**3. Cannabinoids and Inflammation**

Cannabinoids have been used for their anti-inflammatory properties for millennia; for instance, T'ang Shên-wei records effects such as "undoing rheumatism" or the "discharge of pus" in the 10th century A.D. work called 'Chêng-lei pên-ts'ao' [33]. An increasing number of studies explore their properties and interactions in a wide range of experimental models [34]. The chemical group of cannabinoids includes over 60 natural (phyto-) cannabinoids and over 150 artificial (synthetic) cannabinoids alongside the two well-known endocannabinoids anandamide (AEA) and 2-Arachidonoylglycerol (2-AG), and their few derivates [35,36]. Evidently, the process of testing and comparing the anti-inflammatory effects of these substances in inflammatory conditions is lengthy and complex. There are two G protein-coupled receptor (GPCRs) cannabinoid receptors activated by cannabinoids: CB1, which is mostly located in the central, peripheral and enteric nervous system, and is responsible, among others, for the psychoactive effects; and CB2, which is expressed by immune cells and some tissues, and is mostly involved in immunomodulation [37]. The two receptors exert distinct functions via specific signaling pathways, and different cannabinoids can activate them to various degrees; therefore, cannabinoids can vary in terms of effectiveness and potency [38]. While some anti-inflammatory properties were also described for CB1-specific agonists, their effects may also be carried through non-CB1 non-CB2 signaling, and their most common usage is the management of pain, in which they prove highly effective [39,40]. Conversely, CB2 receptors are mainly involved in regulating inflammation by modulating the levels of various cytokines [41]. A recent systematic review of in vivo studies regarding the anti-inflammatory effects of various cannabinoids concluded that the CB2 antagonist CBD is efficient in reducing inflammation, while CB1 agonists—such as THC—may be used for the alleviation of the associated pain [42].

Some cannabinoids are favorites in the race for the identification of the substance with the optimal anti-inflammatory actions and minimal adverse reactions. Cannabidiol (CBD) is one of the most commonly tested substances due to its lack of psychoactive effects and high potency in modulating the immune response and exerting anti-inflammatory properties in a variety of animal models [43–45]. Tetrahydrocannabinol is still tested, despite its psychoactive effects, due to its activity on the CB1 receptor which triggers specific signaling pathways in inflammation [46]. As for synthetic cannabinoids, there are multiple classes and subclasses defined by their chemical structure, which encompass a growing number of substances, developed with the intent of emulating the favorable effects while maximizing the receptor specificity and limiting side effects. These substances are agonists for CB1 and/or CB2, and usually bind to the cannabinoid receptors with higher affinity than natural compounds, showing great potential in developing new treatments [47].

The following sections explore the roles of synthetic, phyto-, and endocannabinoids in the inflammations of the gastrointestinal tract, the pulmonary apparatus and the skin.

#### **4. Cannabinoids and Gut Inflammations**

The discovery of the intestinal endocannabinoid system was encouraged by numerous reports of the beneficial effects of administering cannabinoids for various digestive tract disorders [48]. This system plays various roles in the homeostasis of the gastrointestinal tract, including the regulation of secretion, sensitivity and motility, as well as upholding the integrity of the gut epithelial barrier [48,49]. Physiological and pharmacological studies have investigated the interactions between endocannabinoids and various receptors, and have concluded that these substances may play a role in modulating intestinal inflammation and cellular proliferation [50]. These findings led to the consideration of phyto- and artificial cannabinoids as candidates for the treatment of intestinal inflammatory disorders, such as irritable bowel syndrome (IBS), inflammatory bowel disease (IBD) and Crohn's disease [51].

In the gastrointestinal tract, CB1 and CB2 receptors are located in the myenteric and submucosal neurons (mostly CB1) as well as the inflammatory and epithelial cells (mostly CB2) [52]. Besides GPCRs, cannabinoids may also bind to the transient receptor potential cation channel subfamily V member 1 (TRPV1) receptors in the capsaicin-sensitive sensory nerves located in the digestive tract wall, especially in the mucosa, muscle layers and blood vessels, but also in epithelial cells [53]. Furthermore, cannabinoids may bind to G protein-coupled receptor (GPR) type 55, which was identified in smooth muscle cells and peroxisome proliferator-activated receptor alpha (PPAR-α), located in blood vessels and smooth muscle cells, and also to GPR119, which is expressed in the digestive mucosa and enteroendocrine cells [54–56].
