The role of opioid antagonist efficacy and constitutive opioid receptor activity in the opioid withdrawal syndrome in mice

► Naltrexone is an inverse agonist and 6β-naltrexol is a neutral opioid antagonist. ► Naltrexone and 6β-naltrexol precipitate opioid withdrawal. ► Naltrexone acts additively with 6β-naltrexol to precipitate withdrawal. ► 6β-naltrexol dose-dependently decreases or increases the potency of naltrexone. ► Constitutive opioid receptor activity may not increase with opioid dependence.