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

Abstract

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 hr intervals (Repeat Morphine), with varying doses of naloxone or 6-alpha-naloxol injected SC 4 hr postmorphine 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, but also indicate that delay in onset of action of 6-alpha-naloxol to opioid receptors in the central nervous system may contribute significantly to its reduced potency relative to naloxone under certain morphine pretreatment conditions.

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

“…This suggests that constitutive opioid receptor activity may develop rapidly, perhaps very soon following opioid agonist exposure. This suggestion is consistent with a previous report using an operant withdrawal model (Schulteis et al, 2009) that found that the relative potency of naloxone (inverse opioid agonist) and 6α-naloxol (neutral opioid antagonist) did not change in rats injected once or twice with morphine; whereas in non-dependent rats, the potency to disrupt operant performance for naloxone increased ≈ 80-fold and that for 6a-naloxol increased ≈ 6-fold following a single morphine injection. The possibility of rapid development of constitutive activity might be important to directly study in future experiments.…”

“…At the end of treatment, mice (N=5–30/dose) were injected s.c. with naltrexone (0.0125–2 mg/kg) or 6β-naltrexol (1.5–140 mg/kg) and immediately observed for withdrawal jumping for 15 min. A decrease in the ED 50 of opioid antagonists to precipitate withdrawal is a common measure of the degree of opioid dependence (Adams and Holtzman, 1990; Azar et al, 2003; Schulteis et al, 2005; 2009; Villarreal and Castro, 1981; Way et al, 1969). …”

“…In the next experiment, the change in the relative potency of naltrexone and 6β-naltrexol to induce withdrawal with increasing dependence was determined. Studies show that the ED 50 of opioid antagonists to precipitate withdrawal decreases with increasing dependence (Adams and Holtzman, 1990; Azar et al, 2003; Schulteis et al, 2005; 2009; Villarreal and Castro, 1981; Way et al, 1969). It was predicted that if constitutive opioid receptor activity develops in parallel with opioid dependence then the potency of naltrexone to precipitate withdrawal should increase more than 6β-naltrexol.…”

Development and validation of a sensitive LC/MS/MS method for the simultaneous determination of naloxone and its metabolites in mouse plasma

“…1, 6␣/␤-naloxol (NLL) and naloxone-3␤-d-glucuronide (NLG) are the metabolites of NLX. The potency of NLL to precipitate opioid withdrawal from acute morphine dependence has been reported [4]. It has also been demonstrated that NLG can antagonize the mobility-lowering effect of morphine in the rat colon [5,6].…”

The Clinical Applications of Extended-Release Abuse-Deterrent Opioids

“…It can cause withdrawal due to an increase in naloxone bioavailability. Rectal administration of Targiniq ER could thus lead to symptoms of withdrawal [47,48]. Several trials have shown that Targiniq ER reduces opioidinduced constipation.…”