title: A multi-target approach for pain treatment: dual inhibition of fatty acid amide hydrolase and TRPV1 in a rat model of osteoarthritis.
abstract: The pharmacological inhibition of anandamide (AEA) hydrolysis by fatty acid amide hydrolase (FAAH) attenuates pain in animal models of osteoarthritis (OA) but has failed in clinical trials. This may have occurred because AEA also activates transient receptor potential vanilloid type 1 (TRPV1), which contributes to pain development. Therefore, we investigated the effectiveness of the dual FAAH-TRPV1 blocker OMDM-198 in an MIA-model of osteoarthritic pain. We first investigated the MIA-induced model of OA by (1) characterizing the pain phenotype and degenerative changes within the joint using X-ray microtomography and (2) evaluating nerve injury and inflammation marker (ATF-3 and IL-6) expression in the lumbar dorsal root ganglia of osteoarthritic rats and differences in gene and protein expression of the cannabinoid CB1 receptors FAAH and TRPV1. Furthermore, we compared OMDM-198 with compounds acting exclusively on FAAH or TRPV1. Osteoarthritis was accompanied by the fragmentation of bone microstructure and destroyed cartilage. An increase of the mRNA levels of ATF3 and IL-6 and an upregulation of AEA receptors and FAAH in the dorsal root ganglia were observed. OMDM-198 showed antihyperalgesic effects in the OA model, which were comparable with those of a selective TRPV1 antagonist, SB-366,791, and a selective FAAH inhibitor, URB-597. The effect of OMDM-198 was attenuated by the CB1 receptor antagonist, AM-251, and by the nonpungent TRPV1 agonist, olvanil, suggesting its action as an "indirect" CB1 agonist and TRPV1 antagonist. These results suggest an innovative strategy for the treatment of OA, which may yield more satisfactory results than those obtained so far with selective FAAH inhibitors in human OA.
authors.affiliation: Laboratory of Pain Pathophysiology, Institute of Pharmacology, Polish Academy of Sciences, Krakow, Poland Department of Pain Pharmacology, Institute of Pharmacology, Polish Academy of Sciences, Krakow, Poland X-ray Microtomography Laboratory, Department of Biomedical Computer Systems, Institute of Computer Science, Faculty of Computer and Material Science, University of Silesia, Chorzów, Poland Department of Chemistry and Technology of Pharmacology, Sapienza University of Rome, Rome, Italy Endocannabinoid Research Group, Institute of Biomolecular Chemistry-C.N.R., Pozzuoli, Italy.
authors.forename: Natalia
authors.initials: N
authors.lastname: Malek
authors.forename: Monika
authors.initials: M
authors.lastname: Mrugala
authors.forename: Wioletta
authors.initials: W
authors.lastname: Makuch
authors.forename: Natalia
authors.initials: N
authors.lastname: Kolosowska
authors.forename: Barbara
authors.initials: B
authors.lastname: Przewlocka
authors.forename: Marcin
authors.initials: M
authors.lastname: Binkowski
authors.forename: Martyna
authors.initials: M
authors.lastname: Czaja
authors.forename: Enrico
authors.initials: E
authors.lastname: Morera
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Di Marzo
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Starowicz
mesh_terms: D051700:Activating Transcription Factor 3 / Q000235:genetics / Q000378:metabolism; D000581:Amidohydrolases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D000813:Anilides / Q000008:administration & dosage / Q000494:pharmacology; D000818:Animals; D001095:Arachidonic Acids / Q000378:metabolism; D001549:Benzamides / Q000494:pharmacology; D002211:Capsaicin / Q000031:analogs & derivatives / Q000494:pharmacology; D002219:Carbamates / Q000008:administration & dosage* / Q000494:pharmacology*; D002934:Cinnamates / Q000008:administration & dosage / Q000494:pharmacology; D004195:Disease Models, Animal; D063388:Endocannabinoids / Q000378:metabolism; D005727:Ganglia, Spinal / Q000166:cytology / Q000378:metabolism*; D015870:Gene Expression / Q000187:drug effects; D006930:Hyperalgesia / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D007249:Inflammation / Q000188:drug therapy / Q000276:immunology; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism; D008159:Lumbar Vertebrae / Q000166:cytology; D008297:Male; D010003:Osteoarthritis / Q000503:physiopathology*; D010146:Pain / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism; D059408:Pain Management / Q000379:methods; D010147:Pain Measurement / Q000379:methods; D010880:Piperidines / Q000494:pharmacology; D053284:Polyunsaturated Alkamides / Q000378:metabolism; D011720:Pyrazoles / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D043884:Receptor, Cannabinoid, CB1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D050916:TRPV Cation Channels / Q000819:agonists / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*; D000099252:Fatty Acid Amide Hydrolases
chemical_list: D051700:Activating Transcription Factor 3; D000581:Amidohydrolases; D000813:Anilides; D001095:Arachidonic Acids; D001549:Benzamides; D002211:Capsaicin; D002219:Carbamates; D002934:Cinnamates; D063388:Endocannabinoids; D015850:Interleukin-6; D010880:Piperidines; D053284:Polyunsaturated Alkamides; D011720:Pyrazoles; D043884:Receptor, Cannabinoid, CB1; D050916:TRPV Cation Channels; D000099252:Fatty Acid Amide Hydrolases; C497108:Atf3 protein, rat; C477659:N-(3-methoxyphenyl)-4-chlorocinnamanilide; C000604341:OMDM-198; C493922:Trpv1 protein, rat; C500528:cyclohexyl carbamic acid 3'-carbamoylbiphenyl-3-yl ester; C103505:AM 251; C054256:olvanil; C078814:anandamide