This study establishes a mechanism for metabolic hyperalgesia based on the glycolytic metabolite methylglyoxal. We found that concentrations of plasma methylglyoxal above 600 nM discriminate between diabetes-affected individuals with pain and those without pain. Methylglyoxal depolarizes sensory neurons and induces post-translational modifications of the voltage-gated sodium channel Na(v)1.8, which are associated with increased electrical excitability and facilitated firing of nociceptive neurons, whereas it promotes the slow inactivation of Na(v)1.7. In mice, treatment with methylglyoxal reduces nerve conduction velocity, facilitates neurosecretion of calcitonin gene-related peptide, increases cyclooxygenase-2 (COX-2) expression and evokes thermal and mechanical hyperalgesia. This hyperalgesia is reflected by increased blood flow in brain regions that are involved in pain processing. We also found similar changes in streptozotocin-induced and genetic mouse models of diabetes but not in Na(v)1.8 knockout (Scn10(-/-)) mice. Several strategies that include a methylglyoxal scavenger are effective in reducing methylglyoxal- and diabetes-induced hyperalgesia. This previously undescribed concept of metabolically driven hyperalgesia provides a new basis for the design of therapeutic interventions for painful diabetic neuropathy.

Nitroxyl (HNO) is a redox sibling of nitric oxide (NO) that targets distinct signalling pathways with pharmacological endpoints of high significance in the treatment of heart failure. Beneficial HNO effects depend, in part, on its ability to release calcitonin gene-related peptide (CGRP) through an unidentified mechanism. Here we propose that HNO is generated as a result of the reaction of the two gasotransmitters NO and H2S. We show that H2S and NO production colocalizes with transient receptor potential channel A1 (TRPA1), and that HNO activates the sensory chemoreceptor channel TRPA1 via formation of amino-terminal disulphide bonds, which results in sustained calcium influx. As a consequence, CGRP is released, which induces local and systemic vasodilation. H2S-evoked vasodilatatory effects largely depend on NO production and activation of HNO–TRPA1–CGRP pathway. We propose that this neuroendocrine HNO–TRPA1–CGRP signalling pathway constitutes an essential element for the control of vascular tone throughout the cardiovascular system.

The Sox10 transcription factor is required to maintain as well as specify glial identity, adding new causes for the neuropathies associated with SOX10 mutations.

No abstract

Transient receptor potential (TRP) cation channel subfamily M member 3 (TRPM3), a member of the TRP channel superfamily, was recently identified as a nociceptor channel in the somatosensory system, where it is involved in the detection of noxious heat; however, owing to the lack of potent and selective agonists, little is known about other potential physiological consequences of the opening of TRPM3. Here we identify and characterize a synthetic TRPM3 activator, CIM0216, whose potency and apparent affinity greatly exceeds that of the canonical TRPM3 agonist, pregnenolone sulfate (PS). In particular, a single application of CIM0216 causes opening of both the central calcium-conducting pore and the alternative cation permeation pathway in a membrane-delimited manner. CIM0216 evoked robust calcium influx in TRPM3-expressing somatosensory neurons, and intradermal injection of the compound induced a TRPM3-dependent nocifensive behavior. Moreover, CIM0216 elicited the release of the peptides calcitonin generelated peptide (CGRP) from sensory nerve terminals and insulin from isolated pancreatic islets in a TRPM3-dependent manner. These experiments identify CIM0216 as a powerful tool for use in investigating the physiological roles of TRPM3, and indicate that TRPM3 activation in sensory nerve endings can contribute to neurogenic inflammation.TRP channel | TRPM3 | peptide release | nociceptor T ransient receptor potential (TRP) channels represent a large and diverse family of nonselective cation channels that respond to a wide range of chemical and physical stimuli and biophysical properties (1). TRP cation channel subfamily M member 3 (TRPM3), a calcium-permeable nonselective cation channel (2), is a typical example of a polymodally gated TRP channel, in that it can be activated by ligands, such as pregnenolone sulfate (PS) and nifedipine, as well as by heat and membrane depolarization (3, 4). Interestingly, recent evidence indicates that combined stimulation with PS and clotrimazole (Clt) leads to the activation of two distinct permeation pathways in TRPM3: the central pore, which is Ca 2+ -permeable and carries an outwardly rectifying current, and an alternative ion permeation pathway that mediates an inwardly rectifying monovalent cation current (5).TRPM3 is highly expressed in somatosensory neurons, where it plays decisive roles in the nocifensive response to PS and heat, as well as in the development of heat hyperalgesia during inflammation (3, 6). In these neurons, TRPM3 is frequently coexpressed with TRPA1 and TRPV1, two TRP channels that have emerged as key regulators of neurogenic inflammation by triggering neuropeptide release from sensory nerve endings (7,8). Whether activation of TRPM3 can also initiate the release of neuropeptides, such as substance P or calcitonin gene-related peptide (CGRP), which elicit vasodilation, vascular leakage, and other responses in peripheral cell types, is unclear, however. In addition, TRPM3 is expressed in pancreatic beta cells, where it is involved in controlling insulin rel...