Relative potency of the opioid antagonists naloxone and 6-alpha-naloxol to precipitate withdrawal from acute morphine dependence varies with time post-antagonist

The current study compared the potency of naloxone versus 6-alpha-naloxol to precipitate opioid withdrawal under varying conditions of morphine pretreatment history using suppression of operant responding for food reward as the index of withdrawal. Male Wistar rats trained to respond on a lever for food reward received pretreatment with either Vehicle (Morphine-Naïve), a single subcutaneous (SC) injection of 5.6 mg/kg morphine (Single Morphine), or two morphine injections at 24 h intervals (Repeat Morphine), with varying doses of naloxone or 6-alpha-naloxol injected SC 4 h post-morphine and 5 min prior to the 30 min test session. When responding over the entire 30 min operant session was examined, naloxone was only 5-fold more potent than 6-alpha-naloxol in suppressing operant responding under Morphine Naïve conditions, but this increased to a 65-fold potency difference after Single or Repeat Morphine pretreatment. Examination of the relative potency of these antagonists in the Early Phase of operant testing (5-15 min post-antagonist) revealed an even greater 100-fold potency difference between naloxone and 6-alpha-naloxol, but in the Late Phase of testing (25-35 min post-antagonist), this had declined to a 9-fold potency difference, comparable to the relative potency of naloxone to 6-alpha-naloxol under Morphine-Naïve conditions. The results confirm a differential potency of naloxone to its reduced conjugate 6-alpha-naloxol in vivo, and extend the observation of this phenomenon to an acute (single) pretreatment with a low dose of morphine and an additional sign of opioid withdrawal to those previously used. However, the results also indicate that delay in onset of action of 6-alpha-naloxol at opioid receptors in the central nervous system may contribute significantly to its reduced potency relative to naloxone under certain morphine pretreatment conditions.