Freye E, Neruda B, Smith O W
Department of Vascular Surgery and Renal Transplantation, Heinrich-Heine-University Clinics of Düsseldorf, Germany.
Arzneimittelforschung. 1997 Jan;47(1):6-9.
Reversal of opioid-related respiratory depression is often accompanied by an "acute abstinence like syndrome" with hypertension, tachycardia, and pain. This overshoot was used to investigate the extent at which opioids of high potency but different structure are involved in naloxone-induced abstinence. In 10 awake and trained mongrel dogs two highly mu-selective compounds, alfentanil and fentanyl, were given in cumulative doses and at different occasions (30-60-120-240 micrograms/kg, and 6-12-24-48 micrograms/kg, respectively). Subsequently, a high dose of naloxone (100 micrograms/kg) was given at 5 min intervals while arterial blood gases, blood pressure, heart rate and the somatosensory evoked potential (SEP) were measured continuously. Following a wash-out period, the 19-isoamyl derivative of etorphine (M-140; 10,000 times more potent than normorphine and a 4.5 fold potency of ethylketocyclazocine in a bioessay preparation) was also given in increasing doses (0.2-0.4-0.8-3.2 micrograms/kg). Again, naloxone was given (100 micrograms/kg) at 5 min interval, while cardiovascular parameters, blood gases and SEPs were measured continuously. 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 nociceptive afferents. Naloxone was sufficient to reverse respiratory impairment after fentanyl, alfentanil and M-140. However, in contrast to fentanyl and alfentanil, there was no cardiovascular or evoked potential overshoot 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 state of the cardiovascular system and an increase of nociceptive stimuli to pain modulating centres. After M-140 reversal of mu-related respiratory depression by naloxone was possible. However, no precipitation on an acute abstinence-like syndrome affecting antinociception or inducing cardiovascular overshoot was observed. This may stem from an intense binding and slow dissociation of the ligand from the receptor site or may be due to 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.
阿片类药物相关呼吸抑制的逆转常伴有“急性戒断样综合征”，表现为高血压、心动过速和疼痛。这种过度反应被用于研究高效但结构不同的阿片类药物在纳洛酮诱导的戒断中所涉及的程度。在10只清醒且经过训练的杂种犬中，分别在不同时间给予两种高度μ-选择性化合物阿芬太尼和芬太尼累积剂量（分别为30 - 60 - 120 - 240微克/千克和6 - 12 - 24 - 48微克/千克）。随后，每隔5分钟给予高剂量纳洛酮（100微克/千克），同时连续测量动脉血气、血压、心率和体感诱发电位（SEP）。经过洗脱期后，还给予埃托啡的19 - 异戊基衍生物（M - 140；在生物测定制剂中比去甲吗啡强10000倍，比乙基酮环唑新强4.5倍）递增剂量（0.2 - 0.4 - 0.8 - 3.2微克/千克）。同样，每隔5分钟给予纳洛酮（100微克/千克），同时连续测量心血管参数、血气和SEP。所有三种阿片类药物均引起与剂量相关的呼吸抑制，伴有高碳酸血症和低氧血症、与剂量相关的心动过缓和轻度低血压。这伴随着SEP波幅与剂量相关的降低，反映了伤害性传入阻滞的程度。纳洛酮足以逆转芬太尼、阿芬太尼和M - 140后的呼吸损害。然而，与芬太尼和阿芬太尼不同，纳洛酮逆转M - 140后未出现心血管或诱发电位过度反应。阿芬太尼后，纳洛酮使血压、心率和SEP波幅分别升高7%、41%和38%。芬太尼后，血压、心率和SEP波幅的升高分别为17%、43%和96%。该研究表明，阿片类μ配体越强效，纳洛酮就越容易诱导心血管系统的过度兴奋状态，并增加对疼痛调节中枢的伤害性刺激。纳洛酮能够逆转M - 140引起的与μ相关的呼吸抑制。然而，未观察到影响抗伤害感受或诱导心血管过度反应的急性戒断样综合征的发作。这可能源于配体与受体位点的强烈结合和缓慢解离，或者可能是由于对μ和κ受体位点的高结合亲和力。与各种受体位点相互作用的阿片类药物可能对阿片类药物依赖成瘾者的替代治疗具有临床意义。
