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Endocannabinoid modulation of scratching response in an acute allergenic model: a new prospective neural therapeutic target for pruritus.
J Pharmacol Exp Ther. 2009 Apr; 329(1):314-23.JP

Abstract

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 Delta(9)-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 CB(1) 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 CB(1) receptors. More generally, these are the first preclinical data suggesting that FAAH represents a novel target to treat pruritus without eliciting overt side effects.

Authors+Show Affiliations

Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, VA 23298-0613, USA.No affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural

Language

eng

PubMed ID

19168707

Citation

Schlosburg, Joel E., et al. "Endocannabinoid Modulation of Scratching Response in an Acute Allergenic Model: a New Prospective Neural Therapeutic Target for Pruritus." The Journal of Pharmacology and Experimental Therapeutics, vol. 329, no. 1, 2009, pp. 314-23.
Schlosburg JE, Boger DL, Cravatt BF, et al. Endocannabinoid modulation of scratching response in an acute allergenic model: a new prospective neural therapeutic target for pruritus. J Pharmacol Exp Ther. 2009;329(1):314-23.
Schlosburg, J. E., Boger, D. L., Cravatt, B. F., & Lichtman, A. H. (2009). Endocannabinoid modulation of scratching response in an acute allergenic model: a new prospective neural therapeutic target for pruritus. The Journal of Pharmacology and Experimental Therapeutics, 329(1), 314-23. https://doi.org/10.1124/jpet.108.150136
Schlosburg JE, et al. Endocannabinoid Modulation of Scratching Response in an Acute Allergenic Model: a New Prospective Neural Therapeutic Target for Pruritus. J Pharmacol Exp Ther. 2009;329(1):314-23. PubMed PMID: 19168707.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Endocannabinoid modulation of scratching response in an acute allergenic model: a new prospective neural therapeutic target for pruritus. AU - Schlosburg,Joel E, AU - Boger,Dale L, AU - Cravatt,Benjamin F, AU - Lichtman,Aron H, Y1 - 2009/01/23/ PY - 2009/1/27/entrez PY - 2009/1/27/pubmed PY - 2009/4/29/medline SP - 314 EP - 23 JF - The Journal of pharmacology and experimental therapeutics JO - J. Pharmacol. Exp. Ther. VL - 329 IS - 1 N2 - 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 Delta(9)-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 CB(1) 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 CB(1) receptors. More generally, these are the first preclinical data suggesting that FAAH represents a novel target to treat pruritus without eliciting overt side effects. SN - 1521-0103 UR - https://www.unboundmedicine.com/medline/citation/19168707/Endocannabinoid_modulation_of_scratching_response_in_an_acute_allergenic_model:_a_new_prospective_neural_therapeutic_target_for_pruritus_ L2 - http://jpet.aspetjournals.org/cgi/pmidlookup?view=long&pmid=19168707 DB - PRIME DP - Unbound Medicine ER -