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. 2025 Jul 11:10.1097/j.pain.0000000000003700.
doi: 10.1097/j.pain.0000000000003700. Online ahead of print.

Decreased KCC2 expression in the human spinal dorsal horn associated with chronic pain and long-term opioid use

Olivia C Davis  1 , Samuel Ferland  2 , Louis-Etienne Lorenzo  2 , Clare Murray-Lawson  3   4 , Stephanie Shiers  1 , Muhammad Saad Yousuf  1 , Annemarie Dedek  3   4   5 , Eve C Tsai  4 , Erin Vines  6 , Peter Horton  6 , Anna Cervantes  6 , Tariq Khan  6 , Geoffrey Funk  6 , Gregory Dussor  1 , Antoine G Godin  2 , Francesco Ferrini  2   7 , Yves De Koninck  2 , Michael E Hildebrand  3   4 , Theodore J Price  1
Affiliations

Decreased KCC2 expression in the human spinal dorsal horn associated with chronic pain and long-term opioid use

Olivia C Davis et al. Pain. .

Abstract

Loss of GABAergic and glycinergic inhibitory efficacy in the spinal dorsal horn is associated with neuropathic pain and opioid-induced hyperalgesia in rodent models. Downregulation of the KCC2 chloride extrusion transporter is a key mechanism underlying this decreased inhibitory efficacy, but to-date there is no evidence supporting or opposing this hypothesis in humans. Here, we demonstrate that KCC2 expression is decreased in superficial dorsal horn neurons of organ donors who died with a documented history of pain, or of long-term opioid use. We show profoundly decreased KCC2 dorsal horn membrane expression in a primary cohort associated with either chronic pain or opioid use, and in a replication cohort of mixed chronic pain and opioid use history. These results show that decreased dorsal horn inhibitory efficacy likely promotes chronic pain in humans and support the development of therapeutics augmenting KCC2 function as a treatment for chronic pain and opioid use disorders.

Keywords: Dorsal horn; KCC2; Neuropathic pain; Opioid use disorder.

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Conflict of interest statement

Conflict of Interest Statement: T.J.P. is a co-founder of and holds equity in 4E Therapeutics, NuvoNuro, PARMedics, Nerveli, and Doloromics. T.J.P. has received research grants from AbbVie, Eli Lilly, Grunenthal, Evommune, Hoba Therapeutics, and The National Institutes of Health. YDK has received grants from Axonis Therapeutics, holds equity and chairs their scientific advisory board. M.S.Y. is a co-founder of and holds equity in NuvoNuro.

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