A multi-target approach for pain treatment

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.

Alterations in Anandamide Synthesis and Degradation during Osteoarthritis Progression in an Animal Model

“…Both papers characterized OA-related pain behavior by Pressure Application Measurement test (Ugo Basile, Italy) and Dynamic Weight Bearing test (Bioseb, France). Additionally, these results were supported by microtomography–based 3-dimensional visualizations of rat knees in the consecutive days of the experiment [ 24 ], confirming permanent and irreversible changes within the studied subchondral bones of OA rats, correlated with disease progression.…”

“…A biphasic pain response was observed in the early inflammatory stage (associated with i.a. injection) and advanced stage beginning on day 14 after MIA treatment [ 24 ]. Thus, in most experiments, days 21 or 28 after i.a.…”

“…Bearing in mind the 3R rule for the ethical use of animals in testing, we decided not to repeat the behavioral experiments performed previously by our group. In the previous studies, a behavioral pattern of changes occurring during OA progression was precisely described [ 24 , 54 ]. Both papers characterized OA-related pain behavior by Pressure Application Measurement test (Ugo Basile, Italy) and Dynamic Weight Bearing test (Bioseb, France).…”

“…Thus, we aimed to improve the understanding of a possible cross-talk between the endocannabinoid and endovanilloid systems to assist with fine-tuning of analgesic strategies particularly for patients suffering from chronic pain. The degree of pain does not always correlate with the extent of joint damage or presence of active inflammation, we investigated the occurrence of a central component of OA pain by correlating OA pain behavior of the animals reported in the previous studies [ 24 ] with the assessment of ATF-3, a marker of spinal neuronal activity. Involvement of mitogen-activated protein kinases 3 and 14 (MAPK3 and MAPK14, respectively) in the chronic pain formation has been shown in preclinical studies [ 25 , 26 ].…”

LC-MS/MS analysis and evaluation of the anti-inflammatory activity of components from BushenHuoxue decoction

“… 2015 ), and IL-6 can be considered as a marker of nerve injury and proinflammatory cytokines which produced by joint tissue (Malek et al. 2015 ). Imbalance of catabolic and anabolica factors including cytokines and NO could result in OA (Chevalier et al.…”