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Pharmacological characterization of the peripheral FAAH inhibitor URB937 in female rodents: interaction with the Abcg2 transporter in the blood-placenta barrier.
Br J Pharmacol 2012; 167(8):1620-8BJ

Abstract

BACKGROUND AND PURPOSE

URB937 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 APPROACH

We 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 RESULTS

Abcg2 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 IMPLICATIONS

Peripheral 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.

Authors+Show Affiliations

Departments of Pharmacology and Biological Chemistry, University of California, Irvine, Irvine, CA 92697, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural

Language

eng

PubMed ID

22774772

Citation

Moreno-Sanz, G, et al. "Pharmacological Characterization of the Peripheral FAAH Inhibitor URB937 in Female Rodents: Interaction With the Abcg2 Transporter in the Blood-placenta Barrier." British Journal of Pharmacology, vol. 167, no. 8, 2012, pp. 1620-8.
Moreno-Sanz G, Sasso O, Guijarro A, et al. Pharmacological characterization of the peripheral FAAH inhibitor URB937 in female rodents: interaction with the Abcg2 transporter in the blood-placenta barrier. Br J Pharmacol. 2012;167(8):1620-8.
Moreno-Sanz, G., Sasso, O., Guijarro, A., Oluyemi, O., Bertorelli, R., Reggiani, A., & Piomelli, D. (2012). Pharmacological characterization of the peripheral FAAH inhibitor URB937 in female rodents: interaction with the Abcg2 transporter in the blood-placenta barrier. British Journal of Pharmacology, 167(8), pp. 1620-8. doi:10.1111/j.1476-5381.2012.02098.x.
Moreno-Sanz G, et al. Pharmacological Characterization of the Peripheral FAAH Inhibitor URB937 in Female Rodents: Interaction With the Abcg2 Transporter in the Blood-placenta Barrier. Br J Pharmacol. 2012;167(8):1620-8. PubMed PMID: 22774772.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Pharmacological characterization of the peripheral FAAH inhibitor URB937 in female rodents: interaction with the Abcg2 transporter in the blood-placenta barrier. AU - Moreno-Sanz,G, AU - Sasso,O, AU - Guijarro,A, AU - Oluyemi,O, AU - Bertorelli,R, AU - Reggiani,A, AU - Piomelli,D, PY - 2012/7/11/entrez PY - 2012/7/11/pubmed PY - 2013/5/7/medline SP - 1620 EP - 8 JF - British journal of pharmacology JO - Br. J. Pharmacol. VL - 167 IS - 8 N2 - BACKGROUND AND PURPOSE: URB937 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 APPROACH: We 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 RESULTS: Abcg2 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 IMPLICATIONS: Peripheral 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. SN - 1476-5381 UR - https://www.unboundmedicine.com/medline/citation/22774772/Pharmacological_characterization_of_the_peripheral_FAAH_inhibitor_URB937_in_female_rodents:_interaction_with_the_Abcg2_transporter_in_the_blood_placenta_barrier_ L2 - https://doi.org/10.1111/j.1476-5381.2012.02098.x DB - PRIME DP - Unbound Medicine ER -