Tolerance and the hormone axis

Repeated exposure does build tolerance and dependence, as any mu agonist does, but in animals both were consistently less marked than with morphine at equivalent effect. It also moves the pituitary: infused into a vein in healthy people it raised prolactin, growth hormone and thyrotropin, lowered cortisol, and raised renin activity, and naloxone blocked every one of those changes. That is the opioid system's normal reach into the endocrine axis, visible because this molecule is strong enough to show it clearly. Any opioid acting centrally touches those levers.