Silent cold-sensing neurons contribute to cold allodynia in neuropathic pain

<b>Neuropathic pain patients often experience innocuous cooling as excruciating pain. The cell and molecular basis of this cold allodynia is little understood. We used <i>in vivo </i>calcium imaging of sensory ganglia to investigate how the activity of peripheral cold-sensing neurons was altered 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 of these silent cold-sensing neurons responded to noxious mechanical stimuli and expressed the nociceptor markers Na_V1.8 and CGRPα. Ablating neurons expressing Na_V1.8 resulted in diminished cold allodynia. The silent cold-sensing neurons could also be activated by cooling in control mice through blockade of K_V1 voltage-gated potassium channels. Thus silent cold-sensing neurons are unmasked in diverse neuropathic pain states and cold allodynia results from peripheral sensitization caused by altered nociceptor excitability. </b>