SEROTONIN AND NOREPINEPHRINE UPTAKE INHIBITING ACTIVITY OF CENTRALLY ACTING ANALGESICS - STRUCTURAL DETERMINANTS AND ROLE IN ANTINOCICEPTION

Although it is well established that the analgesic effects of morphine are mediated by opioid receptors, previous studies have shown that so me opioids additionally inhibit the uptake of serotonin and norepineph rine. The present investigation of a diverse group of opioids revealed that structurally identifiable subgroups inhibited the neuronal reupt ake of these monoamines. Phenanthrene opioids with an oxygen bridge be tween C4 and C5, such as morphine and naloxone (group I), did not bloc k norepinephrine or serotonin uptake, whereas phenanthrene opioids wit hout the oxygen bridge and the C6-OH moiety, such as levorphanol and l evomethorphan (group II), did inhibit uptake, as did nonphenanthrene o pioids, such as d-propoxyphene and methadone (group III). Affinity at the mu opioid receptor correlated with antinociceptive potency (r = 0. 87, P < .05). Although the antinociceptive activity of the ''active en an tiomers'' of group II and III compounds also correlated with their affinity at the mu opioid receptor (r = 0.85, P = .007), additional co nsideration of serotonin uptake inhibiting activity (but not of norepi nehrine uptake inhibiting activity) significantly improved the correla tion between antinociceptive potency and the in vitro activity of thes e compounds (r = 0.915, P = .0017). Additionally, for group II and Ill (but not group I) compounds, smaller differences between enantiomers in antinociceptive potency than in mu receptor affinity were noted, pr esumably because of the contribution of uptake inhibition to the antin ociceptive activity of group II and III compounds. Evidence also is pr ovided suggesting a broader role for the combination of mu opioid affi nity and 5-hydroxytryptamine uptake inhibition in the activity of othe r antinociceptive agents.