RT Journal Article
SR Electronic
T1 Endocannabinoid Modulation of Scratching Response in an Acute Allergenic Model: A New Prospective Neural Therapeutic Target for Pruritus
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 314
OP 323
DO 10.1124/jpet.108.150136
VO 329
IS 1
A1 Joel E. Schlosburg
A1 Dale L. Boger
A1 Benjamin F. Cravatt
A1 Aron H. Lichtman
YR 2009
UL http://jpet.aspetjournals.org/content/329/1/314.abstract
AB Pruritus (itch) is a common cause of discomfort by dermatological disorders. Several peripherally and centrally mediated pathologies that induce pruritus do not generally respond to typical allergenic and anti-inflammatory treatments. In accordance, we employed an acute allergenic murine model to determine whether the endogenous cannabinoid system could be targeted to treat pruritus. Subcutaneous administration of the mast cell degranulator compound 48/80 evoked an intense, concentration-dependent scratching response. Systemic Δ9-tetrahydrocannabinol reduced the scratching response, although this effect was accompanied with hypomotility. Complementary genetic and pharmacological approaches to target fatty acid amide hydrolase (FAAH), the primary enzyme responsible for the degradation of the endocannabinoid anandamide, were evaluated in the compound 48/80 model. FAAH(-/-) mice and mice treated with the respective irreversible and reversible FAAH inhibitors, URB597 (cyclohexylcarbamic acid 3′-carbamoylbiphenyl-3-yl ester) and OL-135 [1-oxo-1-[5-(2-pyridyl)-2-yl]-7-phenylheptane], displayed comparable reductions in scratching to mice treated with common nonsedative allergenic treatments (loratadine and dexamethasone) but without affecting locomotor behavior. The antiscratching phenotype of FAAH-compromised mice was completely blocked by either genetic deletion or pharmacological antagonism of the CB1 receptor. Neural-specific conditional FAAH knockout (FAAH-NS) mice, which have FAAH exclusively restricted to neural tissues, showed a similar magnitude of scratching as wild-type mice. It is important that URB597 reduced compound 48/80-induced scratching in FAAH-NS mice, but it did not produce any further reduction in FAAH(-/-) mice. These findings indicate that neuronal FAAH suppression reduces the scratching response through activation of CB1 receptors. More generally, these are the first preclinical data suggesting that FAAH represents a novel target to treat pruritus without eliciting overt side effects. The American Society for Pharmacology and Experimental Therapeutics