期刊
ACS CHEMICAL NEUROSCIENCE
卷 8, 期 3, 页码 460-467出版社
AMER CHEMICAL SOC
DOI: 10.1021/acschemneuro.6b00382
关键词
Chloride channel; pharmacogenetic; chemogenetic; pain; gene transfer; ligand-gated; glycine receptor
资金
- Australian Research Council [LP120100297]
- National Health and Medical Research Council [APP1058542, APP1060707]
- Australian Research Council [LP120100297] Funding Source: Australian Research Council
The gene transfer-mediated expression of inhibitory ion channels in nociceptive neurons holds promise for treating intractable pain. Chemogenetics, which involves expressing constructs activated by biologically inert molecules, is of particular interest as it permits tunable neuromodulation. However, current chloride permeable chemogenetic constructs are problematic as they mediate a tonic chloride influx which over time would deplete the chloride electrochemical gradient and reduce inhibitory efficacy. Inflammatory pain sensitization can be caused by prostaglandin E2-mediated inhibition of glycinergic inhibitory postsynaptic currents in spinal nociceptive neurons. We developed a highly conducting (100 PS) inhibitory chemogenetic construct based on a human glycine receptor (alpha 1(Y279F,A288G)) with high ivermectin sensitivity. When virally infected into spinal neurons, 10 nM ivermectin increased the magnitude and frequency of glycinergic postsynaptic currents without activating a tonic chloride flux. The construct should analgesia. Its human origin and the well-established biocompatibility of its ligand suggest it may be suited to human use.
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