Year-end Sale % OFF 
Abstract
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.
Highlights
Potassium channels play a crucial role in controlling the excitability of neurons, including nociceptors and second order neurons in the spinal cord (Rasband et al, 2001)
Kcnj11 iso1 potassium channel subunits were significantly decreased in the dorsal root ganglia (DRG) of Morphine tolerant (MT) + spinal nerve ligation (SNL) mice [Figure 1B, two-way ANOVA, Dunnett post hoc, F(3,52) = 0.015, confidence intervals (CI) MT+SNLIpsi = 0.1382 to 2.126 and CI MT+SNLContra = 0.1367 to 2.127]
The results presented here show the expression of KATP channels during morphine tolerance is highly dependent on whether underlying nerve injury was present or absent in mice
Summary
Potassium channels play a crucial role in controlling the excitability of neurons, including nociceptors and second order neurons in the spinal cord (Rasband et al, 2001). Chronic morphine exposure decreases the gating kinetics of potassium channels, indicating that decreased downstream opioid receptor coupling may account for opioid tolerance in the nervous system (Chen et al, 2000). The identity of these potassium channels is still up for debate, but it creates a compelling argument that activation of potassium channels could represent an interesting therapeutic solution to morphine tolerance and withdrawal due to their ability to hyperpolarize the membranes in the peripheral and central nervous system and make the neurons less excitable (Christie, 2008)
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
