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Background and purposeURB937 is a peripherally restricted inhibitor of the anandamide-deactivating enzyme fatty-acid amide hydrolase (FAAH). Despite its limited access to the CNS, URB937 produces marked antinociceptive effects in rodents. URB937 is actively extruded from the CNS by the ATP-binding cassette (ABC) membrane transporter, Abcg2. Tissue Abcg2 levels are markedly different between males and females, and this transporter is known to limit the access of xenobiotics to the fetoplacental unit in gestating female rodents. In the present study, we investigated the tissue distribution and antinociceptive properties of URB937 in female mice and rats.Experimental approachWe studied the systemic disposition of URB937 in female mice and the antinociceptive effects of this compound in models of visceral (acetic acid-induced writhing) and inflammatory nociception (carrageenan-induced hyperalgesia) in female mice and rats. Furthermore, we evaluated the interaction of URB937 with the blood-placenta barrier in gestating mice and rats.Key resultsAbcg2 restricted the access of URB937 to the CNS of female mice and rats. Nevertheless, URB937 produced a high degree of antinociception in female mice and rats in models of visceral and inflammatory pain. Moreover, the compound displayed a restricted access to placental and fetal tissues in pregnant mice and rats.Conclusions and implicationsPeripheral FAAH blockade with URB937 reduces nociception in female mice and rats, as previously shown for males of the same species. In female mice and rats, Abcg2 limits the access of URB937, not only to the CNS, but also to the fetoplacental unit. LINKED ARTICLES This article is part of a themed section on Cannabinoids. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2012.167.issue-8.

Norbuprenorphine is the major active metabolite of buprenorphine which is commonly used to treat opiate addiction during pregnancy. Norbuprenorphine produces marked respiratory depression and was 10 times more potent than buprenorphine. Therefore, it is important to understand the mechanism that controls fetal exposure to norbuprenorphine, as exposure to this compound may pose a significant risk to the developing fetus. P-gp/ABCB1 and BCRP/ABCG2 are two major efflux transporters regulating tissue distribution of drugs. Previous studies have shown that norbuprenorphine, but not buprenorphine, is a P-gp substrate. In this study, we systematically examined and compared the roles of P-gp and BCRP in determining maternal brain and fetal distribution of norbuprenorphine using transporter knockout mouse models. We administered 1 mg/kg norbuprenorphine by retro-orbital injection to pregnant FVB wild-type, Abcb1a −/− / 1b −/− , and Abcb1a −/− / 1b −/− / Abcg2 −/− mice on gestation day 15. The fetal AUC of norbuprenorphine was ∼64% of the maternal plasma AUC in wild-type mice, suggesting substantial fetal exposure to norbuprenorphine. The maternal plasma AUCs of norbuprenorphine in Abcb1a −/− / 1b −/− and Abcb1a −/− / 1b −/− / Abcg2 −/− mice were ∼2 times greater than that in wild-type mice. Fetal AUCs in Abcb1a −/− / 1b −/− and Abcb1a −/− / 1b −/− / Abcg2 −/− mice were also increased compared to wild-type mice; however, the fetal-to-maternal plasma AUC ratio remained relatively unchanged by the knockout of Abcb1a/1b or Abcb1a/1b/Abcg2 . In contrast, the maternal brain-to-maternal plasma AUC ratio in Abcb1a −/− / 1b −/− or Abcb1a −/− / 1b −/− / Abcg2 −/− mice was increased ∼30-fold compared to wild-type mice. Protein quantification by LC–MS/MS proteomics revealed significantly higher amounts of P-gp protein in the wild-type mice brain than that in the placenta. These results indicate that fetal exposure to norbuprenorphine is substantial and that P-gp has a minor impact on fetal exposure to norbuprenorphine, but plays a significant role in restricting its brain distribution. The differential impacts of P-gp on norbuprenorphine distribution into the brain and fetus are likely, at least in part, due to the differences in amounts of P-gp protein expressed in the blood-brain and blood-placental barriers. BCRP is not as important as P-gp in determining both the systemic and tissue exposure to norbuprenorphine. Finally, fetal AUCs of the metabolite norbuprenorphine-β- d -glucuronide were 3–7 times greater than maternal plasma AUCs, while the maternal brain AUCs were <50% of maternal plasma AUCs, suggesting that a reversible pool of conjugated metabolite in the fetus may contribute to the high fetal exposure to norbuprenorphine. [ABSTRACT FROM AUTHOR]