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

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 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 NaV1.8
and CGRPα. Ablating neurons expressing NaV1.8 resulted in diminished
cold allodynia. The silent cold-sensing neurons could also be activated by cooling
in control mice through blockade of KV1 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.