KATP channel prodrugs reduce hypersensitivity in neuropathic and inflammatory pain models, morphine-induced hypersensitivity, and reduce withdrawal behaviors in mice

Abstract

<b>Abstract ID 16640</b> <b>Poster Board 8</b> Pharmaceutical strategies to utilize KATP channels for therapeutics have been hindered due to low solubility and/or ability to be delivered systemically.Recently developed novel prodrugs with high aqueous solubility, called cromakalim prodrugs (CKLP), are based on the structure of the KATP channel opener cromakalim. Cromakalim, and other KATP channel openers, has been shown to reduce hyperalgesia in various chronic pain models in rodents. KATP channels are also downstream of mu-opioid receptor singaling, and opioid antinociception can be attenuated after blocking or downregulating KATP channel function. The objective ofthis study is to test novel KATP channel-targeting prodrugs in rodent models of neuropathic and inflammatory pain in addition to opioid tolerance after chronic morphine administration. Male and female mice were subjected to spinal nerve ligation (SNL) or intraplantar injection of Complete Freund9s Adjuvant (CFA) to induce a model of neuropathic and inflammatory pain, respectively. Intrathecal administration of either of the KATP channel prodrugs, CKLP1, CF3-CKLP1, or CKLP2 (0-60ug) attenuated mechanical hypersensitivity after SNL or CFA compared to vehicle (saline). Mechanical hypersensitivity was improved in mice during chronic morphine treatment (15mg/kg, twice daily, 5 days) with administration of either CKLP1, CF3-CKLP1, or CKLP2. Naloxone precipitated withdrawal behaviors, were improved after CKLP2 administration, including jumping and rearing measured one day after thecompletion of morphine tolerance. These results are consistent with our previous data indicating non-water soluble KATP channel agonists produce analgesia and attenuate morphine tolerance in mice. Newly developed, cromakalim prodrug 1 (CKLP1), CF3-CKLP1,and CKLP2 are water-soluble KATP channel openers that could be useful to reduce chronic pain, opioid tolerance, and withdrawal. This research was funded by National Institutes of Health (K01DA042902, R01DA051876 to Klein) and the University of Minnesota Pain Consortium. 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.