Neurotransmitters participate in pain perception effectively. One prominent example of peripheral regulation is provided by the endogenous opioids, which are released from activated immune cells during inflammation and inhibit pain initiation. Increasing studies have demonstrated that the endocannabinoid system serves an important function in the peripheral regulation of nociception. In the study from Jason R Clapper, et al. the authors described a potent brain-in penetrant inhibitor of the anandamide-degrading enzyme FAAH, URB937.
URB937 is actively extruded from the CNS by the ATP-binding cassette (ABC) membrane transporter, Abcg2.
In addition in vivo, URB937 (1 mg/kg, i.p.) administrated in mice increases anandamide levels in peripheral tissues, but not forebrain or hypothalamus. The compound (1 mg/kg, s.c.) suppresses pain responses elicited by i.p. injections of acetic acid.
What’s more, URB937 in male rats (an oral dose of 3 mg/kg, F = 36%) absorbs at a moderate rate and displays a peak plasma concentration (Cmax) of 159.47 ng/mL (one hour after administration). URB937 exhibits T1/2 of 60 min by an oral dose of 3 mg/kg.
Especially, URB937 produces a high degree of antinociception in female mice and rats in models of visceral and inflammatory pain. Moreover, the compound displayed restricted access to placental and fetal tissues in pregnant mice and rats. It (1 mg/kg, every 2 days for 30 days) also attenuates radiation-induced lung injury and increased endocannabinoid concentration in lung tissue.
To conclude, URB937 is an orally active and peripherally restricted FAAH inhibitor (IC50=26.8 nM) and increases anandamide levels. Moreover, URB937 fails to affect FAAH activity in the brain (not penetrate the blood-brain barrier).
Jason R Clapper, et al. Anandamide suppresses pain initiation through a peripheral endocannabinoid mechanism. Nat Neurosci. 2010 Oct;13(10):1265-70.