Effect of Naloxone-3-Glucuronide and N-Methylnaloxone on the Motility of the Isolated Rat Colon After Morphine

Abstract

The effect of the opioid antagonists naloxone-3-glucuronide and N-methylnaloxone on rat colon motility after morphine stimulation was measured. The rat model consisted of the isolated, vascularly perfused colon. The antagonists (10(-4) M, intraluminally) and morphine (10(-4) M, intra-arterially) were administered from 20 to 30 and from 10 to 50 min, respectively. Colon motility was determined by the luminal outflow. The antagonist concentrations in the luminal and venous outflow were measured by high-performance liquid chromatography. Naloxone-3-glucuronide and N-methylnaloxone reversed the morphine-induced reduction of the luminal outflow to baseline within 10 and 20 min, respectively. These antagonists were then excreted in the luminal outflow and could not be found in the venous samples. Naloxone, produced by hydrolysis or demethylation, was not detectable. In conclusion, highly polar naloxone derivatives peripherally antagonize the motility-lowering effect of morphine in the perfused isolated rat colon, are stable, and are not able to cross the colon-mucosal blood barrier.

Physiology, signaling, and pharmacology of opioid receptors and their ligands in the gastrointestinal tract: current concepts and future perspectives

“…This suggests that the action of opioids in the GI tract is mediated mainly by peripheral receptors. Highly polar naloxone derivatives peripherally antagonize the effect of morphine-delayed GI motility in the perfused isolated rat colon [93]. However, some studies imply that only the CNS is involved.…”

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

“…However, optimal collision energy was not applied to NLL and NLG to minimize some interference peaks near the analyte peaks of interest. The instrument parameters for monitoring NLX, NLL, NLG, NLX-d 5 , NLL-d 5 , and NLG-d 5 during method validation and sample analysis were as follows: TIS temperature, 600 • C; TIS voltage, 3500 V; curtain gas (CUR), nitrogen, 25; nebulizing gas (GS1), 80; TIS gas (GS2), 60; collision gas, 10; declustering potential (DP), 80 V; entrance potential (EP), 10 V; collision energy (CE), 52 eV for NLX, NLG, NLXd 5 , and NLG-d 5 …”

“…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]. Therefore, development of a bioanalytical method for the quantification of NLX, NLL, and NLG in plasma samples is needed to better understand their toxicokinetic and pharmacokinetic behaviors.…”

Pharmacokinetics of Sublingual Buprenorphine and Naloxone in Subjects with Mild to Severe Hepatic Impairment (Child-Pugh Classes A, B, and C), in Hepatitis C Virus-Seropositive Subjects, and in Healthy Volunteers

“…The N-dealkylation and reduction of 6-oxo group further precede glucuronidation and naloxone-3-b-D-glucuronide is the predominant metabolite of naloxone in humans [16]. Naloxone-3-b-D-glucuronide has demonstrated peripheral opioid antagonist activity in an ex-vivo model and in humans [20,21]. Therefore, its pharmacokinetics profile was evaluated in this study.…”