Silent cold-sensing neurons drive cold allodynia in neuropathic pain states

Neuropathic pain patients often experience innocuous cooling as excruciating pain. The cell and molecular basis of this cold allodynia is little understood. We used in vivo calcium imaging of sensory ganglia to investigate the activity of peripheral cold-sensing neurons in three mouse models of neuropathic pain: oxaliplatin-induced neuropathy, partial sciatic nerve ligation and ciguatera poisoning. In control mice, cold-sensing neurons were few in number and small in size. In neuropathic animals with cold allodynia, a set of normally silent large-diameter neurons became sensitive to cooling. Many silent cold-sensing neurons expressed the nociceptor markers NaV1.8 and CGRP. Ablating these neurons diminished cold allodynia. Blocking KV1 voltage-gated potassium channels was sufficient to trigger de novo cold sensitivity in silent cold-sensing neurons. Thus silent cold-sensing neurons are unmasked in diverse neuropathic pain states and cold allodynia results from peripheral sensitization caused by altered nociceptor excitability. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/073999v1_ufig1.gif" ALT="Figure 1"> View larger version (60K): org.highwire.dtl.DTLVardef@e3aeforg.highwire.dtl.DTLVardef@3f40bdorg.highwire.dtl.DTLVardef@b344baorg.highwire.dtl.DTLVardef@16540ef_HPS_FORMAT_FIGEXP M_FIG C_FIG