The role of the EC has attracted our particular attention for its influence on different skin conditions, including pruritus. There are data on significant relief of pruritus in different systemic diseases after the use of cannabinoid receptor agonists. Neff et al. [21] reported a relief in an unmanageable pruritus in a group of patients with cholestasis after the use of dronabinol. Furthermore, our group confirmed the antipruritic effect of cannabinoids in a pilot study on patients with UP in which the application of a cream containing cannabinoid agonists (AEA and PEA) resulted in a significant reduction or even elimination of this symptom in most of the patients [17, 18]. Another research with topical cannabinoid agonists confirmed their antipruritic properties in patients with prurigo, lichen simplex, or refractory pruritus [22]. In addition, it was found that suppression of the neuronal FAAH reduces the scratching response through the inhibition of AEA degradation and activation of CNR1 [8]. Moreover, there is a reliable evidence that endocannabinoids play also a role in modulation of pain perception and nowadays they are being considered as potential analgesic drugs [23, 24]. We already know that some pathways of itch and pain conduction can overlap [25] and this gave us another rationale to evaluate further the relationship between cannabinoid receptors and UP. The distribution and expression of CNR1 gene were confirmed by the study of Ständer et al. [26] found in skin biopsies taken from different body sites. In the skin, CB1 receptor was mainly expressed on cutaneous nerves in dermis and epidermis especially on skin nerve fibers and mast cells which again provides implications for an antipruritic but also anti-inflammatory and antinociceptive action of cannabinoid receptor agonists.

Our study suggests no associations between the CNR1 gene polymorphism and the presence of UP which, in the context of the aforementioned therapy strategies, seems to be rather unexpected. However, it has to be highlighted that cannabinoid receptor agonists are not fully specific ligands and they may regulate other mechanisms that play a role in the pathogenesis of pruritus. Although CNR1 seems to have predominant role in the cutaneous physiopathology, CNR2 has also been found in the skin, especially on large myelinated nerve fiber bundles of the superficial and deep reticular dermis, small unmyelinated nerves of the papillary dermis, and occasionally on nerves in epidermis [8]. Moreover, N-palmitoylethanolamine can downmodulate mast cell degranulation by interacting with CNR2 receptors which are additionally expressed on mast cells [27]. It has been shown that topical administration of cannabinoid receptor agonists, probably via CNR2 activation, significantly reduces histamine-induced itch and vasodilatation [28]. It has also been reported that cannabinoids can activate non-CNR1/CNR2 mechanisms. It was observed that cannabinoids may activate numerous other receptors, including PPARs (peroxisome-proliferators-activated receptors), which have already been reported to have an important role in pruritus pathogenesis, as their activation can significantly diminish itch in some skin diseases [29].

We are aware of the fact that many different factors can interfere with the polymorphism of CNR1 gene. That is why we also did our statistical analysis after excluding from the HD patients' group individuals with diabetes and dyslipidemia. However, it did not make any change in the final result. As EC is still not fully discovered, we might not know all possible factors and physiological conditions that may influence the CNR1 polymorphism. In addition, we revealed a slightly higher incidence of GA genotype and lower incidence of GG genotype in the polymorphism rs806381s in the whole hemodialysis group versus the control group. This result seems to be difficult to be clearly explained based on current knowledge. However, we would like to underline that no difference in the genotype distribution was observed when comparing patients with and without pruritus, which was the main focus of the study.

Based on our study, we suggest that there is no relationship in the CNR1 gene polymorphism and the presence of UP. Due to some limitations of our research such as limited number of patients and the eventual influence of not studied systemic factors, further studies are needed to confirm our results.