KATP Channel Prodrugs Reduce Inflammatory and Neuropathic Hypersensitivity, Morphine-Induced Hypersensitivity, and Precipitated Withdrawal in Mice
Copyright © 2023 by The American Society for Pharmacology and Experimental Therapeutics..
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.
| Errataetall: |
CommentIn: J Pharmacol Exp Ther. 2023 Oct;387(1):15-17. - PMID 37714690 |
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| Medienart: |
E-Artikel |
| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:387 |
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| Enthalten in: |
The Journal of pharmacology and experimental therapeutics - 387(2023), 1 vom: 17. Okt., Seite 18-26 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Doucette, Alexis [VerfasserIn] |
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| Links: |
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| Themen: |
76I7G6D29C |
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| Anmerkungen: |
Date Completed 18.09.2023 Date Revised 02.10.2023 published: Print-Electronic CommentIn: J Pharmacol Exp Ther. 2023 Oct;387(1):15-17. - PMID 37714690 Citation Status MEDLINE |
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| doi: |
10.1124/jpet.122.001522 |
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NLM354370472 |
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| 245 | 1 | 0 | |a KATP Channel Prodrugs Reduce Inflammatory and Neuropathic Hypersensitivity, Morphine-Induced Hypersensitivity, and Precipitated Withdrawal in Mice |
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| 500 | |a Date Revised 02.10.2023 | ||
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| 500 | |a CommentIn: J Pharmacol Exp Ther. 2023 Oct;387(1):15-17. - PMID 37714690 | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Copyright © 2023 by The American Society for Pharmacology and Experimental Therapeutics. | ||
| 520 | |a 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 | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, N.I.H., Extramural | |
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| 650 | 7 | |a Adenosine Triphosphate |2 NLM | |
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| 700 | 1 | |a Hulke, Shelby |e verfasserin |4 aut | |
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| 700 | 1 | |a Dosa, Peter I |e verfasserin |4 aut | |
| 700 | 1 | |a Klein, Amanda H |e verfasserin |4 aut | |
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