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.
Supplemental Digital Content is Available in the Text.We have demonstrated in a well-validated osteoarthritis model that dual targeting of FAAH and TRPV1 is a very efficacious way to treat pain.
aLaboratory of Pain Pathophysiology, Institute of Pharmacology, Polish Academy of Sciences, Krakow, Poland
bDepartment of Pain Pharmacology, Institute of Pharmacology, Polish Academy of Sciences, Krakow, Poland
cX-ray Microtomography Laboratory, Department of Biomedical Computer Systems, Institute of Computer Science, Faculty of Computer and Material Science, University of Silesia, Chorzów, Poland
dDepartment of Chemistry and Technology of Pharmacology, Sapienza University of Rome, Rome, Italy
eEndocannabinoid Research Group, Institute of Biomolecular Chemistry—C.N.R., Pozzuoli, Italy
Corresponding author. Address: Laboratory of Pain Pathophysiology, Department of Pain Pharmacology, Institute of Pharmacology, Polish Academy of Sciences, ul. Smetna 12, 31-343 Krakow, Poland. Tel.: +48 12 6623398; fax: +48 12 6374500. E-mail address: email@example.com (K. Starowicz).
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Received September 18, 2014
Received in revised form January 30, 2015
Accepted February 02, 2015