The kappa
opioid agonists U50,488,
bremazocine,
ethylketazocine and
tifluadom and the
opioid antagonist naltrexone were examined alone and in combination with
morphine in a squirrel monkey
shock titration procedure, before and during chronic
morphine administration. Before chronic
morphine administration (prechronic phase), all
opioids except
naltrexone produced dose-dependent increases in median
shock level when administered alone. When combined with a dose of
morphine that increased median
shock level to 90% of maximum (ED90),
naltrexone, U50,488 and
bremazocine completely antagonized the effects of
morphine in most monkeys, whereas
ethylketazocine and
tifluadom partially antagonized the effects of this dose of
morphine. After 10 weeks of daily
morphine administration (chronic phase), the average ED90 for
morphine was increased 1 log unit. In contrast, average ED50 values for U50,488,
bremazocine and
tifluadom were decreaed 1/4 to 1/2 log unit, whereas the average ED50 for
ethylketazocine did not change from the prechronic to chronic phases. When combined with
morphine during the chronic phase,
naltrexone completely antagonized the effects of the
morphine ED90 at approximately the same doses as during the prechronic phase. In contrast, antagonist activity decreased for U50,488 and
bremazocine, increased for
ethylketazocine and did not change consistently for
tifluadom, compared with the prechronic phase. The present study demonstrates that chronic
morphine administration alters both the agonist and antagonist activity of kappa
opioids. Changes in antagonist activity of kappa
opioids after chronic
morphine administration may be explained by concurrent changes in their agonist potency and the extent to which their agonist effects are mu-mediated.