A balance theory of peripheral corticotropin-releasing factor receptor type 1 and type 2 signaling to induce colonic contractions and visceral hyperalgesia in rats.
Several recent studies suggest that peripheral corticotropin-releasing factor (CRF) receptor type 1 (CRF1) and CRF2 have a counter regulatory action on gastrointestinal functions. We hypothesized that the activity balance of each CRF subtype signaling may determine the changes in colonic motility and visceral sensation. Colonic contractions were assessed by the perfused manometry, and contractions of colonic muscle strips were measured in vitro in rats. Visceromotor response was determined by measuring contractions of abdominal muscle in response to colorectal distensions (CRDs) (60 mm Hg for 10 min twice with a 30-min rest). All drugs were administered through ip route in in vivo studies. CRF increased colonic contractions. Pretreatment with astressin, a nonselective CRF antagonist, blocked the CRF-induced response, but astressin2-B, a selective CRF2 antagonist, enhanced the response by CRF. Cortagine, a selective CRF1 agonist, increased colonic contractions. In in vitro study, CRF increased contractions of muscle strips. Urocortin 2, a selective CRF2 agonist, itself did not alter the contractions but blocked this increased response by CRF. Visceromotor response to the second CRD was significantly higher than that of the first. Astressin blocked this CRD-induced sensitization, but astressin2-B or CRF did not affect it. Meanwhile, astressin2-B together with CRF significantly enhanced the sensitization. Urocortin 2 blocked, but cortagine significantly enhanced, the sensitization. These results indicated that peripheral CRF1 signaling enhanced colonic contractility and induced visceral sensitization, and these responses were modulated by peripheral CRF2 signaling. The activity balance of each subtype signaling may determine the colonic functions in response to stress.
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