Central and peripheral mechanisms of pain and itch

Pain and itch are two distinct yet related sensations. Here we present a series of experiments elucidating mechanisms of pain and itch in central and peripheral nervous systems. Coding of itch versus pain has been hotly debated for decades. However, the current coding theories (labeled line, intensity and selectivity theory) cannot accommodate all experimental observations. We identified a subset of spinal interneurons, labeled by gastrin releasing peptide (Grp), that receive direct synaptic input from both pain and itch primary sensory neurons. When activated, these Grp+ neurons generated rarely-seen simultaneous robust pain and itch responses that were intensity-dependent. Accordingly, we propose a “leaky gate” model, in which Grp+ neurons transmit both itch signals and weak pain signals (ensuring pain sensitivity) through the “gate”, but recruit endogenous opioid systems to close the “gate” upon strong painful stimuli to prevent overwhelming pain. Consistent with our model, loss of these Grp+ neurons increased pain responses while itch was decreased. Our new model incorporates currently underappreciated non-monotonic coding in the spinal cord and better explains observations in human psychophysical studies. We also explored peripheral mechanisms mediating protease induced itch. Various endogenous and exogenous proteases can trigger intense itch sensation, presumably via Protease-Activated-Receptor, PAR2. Here we demonstrate that in contrary to the current hypothesis, cysteine proteases including cathepsin S, activate dorsal root ganglion neurons and elicit scratching through Mas-related G protein coupled receptor, MrgprC11, but not PAR2. In contrast to its activation of conventional protease-activated receptors, cathepsin S-mediated activation of MrgprC11 did not involve the generation of a tethered ligand. This expansion of our understanding by which proteases interact with G-protein-coupled receptors (GPCRs) redefines the concept of what constitutes a protease-activated receptor. The findings also implicate proteases as endogenous ligands to members of this orphan receptor family while providing new insights into how cysteine proteases contribute to itch