TY  - JOUR
A1  - Iseppon, Federico
A1  - Luiz, Ana P
A1  - Linley, John E
A1  - Wood, John N
KW  - Oaxliplatin
KW  -  Pain
KW  -  Pregabalin
KW  -  sensory neurons
KW  -  silent nociceptors
JF  - eNeuro
UR  - https://doi.org/10.1523/ENEURO.0395-22.2022
PB  - Society for Neuroscience
N2  - 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 oxaliplatin-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 sensitive neurons by altering their excitability and temperature thresholds. The silenced neurons are predominantly medium/large mechano-cold sensitive neurons, corresponding to the 'silent' cold sensors activated during neuropathy. Deletion of ?2?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.Significance StatementPregabalin is an analgesic drug in the clinic, that is supposed to act by blocking neurotransmitter release. Here we show that silent nociceptors that are activated by chemotherapeutic insults like oxaliplatin are silenced by pregabalin, which blocks the associated pain. This mode of action suggests that peripheral acting pregabalin-like drugs could be very useful for pain during chemotherapy, as they would have no CNS side effects - a problem for many patients with pregabalin. This novel effect of pregabalin is mediated by its interaction with the ?2?1 calcium channel subunit, but how this works is not yet understood.
ID  - discovery10164655
IS  - 2
N1  - Copyright © 2023 Iseppon et al. This is an open-access article distributed under the terms of the Creative
Commons Attribution 4.0 International license, which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed.
VL  - 10
AV  - public
Y1  - 2023/02//
TI  - Pregabalin silences oxaliplatin-activated sensory neurons to relieve cold allodynia
ER  -