KATP Channel Prodrugs Reduce Hypersensitivity in MouseModels of Chronic Pain (2022-03-04)

Abstract

Opioids are commonly used for the treatment of chronic pain, but long-term opioiduse can lead to tolerance. As the analgesic effect of opioids is attenuated over time,this leads to dosage escalation to accomplish the same level of analgesia, which canpotentially lead to substance dependence. While opioids are incredibly effectivetherapeutics for chronic pain, it is necessary to find therapeutics that willpharmacologically reduce the need for opioid analgesics and alleviate opioidtolerance development and symptoms of withdrawal to help fight the opioidepidemic in the United States. The goal of this project is to develop therapeutics for chronic pain treatment tocombat the overuse of opioids. The body produces similar physiological changes inits response to chronic pain and opioid therapy, including the loss of activity ofpotassium channels in the nervous system. Previous studies show ATP-sensitivepotassium (KATP) channel agonists can counteract the decreased antinociceptiveeffects seen with long term use of opioids. Many agonists of KATP channels are notsoluble in physiologically relevant vehicles, needing adaptation for clinical use.Novel KATP channel targeting prodrugs, CKLP1, CF3-CKLP1 and CKLP2, weredeveloped as they are cleaved by endogenous alkaline phosphatase enzymespresent in the nervous system. Analgesic capabilities of intrathecally injectedprodrugs were tested in a rodent model of chronic neuropathic and inflammatorypain. The reduction of opioid tolerance and opioid-induced hypersensitivity in micetreated chronically with morphine was also evaluated. Future studies will determinehow prodrug pharmacokinetics affect analgesic efficacy in our mouse models. Thestudies may aid in the further development of KATP channel prodrugs for use intreatments of chronic pain, opioid tolerance, and withdrawal.