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Int. J. Mol. Sci. 2018, 19(2), 342; https://doi.org/10.3390/ijms19020342

Molecular Understanding of the Activation of CB1 and Blockade of TRPV1 Receptors: Implications for Novel Treatment Strategies in Osteoarthritis

1
Laboratory of Pain Pathophysiology, Department of Pain Pharmacology, Institute of Pharmacology Polish Academy of Sciences, 31-343 Krakow, Poland
2
Department of Neurochemistry, Institute of Pharmacology Polish Academy of Sciences, 31-343 Krakow, Poland
*
Author to whom correspondence should be addressed.
Received: 14 December 2017 / Revised: 18 January 2018 / Accepted: 19 January 2018 / Published: 24 January 2018
(This article belongs to the Special Issue Cannabinoid Signaling in Nervous System)
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Abstract

Osteoarthritis (OA) is a joint disease in which cartilage degenerates as a result of mechanical and biochemical changes. The main OA symptom is chronic pain involving both peripheral and central mechanisms of nociceptive processing. Our previous studies have implicated the benefits of dual- over single-acting compounds interacting with the endocannabinoid system (ECS) in OA treatment. In the present study, we focused on the specific molecular alterations associated with pharmacological treatment. OA was induced in Wistar rats by intra-articular injection of 3 mg of monoiodoacetate (MIA). Single target compounds (URB597, an FAAH inhibitor, and SB366791, a TRPV1 antagonist) and a dual-acting compound OMDM198 (FAAH inhibitor/TRPV1 antagonist) were used in the present study. At day 21 post-MIA injection, rats were sacrificed 1 h after i.p. treatment, and changes in mRNA expression were evaluated in the lumbar spinal cord by RT-qPCR. Following MIA administration, we observed 2-4-fold increase in mRNA expression of targeted receptors (Cnr1, Cnr2, and Trpv1), endocannabinoid degradation enzymes (Faah, Ptgs2, and Alox12), and TRPV1 sensitizing kinases (Mapk3, Mapk14, Prkcg, and Prkaca). OMDM198 treatment reversed some of the MIA effects on the spinal cord towards intact levels (Alox12, Mapk14, and Prkcg). Apparent regulation of ECS and TRPV1 in response to pharmacological intervention is a strong justification for novel ECS-based multi-target drug treatment in OA. View Full-Text
Keywords: osteoarthritis; endocannabinoids; OMDM198; TRPV1; sensitization osteoarthritis; endocannabinoids; OMDM198; TRPV1; sensitization
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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Mlost, J.; Kostrzewa, M.; Malek, N.; Starowicz, K. Molecular Understanding of the Activation of CB1 and Blockade of TRPV1 Receptors: Implications for Novel Treatment Strategies in Osteoarthritis. Int. J. Mol. Sci. 2018, 19, 342.

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