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Characterization of the effects of reuptake and hydrolysis inhibition on interstitial endocannabinoid levels in the brain: an in vivo microdialysis study.

ABSTRACT: The present experiments employed in vivo microdialysis to characterize the effects of commonly used endocannabinoid clearance inhibitors on basal and depolarization-induced alterations in interstitial endocannabinoid levels in the nucleus accumbens of rat brain. Compounds targeting the putative endocannabinoid transporter and hydrolytic enzymes (FAAH and MAGL) were compared. The transporter inhibitor AM404 modestly enhanced depolarization-induced increases in 2-arachidonoyl glycerol (2-AG) levels but did not alter levels of N-arachidonoyl-ethanolamide (anandamide, AEA). The transport inhibitor UCM707 did not alter dialysate levels of either endocannabinoid. The FAAH inhibitors URB597 and PF-3845 robustly increased AEA levels during depolarization without altering 2-AG levels. The MAGL inhibitor URB602 significantly enhanced depolarization-induced increases in 2-AG, but did not alter AEA levels. In contrast, the MAGL inhibitor JZL184 did not alter 2-AG or AEA levels under any condition tested. Finally, the dual FAAH/MAGL inhibitor JZL195 significantly enhanced depolarization-induced increases in both AEA and 2-AG levels. In contrast to the present observations in rats, prior work in mice has demonstrated a robust JZL184-induced enhancement of depolarization-induced increases in dialysate 2-AG. Thus, to further investigate species differences, additional tests with JZL184, PF-3845, and JZL195 were performed in mice. Consistent with prior reports, JZL184 significantly enhanced depolarization-induced increases in 2-AG without altering AEA levels. PF-3845 and JZL195 produced profiles in mouse dialysates comparable to those observed in rats. These findings confirm that interstitial endocannabinoid levels in the brain can be selectively manipulated by endocannabinoid clearance inhibitors. While PF-3845 and JZL195 produce similar effects in both rats and mice, substantial species differences in JZL184 efficacy are evident, which is consistent with previous studies.

SUBMITTER: Wiskerke J

PROVIDER: S-EPMC3382459 | biostudies-other | 2012 May

REPOSITORIES: biostudies-other

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Project description:Different anandamide (AEA) transport inhibitors show antinociceptive and antiinflammatory effects in vivo, but due to their concomitant inhibition of fatty acid amide hydrolase (FAAH) and overall poor bioavailability, they cannot be used unequivocally to study the particular role of endocannabinoid (EC) transport in pathophysiological conditions in vivo. Here, the potent and selective endocannabinoid reuptake inhibitor WOBE437, which inhibits AEA and 2-arachidonoylglycerol (2-AG) transport, was tested for its oral bioavailability to the brain. WOBE437 is assumed to locally increase EC levels in tissues in which facilitated EC reuptake intermediates subsequent hydrolysis. Given the marked polypharmacology of ECs, we hypothesized to see differential effects on distinct EC receptors in animal models of acute and chronic pain/inflammation. In C57BL6/J male mice, WOBE437 was orally bioavailable with an estimated tmax value of ?20 min in plasma (Cmax ? 2000 pmol/mL after 50 mg/kg, p.o.) and brain (Cmax ? 500 pmol/g after 50 mg/kg, p.o.). WOBE437 was cleared from the brain after approximately 180 min. In addition, in BALB/c male mice, acute oral administration of WOBE437 (50 mg/kg) exhibited similar brain concentrations after 60 min and inhibited analgesia in the hot plate test in a cannabinoid CB1 receptor-dependent manner, without inducing catalepsy or affecting locomotion. WOBE437 significantly elevated AEA in the somatosensory cortex, while showing dose-dependent biphasic effects on 2-AG levels in plasma but no significant changes in N-acylethanolamines other than AEA in any of the tissues. In order to explore the presumed polypharmacology mediated via elevated EC levels, we tested this EC reuptake inhibitor in complete Freud's adjuvant induced monoarthritis in BALB/c mice as a model of chronic inflammation. Repetitive doses of WOBE437 (10 mg/kg, i.p.) attenuated allodynia and edema via cannabinoid CB2, CB1, and PPAR? receptors. The allodynia inhibition of WOBE437 treatment for 3 days was fully reversed by antagonists of any of the receptors. In the single dose treatment the CB2 and TRPV1 antagonists significantly blocked the effect of WOBE437. Overall, our results show the broad utility of WOBE437 for animal experimentation for both p.o. and i.p. administrations. Furthermore, the data indicate the possible involvement of EC reuptake/transport in pathophysiological processes related to pain and inflammation.

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Characterization of the effects of reuptake and hydrolysis inhibition on interstitial endocannabinoid levels in the brain: an in vivo microdialysis study.

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