G protein‐coupled estrogen receptor and estrogen receptor ligands regulate colonic motility and visceral pain

<jats:title>Abstract</jats:title><jats:sec><jats:title>Background</jats:title><jats:p>Diarrhea‐predominant irritable bowel syndrome (<jats:styled-content style="fixed-case">IBS</jats:styled-content>‐D) is a functional gastrointestinal (<jats:styled-content style="fixed-case">GI</jats:styled-content>) disorder, which occurs more frequently in women than men. The aim of our study was to determine the role of activation of classical estrogen receptors (ER) and novel membrane receptor, G protein‐coupled estrogen receptor (<jats:styled-content style="fixed-case">GPER</jats:styled-content>) in human and mouse tissue and to assess the possible cross talk between these receptors in the <jats:styled-content style="fixed-case">GI</jats:styled-content> tract.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>Immunohistochemistry was used to determine the expression of <jats:styled-content style="fixed-case">GPER</jats:styled-content> in human and mouse intestines. The effect of G‐1, a <jats:styled-content style="fixed-case">GPER</jats:styled-content> selective agonist, and estradiol, a non‐selective <jats:styled-content style="fixed-case">ER</jats:styled-content> agonist, on muscle contractility was characterized in isolated preparations of the human and mouse colon. To characterize the effect of G‐1 and estradiol <jats:italic>in vivo</jats:italic>, colonic bead expulsion test was performed. G‐1 and estradiol activity on the visceral pain signaling was assessed in the mustard oil‐induced abdominal pain model.</jats:p></jats:sec><jats:sec><jats:title>Key Results</jats:title><jats:p>GPER is expressed in the human colon and in the mouse colon and ileum. G‐1 and estradiol inhibited muscle contractility <jats:italic>in vitro</jats:italic> in human and mouse colon. G‐1 or estradiol administered intravenously at the dose of 20 mg/kg significantly prolonged the time to bead expulsion in females. Moreover, G‐1 prolonged the time to bead expulsion and inhibited <jats:styled-content style="fixed-case">GI</jats:styled-content> hypermotility in both genders. The injection of G‐1 or estradiol resulted in a significant reduction in the number of pain‐induced behaviors in mice.</jats:p></jats:sec><jats:sec><jats:title>Conclusions and Inferences</jats:title><jats:p>GPER and <jats:styled-content style="fixed-case">ER</jats:styled-content> receptors are involved in the regulation of <jats:styled-content style="fixed-case">GI</jats:styled-content> motility and visceral pain. Both may thus constitute an important pharmacological target in the <jats:styled-content style="fixed-case">IBS</jats:styled-content>‐D therapy.</jats:p></jats:sec>