Beschreibung:
Constipation is a common and problematic side effect associated with opioid therapy. Opioid analgesics such as morphine exert their physiological effects primarily through activation of the mu opioid receptor (MOR), a G protein‐coupled receptor (GPCR). Although opioids are known to decrease gastrointestinal motility by decreasing secretion and muscle contractions, the cellular signaling mechanisms downstream of MOR activation that mediate these physiologies are not completely understood. We have previously shown that morphine‐induced constipation is significantly reduced in βarrestin2 knockout (βarr2‐KO) mice. Moreover, this reduction appears to be due to altered opioid receptor responses in the enteric nervous system, specifically at the level of the colon. Here, we have assessed the contribution of βarrestin2 in mediating morphine‐inhibition of secretion within the colon by assessing changes in nicotinic stimulation of secretion in colonic tissue preparations using Ussing chambers. We find that the βarr2‐KO mice display significantly less morphine‐induced inhibition of secretion compared to WT controls, suggesting that βarrestin2 may facilitate the effects of constipatory effects of morphine in the colon. These results provide further evidence that βarrestin2 is a critical regulator of morphine‐induced constipation. Supported by NIDA DA021952 (KMR), DA14600 and DA18860 (LMB).