Inverse agonists and neutral antagonists at mu opioid receptor (MOR): possible role of basal receptor signaling in narcotic dependence

The mu opioid receptor, MOR, displays spontaneous agonist-independent (basa l) G protein coupling in vitro. To determine whether basal MOR signaling co ntributes to narcotic dependence, antagonists were tested for intrinsic eff ects on basal MOR signaling in vitro and in vivo, before and after morphine pretreatment. Intrinsic effects of MOR ligands were tested by measuring GT P gammaS binding to cell membranes and cAMP levels in intact cells. beta -C NA, C-CAM, BNTX, and nalmefene were identified as inverse agonists (suppres sing basal MOR signaling). Naloxone and naltrexone were neutral antagonists (not affecting basal signaling) in untreated cells, whereas inverse agonis tic effects became apparent only after morphine pretreatment. In contrast, 6 alpha- and 6 beta -naltrexol and -nalbxol, and 6 beta -naltrexamine were neutral antagonists regardless of morphine pretreatment. In an acute and ch ronic mouse model of morphine-induced dependence, 6 beta -naltrexol caused significantly reduced withdrawal jumping compared to naloxone and naltexone , at doses effective in blocking morphine antinociception. This supports th e hypothesis that naloxone-induced withdrawal symptoms result at least in p art from suppression of basal signaling activity of MOR in morphine-depende nt animals. Neutral antagonists have promise in treatment of narcotic addic tion.