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 this event has been causally linked to the development of cold allodynia. We examined the effects of pregabalin on oxali-platin-evoked unmasking of cold sensitive neurons using mice expressing GCaMP-3 in all sensory neurons. Intravenous injection of pregabalin significantly ameliorates cold allodynia, while decreasing the number of cold sensi-tive neurons by altering their excitability and temperature thresholds. The silenced neurons are predominantly me-dium/large mechano-cold sensitive neurons, corresponding to the silent cold sensors activated during neuropathy. Deletion of a28 1 subunits abolished the effects of pregabalin on both cold allodynia and the silencing of sensory neurons. Thus, 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.

Automated summary

Oxaliplatin can cause cold and mechanical allodynia in patients, and this study found that it unmasks silent Nav1.8-positive nociceptive cold sensors, which is causally linked to cold allodynia. Pregabalin, when intravenously injected, significantly improves cold allodynia by reducing the number of cold sensitive neurons and changing their excitability and temperature thresholds. Deletion of a28 1 subunits abolishes the effects of pregabalin on cold allodynia and the silencing of sensory neurons, indicating a novel peripheral inhibitory effect of pregabalin on silent cold-sensing neurons in oxaliplatin-dependent cold allodynia.