Attenuation of serotonin-induced itch responses by inhibition of endocannabinoid degradative enzymes, fatty acid amide hydrolase and monoacylglycerol lipase

Abstract

Itch and pain are two irritating sensations sharing a lot in common. Considering the antinociceptive effects of blockade of endocannabinoid degrading enzymes in pain states, we attempted to reduce scratching behavior by endocannabinoid modulation, i.e. by inhibiting fatty acid amide hydrolase (FAAH), monoacylglycerol lipase (MAGL), or cellular uptake of endocannabinoids. Scratching behavior was induced by intradermal injection of serotonin to Balb/c mice. URB597 (10 mg/kg, i.p.), a FAAH inhibitor, JZL184 (16 mg/kg, i.p.), a MAGL inhibitor, and AM404 (10 mg/kg, i.p.), an endocannabinoid transport inhibitor, were given to evaluate the effects of endocannabinoid modulation on scratching responses. Then, the CB1 receptor antagonist, AM251 (1 mg/kg, i.p.), and the CB2 receptor antagonist, SR144528 (1 mg/kg, i.p.), were administered to determine whether cannabinoid receptors mediate these effects. URB597 and JZL184, but not AM404, attenuated serotonin-induced scratches. The inhibitory effect of URB597 was reversed by SR144528, but cannabinoid receptor antagonists had no other effects on modulation by the inhibitors. We propose that augmenting the endocannabinoid tonus by inhibition of degradative enzymes, FAAH and MAGL, but not cellular uptake, may be a novel target for the development of antipruritic agents.

Involvement of spinal cannabinoid receptors in the antipruritic effects of WIN 55,212-2, a cannabinoid receptor agonist

“…Cannabinoid receptor agonists have a tendency to attenuate scratching behaviour in mice, whereas CB1 receptors mediate rimonabant‐induced pruritic behaviour . Modulation of itch sensation by augmenting the endocannabinoid anandamide (2‐arachidonylglycerol) tonus through inhibition of the endocannabinoid catabolic enzymes (fatty acid amide hydrolase, monoacylglycerol lipase) also appears to be a promising target for treating pruritus . In line with these previous studies, we found that serotonin‐induced scratching behaviour was dose‐dependently suppressed by the cannabinoid agonist WIN 55,212‐2.…”

“…Scratching of the injection region by the hind paws was regarded as spontaneous scratching. The mice typically scratched several times per second, with such reaction accepted as one bout of scratching …”

“…IT administrations were performed using a 10 μL Hamilton syringe with a 30 G needle, following the previously described technique of Hylden and Wilcox . Drug doses, treatment times and experimental methodology were as described in our previous reports . Serotonin hydrochloride was dissolved in saline, while WIN 55,212‐2 AM‐251 and AM‐630 were dissolved in a mixture of 20% DMSO, 1% Tween 80, 1% ethanol and 78% saline.…”

“…Only in the past 10 years has there been approval in some countries for the medicinal use of cannabinoid drugs in some conditions, such as neuropathic pain and multiple sclerosis . Consequently, extensive experimental and clinical studies have been made in understanding the contribution of cannabinoids/endocannabinoids in modulation of pain, but very little progress has been made to determine the involvement of the cannabinoid system in itch sensation . Cannabinoids appear to be a good candidate for both peripheral and central modulation of itch signalling.…”

The Potential of Inhibitors of Endocannabinoid Metabolism for Drug Development: A Critical Review

“…The effect of URB597 (and the reduced behaviour in the FAAH þ/þ mice) was blocked by rimonabant (Schlosburg et al 2009). Scratching behaviour in mice and rats following intradermal serotonin administration into the rostral part of the back is reduced by both URB597 and JZL184 Tosun et al 2014). In contrast, the two compounds increased, rather than decreased, the scratching behaviour following serotonin injection into the cheek of the rats ).…”