Pregabalin silences oxaliplatin-activated sensory neurons to relieve cold allodynia

Oxaliplatin is a platinum-based chemotherapeutic agent that causes cold and mechanical allodynia in up to 90% of patients. Silent Nav1.8-positive nociceptive cold sensors have been shown to be unmasked by oxaliplatin and other neuropathic insults. This event has been causally linked to the development of cold and mechanical allodynia. Pregabalin is an anti-epileptic and analgesic drug that acts through a calcium channel α2δ1 subunit to lower neurotransmitter release. Recent data also suggest pregabalin can act on NMDA receptors and other proteins, but the site of analgesic action has been considered to be the central nervous system. We examined the effects of pregabalin on oxaliplatin -evoked unmasking of cold sensitive neurons using mice expressing GCaMP3 driven by a Pirt promoter in all sensory neurons. We found that in mice treated with oxaliplatin, intravenous injection of pregabalin significantly decreased cold allodynia. Interestingly, pregabalin also decreased the number of sensory neurons responding to cold nociceptive stimuli by altering their excitability and their temperature thresholds. These silenced neurons are medium/large cells responding to both painful mechanical and cold stimuli, corresponding to the “silent” cold sensors that become active in numerous neuropathic pain models. Deletion of α2δ1 subunits abolished the effects of pregabalin on both cold allodynia and the silencing of sensory neuron unmasked by oxaliplatin. Taken together, these results define a novel, peripheral inhibitory effect of pregabalin on the excitability of silent cold-sensing neurons in a model of oxaliplatin-dependent cold allodynia.