Graphical Abstract Highlights d Excitatory NPYR1 Cre (Y1 Cre ) neurons are required for mechanical itch transmission d Spinal Y1 Cre neurons receive LTMR input and mediate light punctate touch d NPY::Cre interneurons inhibit Y1-expressing neurons in the dorsal horn d NPY signaling via dorsal horn Y1-expressing neurons gates mechanical itch In Brief Acton et al. identify the excitatory neurons in the dorsal spinal cord that drive mechanical itch. These cells mediate responses to light punctate touch and are inhibited by neuropeptide Y (NPY)::Cre interneurons. Light touch sensitivity and mechanical itch responses are gated by NPY signaling mediated by Y1-expressing neurons in the dorsal horn. Mechanical itch Disrupted inhibitory gating Normal inhibitory gating Y1 + Low-threshold mechanoreceptors NPY + Normal touch discrimination NPY Y1 + NPY + Mechanical itch NPY Low-threshold mechanoreceptors SUMMARYAcute itch can be generated by either chemical or mechanical stimuli, which activate separate pathways in the periphery and spinal cord. While substantial progress has been made in mapping the transmission pathway for chemical itch, the central pathway for mechanical itch remains obscure. Using complementary genetic and pharmacological manipulations, we show that excitatory neurons marked by the expression of the neuropeptide Y1 receptor (Y1 Cre neurons) form an essential pathway in the dorsal spinal cord for the transmission of mechanical but not chemical itch. Ablating or silencing the Y1 Cre neurons abrogates mechanical itch, while chemogenetic activation induces scratching. Moreover, using Y1 conditional knockout mice, we demonstrate that endogenous neuropeptide Y (NPY) acts via dorsalhorn Y1-expressing neurons to suppress light punctate touch and mechanical itch stimuli. NPY-Y1 signaling thus regulates the transmission of innocuous tactile information by establishing biologically relevant thresholds for touch discrimination and mechanical itch reflexes.

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SUMMARY1. Physiological and molecular evidence for the presence and functional role of M1 muscarinic cholinergic receptors (mAChRs) in adult guinea-pig ventricular cells is presented.2. Whole-cell clamp measurements of the L-type calcium current (ICa) in isolated myocytes were performed. Caesium was used to suppress potassium currents. ICa was increased by the muscarinic agonist carbachol in cells pretreated with pertussis toxin which blocked the M2 mAChR-triggered cascade of intracellular signalling, while it was not changed in untreated cells.3. If the M2-mediated regulation Of ICa was blocked by directly saturating the cell with cyclic adenosine monophosphate (cAMP) through the patch pipette, application of carbachol induced a further small increase of the current above the level reached after cAMP perfusion. This increase was more pronounced in cells pretreated with pertussis toxin.4. The carbachol-induced increase of ICa was blocked by the selective M1 mAChR antagonist pirenzepine.5.

COVID-19, the illness caused by SARS-CoV-2, has a wide-ranging clinical spectrum that, in the worst-case scenario, involves a rapid progression to severe acute respiratory syndrome and death. Epidemiological data show that obesity and diabetes are among the main risk factors associated with high morbidity and mortality. The increased susceptibility to SARS-CoV-2 infection documented in obesity-related metabolic derangements argues for initial defects in defence mechanisms, most likely due to an elevated systemic metabolic inflammation ("metaflammation"). The NLRP3 inflammasome is a master regulator of metaflammation and has a pivotal role in the pathophysiology of either obesity or diabetes. Here, we discuss the most recent findings suggesting contribution of NLRP3 inflammasome to the increase in complications in COVID-19 patients with diabesity. We also review current pharmacological strategies for COVID-19, focusing on treatments whose efficacy could be due, at least in part, to interference with the activation of the NLRP3 inflammasome.