Abstract
Previous studies show ATP-sensitive potassium (KATP) channel openers can reduce hypersensitivity associated with chronic pain models in rodents, and reduce morphine tolerance. Many agonists of KATP channels are not soluble in physiologically relevant vehicles, requiring adaptation for clinical use. This study compared the antinociceptive activity of novel KATP channel targeting prodrugs, CKLP1, CKLP2, and CF3-CKLP. These prodrugs are activated by endogenous alkaline phosphatase enzymes present in the peripheral and central nervous systems. Analgesic capabilities of intrathecally injected prodrugs were tested in rodent models of spinal nerve ligation (SNL) and complete Freund’s adjuvant (CFA) as models for neuropathic and inflammatory pain, respectively. CKLP1 and CKLP2 significantly increased mechanical paw withdrawal thresholds 1–2 hours after intrathecal administration in the SNL model, but all three prodrugs were able to attenuate hypersensitivity up to 7 days after CFA treatment. The reduction of opioid tolerance and opioid-induced hypersensitivity in mice treated chronically with morphine was significantly reduced in CKLP1 and CKLP2 treated animals. Prodrug cleavage was confirmed in mouse spinal cords using liquid chromatography. These studies may aid in the further development of KATP channel prodrugs for use in treatments of chronic pain, opioid tolerance, and withdrawal.
SIGNIFICANCE STATEMENT The cromakalim prodrugs, CKLP1, CKLP2, and CF3-CKLP1 reduced hypersensitivity in inflammatory and neuropathic pain models in male and female mice. CKLP1 and CKLP2 also reduced morphine-induced hypersensitivity in a mouse model of chronic morphine exposure. CKLP2 reduced jumping and rearing behaviors after naloxone-induced precipitated morphine withdrawal. Taken together, CKLP2 demonstrates the potential for development as a non-opioid analgesic drug.
Footnotes
- Received November 23, 2022.
- Accepted March 6, 2023.
This research was funded by National Institutes of Health National Institute on Drug Abuse [Grants K01-DA042902 and R01-DA051876] (to A.H.K.) and the University of Minnesota Pain Consortium (to A.H.K.). Funding also provided by the National Institutes of Health National Center for Advancing Translational Sciences [Grant UL1-TR002494]. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health National Center for Advancing Translational Sciences. This work was also partially funded by the Summer Undergraduate Research Program from the UMD Chemistry and Biochemistry Department and the Undergraduate Research Opportunity Program from the University of Minnesota.
Dr. Dosa consults with Qlaris Bio, which is developing CKLP1 clinically as QLS-101. These interests have been reviewed and managed by the University of Minnesota in accordance with its Conflict of Interest policies.
Data from these studies appears as a thesis to Doucette from the University of Minnesota (Doucette, 2022). This work was previously presented as a poster presentation at the following workshops: Translational Science 2021, Association for Clinical and Translational Science, Virtual, April, 2021; Center for Translational Science Institute’s Translational Science Symposium & Poster Session, August 2022, University of Minnesota, Minneapolis, MN; IASP 2022 World Congress on Pain, September 2022, Toronto, Canada.
A preprint of this article was deposited in bioRxiv [https://doi.org/10.1101/2022.11.10.515984].
- Copyright © 2023 by The American Society for Pharmacology and Experimental Therapeutics
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