Morphine Efficacy, Tolerance, and Hypersensitivity Are Altered After Modulation of SUR1 Subtype KATP Channel Activity in Mice

Frontiers in Neuroscience

James Bjork¹  Kayla Johnson²  Amanda H. Klein²  Alexis Doucette²  Madelyn Moore²  Erin Salo²  Travis Okerman²  Taylor Jurgenson²  Austin Nickell²  Cole Fisher² 

[1] Department of Biomedical Sciences, Medical School Duluth, Duluth, MN, United States;Department of Pharmacy Practice and Pharmaceutical Sciences, College of Pharmacy, University of Minnesota, Duluth, MN, United States;

关键词: opioid;    tolerance;    withdrawal;    KATP channels;    SUR1;    analgesia;   

DOI  :  10.3389/fnins.2019.01122

来源: DOAJ

【 摘 要 】

ATP-sensitive potassium (KATP) channels are found in the nervous system and are downstream targets of opioid receptors. KATP channel activity can effect morphine efficacy and may beneficial for relieving chronic pain in the peripheral and central nervous system. Unfortunately, the KATP channels exists as a heterooctomers, and the exact subtypes responsible for the contribution to chronic pain and opioid signaling in either dorsal root ganglia (DRG) or the spinal cord are yet unknown. Chronic opioid exposure (15 mg/kg morphine, s.c., twice daily) over 5 days produces significant downregulation of Kir6.2 and SUR1 in the spinal cord and DRG of mice. In vitro studies also conclude potassium flux after KATP channel agonist stimulation is decreased in neuroblastoma cells treated with morphine for several days. Mice lacking the KATP channel SUR1 subunit have reduced opioid efficacy in mechanical paw withdrawal behavioral responses compared to wild-type and heterozygous littermates (5 and 15 mg/kg, s.c., morphine). Using either short hairpin RNA (shRNA) or SUR1 cre-lox strategies, downregulation of SUR1 subtype KATP channels in the spinal cord and DRG of mice potentiated the development of morphine tolerance and withdrawal. Opioid tolerance was attenuated with intraplantar injection of SUR1 agonists, such as diazoxide and NN-414 (100 μM, 10 μL) compared to vehicle treated animals. These studies are an important first step in determining the role of KATP channel subunits in antinociception, opioid signaling, and the development of opioid tolerance, and shed light on the potential translational ability of KATP channel targeting pharmaceuticals and their possible future clinical utilization. These data suggest that increasing neuronal KATP channel activity in the peripheral nervous system may be a viable option to alleviate opioid tolerance and withdrawal.

【 授权许可】

Unknown