Effect of URB602, an inhibitor of monoacylglycerol lipase, in an animal model of acute inflammation

Francesca Comelli, Isabella Bettoni, Gabriella Giagnoni, Barbara Costa. University of Milano-Bicocca, Milano, Italy.

A lot of evidence suggests that cannabinoids may have therapeutic usefulness in different areas, including inflammatory diseases. However, the psychotropic effects of cannabinoids limited their therapeutic use. Inhibition of endocannabinoid metabolism is considered a promising therapeutic target, since it presumably would increase the endocannabinoid levels only at the location where their synthesis has been stimulated, so avoiding side central effects. We previously demonstrated that URB597-induced inhibition of fatty acid amide hydrolase (FAAH), the enzyme responsible for anandamide (AEA) degradation, produced anti-inflammatory effects in the carrageenan model of acute inflammation (Holt et al., 2005). On these bases, in the present study, we investigated whether the inhibition of monoacylglycerol lipase (MAGL), the enzyme involved in the metabolism of another endocannabinoid, 2-arachidonoylglycerol (2-AG), produced the same beneficial effects in the same inflammatory animal model. We tested the anti-inflammatory properties of URB602, a non-competitive inhibitor of MAGL, in the model of acute inflammation induced by an intraplantar injection of carrageenan into male C57BL/6J mouse paw. Before testing this compound, we first examined which dose of URB602 produced the typical tetrad of effects induced by cannabinoids (hypothermia, catalepsy, hypomotility and analgesia). Body temperature, immobility on a ring, spontaneous locomotor activity and nociceptive threshold were evaluated 30, 60 and 90 minutes after a single administration of URB602 (20 mg kg-1 and 10 mg kg-1 i.p.). Mice exerted the typical signs of cannabimimetic effects only at the dose of 20 mg kg-1, even if each effect showed a different time course. Particularly, body temperature decreased of about one degree, catalepsy was present (600% of increase in immobility-time), spontaneous locomotor activity was significantly reduced (81%) and nociceptive threshold increased (50%) demonstrating a marked analgesia. So, after selecting the dose of URB602 (10 mg kg-1) devoid of psychoactive effects, the anti-inflammatory and anti-hyperalgesic efficacy of this compound was assessed 2 hours after carrageenan injection both in a preventive regimen (the drug was administered 30 minutes before the inflammatory stimulus) and in a therapeutic regimen (URB602 administered 30 minutes after the inflammatory stimulus). Preliminary data suggested that URB602 was able to abolish the oedema (difference between the volume of the injected paw and the volume of the controlateral paw, assessed by plethysmometer) and to reduce (30%) thermal hyperalgesia (increased response to noxious stimuli, assessed by plantar test), produced by carrageenan injection. Studies are in progress in order to elucidate the cannabinoid receptor involvement in the anti-inflammatory and anti-hyperalgesic effect evoked by URB602. Further studies will be performed to determine 2-AG levels and MAGL activity in brain and spinal cord, to ascertain whether such pharmacological effects are really related to MAGL inhibition. In conclusion, these preliminary results suggest that MAGL could represent a promising target for the treatment of inflammatory painful disorders.

Holt, S et al. (2005) Br. J. Pharmacol. 146, 467-476