Down-regulation of the opioid receptor is caused by endocytosis from the cell membrane that eliminates its function. Typically, opioid receptors on the cell membrane are engulfed by the membrane and drawn into the body of the cell. Seeing as the intracellular environment does not have high concentrations of opioid ligands for the receptor to bind to, the opioid receptor is non-functional and thus, down-regulated and causing opioid tolerance. This mechanism has been shown in rats where those lacking a down-regulator (􏰀-arrestin2) continued to exhibit morphine-induced analgesia while those with the down-regulator formed a tolerance to the morphine-induced analgesia.