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SYSTEMATIC REVIEW article

Front. Physiol.
Sec. Cell Physiology
Volume 16 - 2025 | doi: 10.3389/fphys.2025.1444270

Activation of KATP channels in pain modulation: A systematic review of preclinical studies

Provisionally accepted
Signe Schønning Beich Signe Schønning Beich 1,2Lili Kokoti Lili Kokoti 1,2Mohammad Al-Mahdi Al-Karagholi Mohammad Al-Mahdi Al-Karagholi 1,2,3*
  • 1 Danish Headache Center, Rigshospitalet, Copenhagen, Denmark
  • 2 Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Capital Region of Denmark, Denmark
  • 3 Department of Neurology, Nordsjaellands Hospital-Hilleroed, Hillerød, Denmark

The final, formatted version of the article will be published soon.

    Abstract Objective: To systematically review the involvement of KATP channel activation in pain modulation in preclinical studies. Background: KATP channels are expressed at several levels in the spinal and trigeminal pain pathways, where they seem to modulate nociceptive transmission. Methods: PubMed and Embase databases were searched until January 29th, 2024, using the following search string: (((pain) OR (nociception)) OR (antinociception)) AND ((KATP channel) OR (ATP sensitive potassium channel)). Non-English and unavailable records, as well as records with non-experimental methodology, were excluded. Inclusion criteria were preclinical studies measuring pain in vivo upon activation of the KATP channel by administering a stimulator or positive modulator. Records were screened based on title and abstract, and those that met the study inclusion criteria were reviewed based on study design, measurements, intervention, and outcomes. Results: The search resulted in 569 records. In total, 126 duplicates were detected. Subsequently, 438 records were screened by title and abstract, resulting in the exclusion of 396. Based on inclusion criteria, 42 studies were included. The main findings of the present systematic review were that KATP channel openers can attenuate induced pain in various animal models and potentiate the effects of analgesics. Conclusions: Local, systemic, spinal, and supraspinal activation of KATP channels can attenuate pain and potentiate the efficacy of analgesic drugs. One exception was levcromakalim, as the systemic levcromakalim administration, but not a local application, induced pain. This finding is consistent with those of recent human trials. Future studies should investigate the differences in KATP channel activation between rodents and humans, as well as the differences in activation sites between levcromakalim and other KATP channel openers.

    Keywords: Nociception1, antinociception2, ATP sensitive potassium channel3, potassium channel4, headache5

    Received: 05 Jun 2024; Accepted: 07 Jan 2025.

    Copyright: © 2025 Beich, Kokoti and Al-Karagholi. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

    * Correspondence: Mohammad Al-Mahdi Al-Karagholi, Danish Headache Center, Rigshospitalet, Copenhagen, Denmark

    Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.