operated (opening of the joint capsule without PMM and TACL surgery) and acutely inflamed (intra-articular kaolin-carrageenan, K-C) animals were used.

Design and characterization of a noncompetitive antagonist of the transient receptor potential vanilloid subunit 1 channel with in vivo analgesic and anti-inflammatory activity.

Unlabelled: Vanilloid receptor subunit 1 (TRPV1) is an integrator of physical and chemical stimuli in the peripheral nervous system. This receptor plays a key role in the pathophysiology of inflammatory pain. Thus, the identification of receptor antagonists with analgesic and anti-inflammatory activity in vivo is an important goal of current neuropharmacology.

Inhibition of a background potassium channel by Gq protein alpha-subunits.

Two-pore-domain K(+) channels provide neuronal background currents that establish resting membrane potential and input resistance; their modulation provides a prevalent mechanism for regulating cellular excitability. The so-called TASK channel subunits (TASK-1 and TASK-3) are widely expressed, and they are robustly inhibited by receptors that signal through Galphaq family proteins. Here, we manipulated G protein expression and membrane phosphatidylinositol 4,5-bisphosphate (PIP(2)) levels in intact and cell-free systems to provide electrophysiological and biochemical evidence that inhibition of TASK channels by Galphaq-linked receptors proceeds unabated in the absence of phospholipase C (PLC) activity, and instead involves association of activated Galphaq subunits with the channels.

Effects of different molecular weight elastoviscous hyaluronan solutions on articular nociceptive afferents.

Objective: To compare 3 different hyaluronan (HA) preparations used as therapeutic agents for osteoarthritis pain in humans in order to establish the degree to which a single application affects the sensitivity of nociceptors in both the normal and the acutely inflamed rat joint.

Methods: In anesthetized rats, single-unit recordings were performed from the medial articular nerve of the right knee joint under normal conditions and during an acute experimental arthritis. Fifty fine afferent units (conduction velocities 0.

GAP43 stimulates inositol trisphosphate-mediated calcium release in response to hypotonicity.

The identification of osmo/mechanosensory proteins in mammalian sensory neurons is still elusive. We have used an expression cloning approach to screen a human dorsal root ganglion cDNA library to look for proteins that respond to hypotonicity by raising the intracellular Ca(2+) concentration ([Ca(2+)](i)). We report the unexpected identification of GAP43 (also known as neuromodulin or B50), a membrane-anchored neuronal protein implicated in axonal growth and synaptic plasticity, as an osmosensory protein that augments [Ca(2+)](i) in response to hypotonicity.