STUDIES ON THE ABSTINENCE-LIKE OVERSHOOT FOLLOWING REVERSAL OF THE POTENT 19-ISOAMYL DERIVATIVE OF ETORPHINE WITH NALOXONE - A COMPARISON WITH THE OPIOIDS FENTANYL AND ALFENTANIL

Reversal of opioid-related respiratory depression is often accompanied by an ''acute abstinence like syndrome'' with hypertension, tachycard ia, and pain. This overshoot was used to investigate the extent at whi ch opioids of high potency but different structure are involved in nal oxone-induced abstinence In 10 awake and trained mongrel dogs two high ly mu-selective compounds, alfentanil and fentanyl, were given in cumu lative doses and at different occasions (30-60-120-240 mu g/kg, and 6- 12-24-48 mu g/kg, respectively). Subsequently, a high dose of naloxone (100 mu g/kg) was given at 5 min intervals while arterial blood gases , blued pressure. heart rate and the somatosensory evoked potential (S EP) were measured continuously. Following a wash-out period. the 19-is oamyl derivative of etorphine (M-140 10,000 times more potent than nor morphine and a 4.5 fold potency of ethylketocyclazocine in a bioessay preparation) was also given in increasing doses (0.2-0.4-0.5-3.2 mu g/ kg). Again, naloxone was given (100 mu g/kg) at 5 min interval, while cardiovascular parameters, blood gases and SEPs were measured continuo usly. All three opioids induced a dose-related respiratory depression with hypercarbia and hypoxia, a dose-related bradycardia, and a modest hypotension. This was accompanied by a dose-related depression of the amplitude of the SEP, reflecting the degree of blockade of nociceptiv e afferents. Naloxone was sufficient to reverse respiratory impairment after fentanyl, alfentanil and M-140. However, in contrast to fentany l and alfentanil, there: was no cardiovascular or evoked potential ove rshoot following naloxone reversal of M-140. After alfentanil naloxone increased blood pressure. heart rate and amplitude of the SEP by, 7 % , 41 %, and 38 %, respectively. After fentanyl this increase in blood pressure, heart rate and amplitude of the SEP was 17 %, 43 % and 96 %, respectively. The study indicates that the more potent the opiate mu ligands are the more is naloxone liable to Induce a hyperexcitatory st ate of the cardiovascular system and an increase of nociceptive stimul i to pain modulating centres. After M-140 reversal of mu-related respi ratory depression by naloxone was possible. However, no precipitation on an acute abstinence-like syndrome affecting antinociception or indu cing cardiovascular overshoot was observed. This may stem from an inte nse binding and slow dissociation of the ligand from the receptor site or may be due to a high binding affinity to both the mu and the kappa receptor site. Opioids which interact with various receptor sites may be of clinical interest for substitution therapy in opioid dependent addicts.