In vivo activation of a mutant mu-opioid receptor by antagonist: future direction for opiate pain treatment paradigm that lacks undesirable side effects.

Based on the in vitro ability of opioid antagonists to activate a mu-opioid receptor mutant, S196A, we reasoned that when expressed in the appropriate sites in vivo, this mutant receptor could be used to elicit the analgesic effects of the opioids without the accompanying side effects, such as tolerance and dependence. To test this hypothesis, we introduced the S196A mutation into the mouse mu-opioid receptor by a knock-in strategy to test the ability of the opioid antagonist to produce analgesic effects. In these homozygous mice, we observed increased intrinsic efficacy of opioid analgesics with two antinociceptive tests: hot water tail-withdrawal and acetic acid-induced writhing tests. Opioid antagonists, such as naloxone and naltrexone, elicited antinociceptive effects similar to that of partial agonists. Most importantly, chronic treatment of the homozygous mice with naltrexone did not produce the expected tolerance response, whereas less physical dependence was observed than with chronic morphine treatment. Such in vivo properties suggest the possibility of using the S196A mutant of the mu-opioid receptor and opioid antagonists to minimize the spectrum of unwarranted side effects in pain management when opiate analgesics are used.