Characterization of prokineticin system in Crohn's disease pathophysiology and pain, and its modulation by alcohol abuse: A preclinical study

Background: Crohn's disease-(CD) pathogenesis is still unknown and chronic pain is a frequent symptom in CD- patients. Identifying novel therapeutic targets and predisposing factors is a primary goal. In this regard, proki- neticin system-(PKS) appears a promising target. Aims and methods: TNBS-model was used. DAI, abdominal and visceral pain, and muscle strength were moni- tored. CD-mice were sacrificed at two times (day 7 and 14 after TNBS) in order to identify PKS involvement in CD pathophysiology and pain. PKS characterization was performed in mesenteric lymph nodes-(MLN), colon, myenteric plexus-(MP), dorsal root ganglia-(DRGs) and spinal cord-(SC). Inflammation/neuroinflammation was also assessed in the same tissues. In order to evaluate alcohol abuse as a possible trigger for CD and its effect on PKS activation, naïve mice were administered (oral-gavage) with ethanol for 10 consecutive days. PKS as well as inflammation/neuroinflammation were evaluated in MLN, colon and MP. Results: TNBS treated-mice showed a rapid increase in DAI, abdominal/visceral hypersensitivity and a progres- sive strength loss. In all tissue analysed of CD-mice, a quick and significant increase of mRNA of PKs and PKRs was observed, associated with an increase of pro-inflammatory cytokines (IL-1β, IL-6 and TNFα) and macro- phage/glia markers (iba1, CD11b and GFAP) levels. In alcohol abuse model, ethanol induced in colon and MP a significant PKS activation accompanied by inflammation/neuroinflammation. Conclusions: We can assume that PKS may be involved in CD development and pain. Furthermore, alcohol ap- pears to activate PKS and may be a trigger factor for CD.