## 1 Introduction  
Osteoarthritis (OA) is a pathology of the whole joint structure, involving several cellular and molecular processes, in different types of cells, such as chondrocytes, osteoblasts, synovioocytes, and immune cells [1]. The clinical symptoms include pain as well as joint dysfunction and deformity, often leading to joint replacement surgery, with high costs for healthcare [2]. Recently, an association between inflammation and endocannabinoid receptors has been described [3]. In particular, the role of CB2 receptors seems very interesting in OA inflammation. CB2 is a peripheral cannabinoid receptor and has been found in immune system cells, raising the possibility that the endocannabinoid system could have a role in immunomodulatory processes [3]. In this respect, several studies reported that mice lacking CB2 receptors showed an exacerbated inflammatory phenotype [4]. Moreover, CB2 receptors are involved also in inhibiting nociceptive transmission [5]. CB2 receptor signaling has been associated with phospholipase C (PI-PLC) activation in calf pulmonary endothelial cells and in mast cells [6; 7]. Moreover, the inhibition of inflammatory pathways, such as NF-kB nuclear translocation, has been obtained by inhibiting the PI-PLC \(\beta\) pathway in osteoblast-like cells [8]. The presence of CB2 in articular joints has been explored, mainly in animal models, and it has been highlighted in chondrocytes and in synoviocytes [9; 10]. Thus, therapeutic strategies able to modulate CB2 signaling could be considered as a novel approach. OA is treated with analgesic agents and anti-inflammatory and painkiller drugs, mainly non-steroidal anti-inflammatory drugs (NSAIDs), with the aim of alleviating symptoms [11]. Structure-modifying agents, such as nutraceuticalals, are also administered to OA patients, with the aim of preventing or delaying cartilage degradation, even though further studies are required to confirm their effectiveness [12; 13; 14]. ARTRIT DOL, an Italian food supplement (Italian Minister of Health food supplement no. 71362 since 2013), is a composition containing glucosamine, chondro sulfate, extracts from _Harpagophytum proumbens_ DC. and _Glycyrrhiz glabra_ L., _Curcuna longa_ L. roots, manganese, and copper in traces. Although this work does not focus on ARTRIT DOL, it is interesting to note that, as stated by the manufacturer, this nutritional supplement obtained good feedback from OA patients, in particular for the reduction of pain. _Harpagophytum proumbens_ ([PERSON].) DC. ex Meisn. (Fam. Pedaliaceae), commonly known as devil's claw, is a plant used worldwide as a traditional remedy for joint pain associated with OA and mild rheumatic ailments [15; 16]. Moreover, it has been described to have analgesic effects on neuropathic pain in rats [17]. The harpagoside, one of the characteristic constituents of _H. proumbens_ root, has been shown to be effective for osteoarthritis and low back pain [18]. The pharmacological activity of devil's claw root is attributed to the whole phytocomplex containing iridoid glucosides, such as harpagoside, phenolic glycosides (ateoside and isoacetoside), mono- and polysaccharides, triterpenes (mainly oleanolic acid, \(3\beta\)-acetyloleanolic acid, and unsolic acid), phytosterols, phenolic acids (caffeic, cinnamic, and chlorogenic acids), flavonoids, and minor components such as volatile compounds [15]. A number of studies have been conducted in order to characterize the analgesic and anti-inflammatory activities of _H. proumbens_ and its secondary metabolites. An in vitro study showed that _H. proumbens_ was able to decrease the production of proinflammatory cytokines and inhibit metalloprotease activity in human monocytes [19]. Studies conducted in animals showed that an aqueous _H. proumbens_ extract showed dose-dependent analgesic and anti-inflammatory activity, but the purified harpagoside did not effectively inhibit the inflammatory pathways, at least at the dosage used in that study [20]. However, human clinical studies showed that the administration of _H.