6β-naltrexol preferentially antagonizes opioid effects on gastrointestinal transit compared to antinociception in mice

Preferential Delivery of an Opioid Antagonist to the Fetal Brain in Pregnant Mice

“…When administered in combination with morphine for several days starting in the second postnatal week, 6b-naltrexol prevents withdrawal behavior with extreme potency (ID 50 0.022-0.044 mg/kg), owing to ready access to the neonatal brain lacking full BBB protection. This 6b-naltrexol dose is ∼500-fold lower than the morphine dose used here for inducing dependence, and is 20-500-fold lower than the ID 50 of 6b-naltrexol for the blockade of opiate antinociception in adults depending on the agonist used and the route (and timing) of administration (Wang et al, 2001;Porter et al, 2002;Sirohi et al, 2009;Yancey-Wrona et al, 2009). The extreme potency of 6b-naltrexol is further highlighted by the observation that even at a dosage that is 1/3000 that of morphine, there is a 20% reduction in quantifiable withdrawal behavior, and a significant inhibition of jump latency.…”

“…We propose that an opioid antagonist that is relatively excluded from the maternal brain (enabling ongoing opioid therapy), but which is able to preferentially penetrate the placenta and immature BBB in the fetus could protect the fetus from opioid exposure and thereby prevent or reduce NAS. Previous studies had already indicated that the opioid antagonist, 6b-naltrexol, is relatively excluded from the brain while acting as a potent antagonist in the periphery (Wang et al, 2004;Yancey Wrona et al, 2009, limiting peripheral adverse opioid effects such as constipation. Here we provide evidence in mice that 6b-naltrexol readily enters the fetal circulation and fetal brain, resulting in substantially higher levels in fetal brain compared with adult brain.…”

“…Peripherally acting antagonists, on the other hand, such as methylnaltrexone (Yuan and Foss, 2000) and naloxegol, a pegylated form of naloxol (Chey et al, 2014), can block some of the peripheral side effects of centrally acting agonists. We have described a neutral antagonist of the m-opioid receptor 6b-naltrexol, which can alleviate opiate-induced constipation in rodents and humans (Yancey-Wrona et al, 2009. This drug is orally available but has poor access to the CNS, presumably due to extrusion by the multidrug resistance protein MDR1 (also called P-glycoprotein transporter; ABCB1 gene; Xie et al, 1999).…”

6β-Naltrexol, a Peripherally Selective Opioid Antagonist that Inhibits Morphine-Induced Slowing of Gastrointestinal Transit: An Exploratory Study

“…While more subjects are needed to be studied with a large dosage range for quantitative assessment, the present results predict a peripheral/central selectivity of at least tenfold in humans, similar to or exceeding the selectivity attained in mice after both systemic and oral administrations in combination with hydrocodone (oral administration yielded slightly greater selectivity for peripheral effects compared with i.v. dosing in mice) [24].…”

“…In mice, 6β‐naltrexol was 10‐fold more potent in antagonizing hydrocodone‐induced gastrointestinal (GI) slowing than CNS‐mediated antinociception [24]. This is in marked contrast to naltrexone, which was found to be equipotent in blocking the peripheral and central effects of hydrocodone under similar conditions [24]. Several additional reports support the hypothesis that 6β‐naltrexol has peripheral selectivity.…”