No Relation of Plasma Morphine Level to the Severity of Naloxone-Induced Withdrawal in Acute Morphine-Dependent Rats

Abstract

ABSTRACT-Plasma morphine concentration and naloxone-precipitated withdrawal body weight loss and plasma corticosterone (PCS) increase were determined at 12, 18 and 24 hr after i.v. infusion of morphine at a constant rate of 10 mg/kg/hr for 4 hr in Sprague-Dawley rats. Plasma morphine concentration declined 98.0% within 12 hr and further declined 58.8% during 12-24 hr after morphine infusion. There was a significant difference between plasma morphine concentrations at 12 and 24 hr after the morphine infusion. Naloxone (0.5 and 2.0 mg/kg)-precipitated withdrawal, but not spontaneous withdrawal, was elicited at 12-24 hr after the morphine infusion, and the severity of withdrawal precipitated by 2.0 mg/kg naloxone was the same at 12-24 hr after the morphine infusion. Furthermore, there was no significant correlation between plasma morphine concentration and body weight loss or PCS increase. The results suggest that a constant degree of morphine dependence is sustained during 12-24 hr after the morphine infusion and the severity of naloxone-precipitated withdrawal is not related to the plasma morphine concentration at the time of naloxone injection, that is, the rate of morphine removal from its receptor sites.Keywords: Intravenous morphine infusion, Plasma morphine concentration, Naloxone-withdrawal, Body weight loss, Plasma corticosterone increase Physical dependence on morphine is evidenced by the withdrawal syndromes that follow the discontinuation of morphine exposure (spontaneous withdrawal) or the treatment with an opioid antagonist (antagonist-precipitated withdrawal) in laboratory animals (1); the severity of the syndrome is thought to reflect the degree of physical dependence. Morphine withdrawal must be initiated by the removal of morphine from opioid receptors.Yoburn et al. (2) demonstrated that the time course of morphine withdrawal was inversely related to the elimination rate of plasma morphine and that body weight loss correlated with plasma morphine levels just before withdrawal in rats implanted with morphine pellets. Furthermore, Domino et al. (3) showed that the negative relationship between the plasma morphine concentration and the severity of withdrawal could be quantified in a simple logarithmic equation in morphine-dependent monkeys. The plasma morphine level has been thought to correlate with the morphine concentration in the vicinity of their binding sites and the amount of morphine bound to opioid receptors. These findings, then, suggest that the severity of morphine withdrawal is related to the rate of removal of morphine from the opioid receptors in spontaneous morphine withdrawal.Opioid antagonist, naloxone-precipitated morphine withdrawal is thought to be initiated through an immediate replacement of morphine by naloxone at their binding sites. Thus the rate of morphine removal from the receptor sites after sufficient naloxone may depend on the morphine concentration in the receptor sites at the time of naloxone injection. If the severity of naloxone-precipitated withdrawal is related ...

Pharmacological examination of contractile responses of the guinea‐pig isolated ileum produced by μ‐opioid receptor antagonists in the presence of, and following exposure to, morphine

“…It would appear, therefore, that prior to the addition of naloxone, morphine was either absent or present at a concentration below which any signi®cant eect on electrically-evoked contractions could be detected (510 nM). Interestingly, the conclusion regarding the relationship between naloxone-induced responses and agonist concentration is similar to that advanced by Kishioki et al (1995) in morphine-dependent rats. It was noted that withdrawal symptoms precipitated by naloxone in this model were as pronounced at 24 h after the last dose of morphine (when plasma morphine was only 1% of steady state levels) as that observed 12 h earlier.…”

Acute withdrawal induced by adenosine A1-receptor activation in isolated guinea-pig ileum: role of opioid receptors and effect of cholecystokinin

“…The fact that a withdrawal response to CPT could be obtained after removal of CPA indicates that this response does not result from the agonist displacement from its receptor binding site. This conclusion is in agreement with the results both of in‐vivo in‐vitro studies on opioid withdrawal, demonstrating that withdrawal symptoms and signs persist for a long time after removal of the agonists [14–16] …”

“…either responded or did not respond to the addition of opioid and adenosine A 1 ‐antagonists). Moreover, guinea‐pig ileum preparations were repeatedly washed out before adding the opioid or the adenosine A 1 ‐antagonists, and this procedure should probably eliminate both the possible differences in the endogenous level and the constitutive activity of the receptors [11–15,40–44] …”

“…It is generally accepted that the opioid antagonist‐induced withdrawal response results from the displacement of the agonist from its receptor binding sites. Its symptoms and signs persist for a long time after removal of the agonist [14–16] . Some of the μ‐opioid withdrawal symptoms are similar to those characterising adenosine A 1 ‐withdrawal responses; this suggests the existence of a functional relationship between μ‐opioid and A 1 ‐adenosine systems [17–19] .…”

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

“…However, it has been demonstrated that significant somatic (body weight loss), endocrine (increased plasma corticosterone release) and aversive stimulus (conditioned place aversion) indices of withdrawal from acute or chronic morphine pretreatment can be elicited by antagonists given up to 24–48 hr post-morphine (Kishioka et al, 1995; Parker and Joshi, 1998; Schulteis et al, 1997; Shoblock and Maidment, 2006, 2007) at a time when there is negligible amounts of morphine present in the system (Kishioka et al, 1995). Recently a possible explanation of the ability of naloxone and naltrexone potency to elicit withdrawal signs in the absence of residual morphine has been offered, based on the observation that mu and delta opioid receptors, like other G-protein-coupled receptors, demonstrate some basal signaling activity as demonstrated by G-protein-coupled second messenger activity in the absence of agonist binding (Burford et al, 2000; Sadee et al, 2005).…”