Cited by 63Pain Mechanisms and TreatmentsCannabis and Cannabinoid ResearchOsteoarthritis Treatment and Mechanisms

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A multi-target approach for pain treatment: dual inhibition of fatty acid amide hydrolase and TRPV1 in a rat model of osteoarthritis

Malek, Natalia, Mrugala, Monika, Makuch, Wioletta, Kolosowska, Natalia, Przewlocka, Barbara, Binkowski, Marcin, Czaja, Martyna, Morera, Enrico, Di Marzo, Vincenzo, Starowicz, Katarzyna·2015·Pain

DOI 10.1097/j.pain.0000000000000132

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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.

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Authors: Malek, N., Mrugala, M., Makuch, W., Kolosowska, N., Przewlocka, B., Binkowski, M., Czaja, M., Morera, E., Di Marzo, V., & Starowicz, K.
Affiliations: University of Silesia in Katowice (PL)
Sapienza University of Rome (IT)
Corresponding author: Starowicz, Katarzyna
ORCID: Makuch, Wioletta
Morera, Enrico
Starowicz, Katarzyna
Venue: Pain
Publisher: Ovid Technologies (Wolters Kluwer Health)
Published: 2015-05
Volume: 156
Issue: 5
Pages: 890-903
ISSN: 0304-3959 (ISSN-L)
DOI: 10.1097/j.pain.0000000000000132
OpenAlex: W1996295130
Cited by: 63
References: 70
Citations by year: 2026: 2 · 2025: 4 · 2024: 2 · 2023: 3 · 2022: 5 · 2021: 9 · 2020: 9 · 2019: 2 · 2018: 10 · 2017: 9 · 2016: 7 · 2015: 1
FWCI: 6.64
Type: journal article
Language: en
Open access: closed
Locations: Pain (publishedVersion)
PubMed (publishedVersion)
IRIS Research product catalog (Sapienza University of Rome) (submittedVersion)
Topics: Health Sciences › Medicine › Physiology (medical) › Pain Mechanisms and Treatments
Health Sciences › Medicine › Pharmacology (medical) › Cannabis and Cannabinoid Research
Health Sciences › Medicine › Rheumatology › Osteoarthritis Treatment and Mechanisms
Keywords: osteoarthritis pain, anandamide, fatty acid amide hydrolase, TRPV1, CB1 receptor, dorsal root ganglia, ATF3, interleukin-6, antihyperalgesia, AM251, olvanil, endocannabinoid system
MeSH terms: Fatty Acid Amide Hydrolases, Amidohydrolases, Anilides, Animals, Arachidonic Acids, Benzamides, Capsaicin, Carbamates, Cinnamates, Disease Models, Animal, Ganglia, Spinal, Hyperalgesia, Inflammation, Lumbar Vertebrae, Male, Osteoarthritis, Pain, Pain Measurement, Piperidines, Pyrazoles, Interleukin-6, Gene Expression, Rats, Wistar, Receptor, Cannabinoid, CB1, TRPV Cation Channels, Rats, Activating Transcription Factor 3, Polyunsaturated Alkamides, Pain Management, Endocannabinoids

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A multi-target approach for pain treatment: dual inhibition of fatty acid amide hydrolase and TRPV1 in a rat model of osteoarthritis

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