eprintid: 10164655
rev_number: 16
eprint_status: archive
userid: 699
dir: disk0/10/16/46/55
datestamp: 2023-02-10 12:47:24
lastmod: 2023-03-03 11:17:59
status_changed: 2023-02-10 12:47:24
type: article
metadata_visibility: show
sword_depositor: 699
creators_name: Iseppon, Federico
creators_name: Luiz, Ana P
creators_name: Linley, John E
creators_name: Wood, John N
title: Pregabalin silences oxaliplatin-activated sensory neurons to relieve cold allodynia
ispublished: pub
divisions: UCL
divisions: B02
divisions: C10
divisions: D17
divisions: G95
keywords: Oaxliplatin, Pain, Pregabalin, sensory neurons, silent nociceptors
note: 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.
abstract: 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 α2δ1 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 α2δ1 calcium channel subunit, but how this works is not yet understood.
date: 2023-02
date_type: published
publisher: Society for Neuroscience
official_url: https://doi.org/10.1523/ENEURO.0395-22.2022
oa_status: green
full_text_type: pub
language: eng
primo: open
primo_central: open_green
verified: verified_manual
elements_id: 2004437
doi: 10.1523/ENEURO.0395-22.2022
medium: Print-Electronic
pii: ENEURO.0395-22.2022
lyricists_name: Wood, John
lyricists_id: JNWOO78
actors_name: Flynn, Bernadette
actors_id: BFFLY94
actors_role: owner
full_text_status: public
publication: eNeuro
volume: 10
number: 2
article_number: 0395-22.2022
event_location: United States
citation:        Iseppon, Federico;    Luiz, Ana P;    Linley, John E;    Wood, John N;      (2023)    Pregabalin silences oxaliplatin-activated sensory neurons to relieve cold allodynia.                   eNeuro , 10  (2)    , Article 0395-22.2022.  10.1523/ENEURO.0395-22.2022 <https://doi.org/10.1523/ENEURO.0395-22.2022>.       Green open access   
 
document_url: https://discovery.ucl.ac.uk/id/eprint/10164655/1/Pregabalin%20silences%20oxaliplatin-activated%20sensory%20neurons%20to%20relieve%20cold%20allodynia.pdf