Comparison of the opioid receptor antagonist properties of naltrexone and 6β-naltrexol in morphine-naïve and morphine-dependent mice

Abstract

It has been proposed that on chronic morphine treatment the μ-opioid receptor becomes constitutively active, and as a consequence, the opioid withdrawal response arises from a reduction in the level of this constitutively active receptor. In support of this, the putative μ-opioid receptor inverse agonist naltrexone has been shown to precipitate more severe withdrawal behavior in mice than the putative neutral receptor antagonist 6β-naltrexol. In the present study naltrexone and 6β-naltrexol were compared in NIH Swiss mice to test the hypothesis that their differential ability to precipitate withdrawal is due to differences in their in vivo opioid receptor antagonist potencies caused by differential access to μ-opioid receptors in the central nervous system and not necessarily by intrinsic differences in their opioid receptor activity. In naïve mice both compounds had similar potencies to antagonize morphine-induced antinociception in the hot plate and warm-water tail-withdrawal assays when measured under equilibrium conditions and afforded similar calculated apparent in vivo μ-opioid receptor affinities. In morphine-dependent mice both compounds precipitated withdrawal jumping but naltrexone was between 10-and 100-fold more potent than 6β-naltrexol. A similar potency difference was seen for other withdrawal behaviors. Both naltrexone and 6β-naltrexol at 1 mg/kg reversed antinociception induced by the long-lasting μ-opioid receptor agonist BU72 in the warm-water tail-withdrawal assay, but antagonism by naltrexone was 6-fold more rapid in onset at equal doses. Since the compounds have similar affinity for the μ-opioid receptor in vivo, the results suggest that the differences observed between the ability of naltrexone and 6β-naltrexol to precipitate withdrawal in the mouse may be explained by differential onset of receptor antagonist action.

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

“…The initial relative potency of naloxone to 6-alpha-naloxol within 15 min of antagonist injection corresponds closely to observed 50–100-fold relative potency differences of naltrexone to 6-beta-naltrexol to precipitate withdrawal jumping, wet dog shakes, and paw tremors in mice after acute high dose or repeated/chronic morphine treatment; these signs were typically assessed in the first 20-min post-antagonist injection (Divin et al, 2008; Raehal et al, 2005; Wang et al, 2001; Wang et al, 2004). By the Late Phase of testing (25–35 min post-antagonist injection), the potency difference of naloxone to 6-alpha-naloxol was similar (about 9-fold) under Morphine Naïve, Single, and Repeat Morphine conditions.…”

“…2–10 hr post-morphine), but elicit little if any withdrawal jumping at extended time points (20–48 hr) where naloxone or naltrexone remain effective (Sadee et al, 2005; Shoblock and Maidment, 2006, 2007; Wang et al, 2001; Wang et al, 2004). Similar findings have been reported with additional somatic signs of withdrawal such as paw tremors, wet dog shakes, increased respiration, and increased defecation (Divin et al, 2008; Raehal et al, 2005), and with measures of the aversive motivational consequences of opioid withdrawal (e.g. conditioned place aversion; (Shoblock and Maidment, 2006, 2007).…”

“…Some argue that constitutive opioid receptor activity is a “prerequisite mechanism involved in acute opioid withdrawal” (Freye and Levy, 2005), and there is evidence that weak inverse agonists or neutral antagonists exhibit little ability to precipitate somatic withdrawal at lower doses of morphine, but do elicit withdrawal after high dose morphine pretreatment (Walker and Sterious, 2005). However, others have argued that differential rate of access to opioid receptors in the central nervous system (CNS) may account for differences in potency of antagonists such as naltrexone and 6-beta-naltrexol in vivo (Divin et al, 2008). …”

“…Antagonist-induced suppression of operant responding is observed after pretreatment with very low doses of morphine (1.0–5.6 mg/kg; (Schulteis et al, 1997; Schulteis et al, 2004, 2003) relative to those used in prior acute dependence studies (20–180 mg/kg; (Divin et al, 2008; Raehal et al, 2005; Sadee et al, 2005; Walker and Sterious, 2005; Wang et al, 2001; Wang et al, 2004)), thereby permitting a direct test of the hypothesis that weak inverse agonists or neutral antagonists cannot effectively precipitate withdrawal after low dose agonist pretreatment (Walker and Sterious, 2005); and…”

The Relative Potency of Inverse Opioid Agonists and a Neutral Opioid Antagonist in Precipitated Withdrawal and Antagonism of Analgesia and Toxicity

“…Nevertheless, it is important that the potential translational value of 6␤-naltrexol and other neutral antagonists be thoroughly studied. Finally, Divin et al (2008) report that 6␤-naltrexol did not block withdrawal precipitated by the putative inverse agonist naltrexone in the mouse. The reason for this outcome is not clear, but there are several studies, including the present report, that have demonstrated that inverse agonist effects, including precipitated withdrawal, are inhibited by neutral antagonists such as 6␤-naltrexol (Raehal et al, 2005;Walker and Sterious, 2005;Marczak et al, 2007;Wang et al, 2007).…”