Neuron
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Stroke remains a significant problem despite decades of work on neuroprotective strategies. NMDA receptor (NMDAR) antagonists are neuroprotective in preclinical models, but have been clinically unsuccessful, in part due to side effects. Here we describe a prototypical GluN2B-selective antagonist with an IC50 value that is 10-fold more potent at acidic pH 6.9 associated with ischemic tissue compared to pH 7.6, a value close to the pH in healthy brain tissue. ⋯ We have determined the mechanism underlying pH-dependent inhibition and demonstrate the utility of this approach in vivo. We also identify dicarboxylate dimers as a novel proton sensor in proteins. These results provide insight into the molecular basis of pH-dependent neuroprotective NMDAR block, which could be beneficial in a wide range of neurological insults associated with tissue acidification.
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The gate control theory of pain proposes that inhibitory neurons of the spinal dorsal horn exert critical control over the relay of nociceptive signals to higher brain areas. Here we investigated how the glycinergic subpopulation of these neurons contributes to modality-specific pain and itch processing. ⋯ Conversely, local pharmacogenetic activation of the same neurons alleviated neuropathic hyperalgesia and chloroquine- and histamine-induced itch. These results establish glycinergic neurons of the spinal dorsal horn as key elements of an inhibitory pain and itch control circuit.