Endothelin ET_A receptor antagonist reverses naloxone-precipitated opioid withdrawal in mice

Long-term use of opioids for pain management results in rapid development of tolerance and dependence leading to severe withdrawal symptoms. We have previously demonstrated that endothelin-A (ET_A) receptor antagonists potentiate opioid analgesia and eliminate analgesic tolerance. This study was designed to investigate the involvement of central ET mechanisms in opioid withdrawal. The effect of intracerebroventricular administration of ET_A receptor antagonist BQ123 on morphine and oxycodone withdrawal was determined in male Swiss Webster mice. Opioid tolerance was induced and withdrawal was precipitated by the opioid antagonist naloxone. Expression of ET_A and ET_B receptors, nerve growth factor (NGF), and vascular endothelial growth factor was determined in the brain using Western blotting. BQ123 pretreatment reversed hypothermia and weight loss during withdrawal. BQ123 also reduced wet shakes, rearing behavior, and jumping behavior. No changes in expression of vascular endothelial growth factor, ET_A receptors, and ET_B receptors were observed during withdrawal. NGF expression was unaffected in morphine withdrawal but significantly decreased during oxycodone withdrawal. A decrease in NGF expression in oxycodone- but not in morphine-treated mice could be due to mechanistic differences in oxycodone and morphine. It is concluded that ET_A receptor antagonists attenuate opioid-induced withdrawal symptoms.