Do Carmo Gail Pereira, Folk John E, Rice Kenner C, Chartoff Elena, Carlezon William A, Negus S Stevens
Alcohol and Drug Abuse Research Center, McLean Hospital-Harvard Medical School, Belmont, MA 02478, United States.
Eur J Pharmacol. 2009 Feb 14;604(1-3):58-65. doi: 10.1016/j.ejphar.2008.12.021. Epub 2008 Dec 24.
Delta opioid receptor agonists are under development for a variety of clinical applications, and some findings in rats raise the possibility that agents with this mechanism have abuse liability. The present study assessed the effects of the non-peptidic delta opioid agonist SNC80 in an assay of intracranial self-stimulation (ICSS) in rats. ICSS was examined at multiple stimulation frequencies to permit generation of frequency-response rate curves and evaluation of curve shifts produced by experimental manipulations. Drug-induced leftward shifts in ICSS frequency-rate curves are often interpreted as evidence of abuse liability. However, SNC80 (1.0-10 mg/kg s.c.; 10-56 mg/kg i.p.) failed to alter ICSS frequency-rate curves at doses up to those that produced convulsions in the present study or other effects (e.g. antidepressant effects) in previous studies. For comparison, the monoamine releaser d-amphetamine (0.1-1.0 mg/kg, i.p.) and the kappa agonist U69,593 (0.1-0.56 mg/kg, i.p.) produced dose-dependent leftward and rightward shifts, respectively, in ICSS frequency-rate curves, confirming the sensitivity of the procedure to drug effects. ICSS frequency-rate curves were also shifted by two non-pharmacological manipulations (reductions in stimulus intensity and increases in response requirement). Thus, SNC80 failed to facilitate or attenuate ICSS-maintained responding under conditions in which other pharmacological and non-pharmacological manipulations were effective. These results suggest that non-peptidic delta opioid receptor agonists have negligible abuse-related effects in rats.
δ阿片受体激动剂正被开发用于多种临床应用，并且在大鼠身上的一些研究结果表明，具有这种作用机制的药物可能存在滥用倾向。本研究评估了非肽类δ阿片激动剂SNC80在大鼠颅内自我刺激（ICSS）试验中的作用。在多个刺激频率下检测ICSS，以生成频率-反应率曲线，并评估实验操作引起的曲线变化。药物引起的ICSS频率-率曲线向左移动通常被解释为滥用倾向的证据。然而，在本研究中，高达引起惊厥剂量的SNC80（皮下注射1.0 - 10mg/kg；腹腔注射10 - 56mg/kg）未能改变ICSS频率-率曲线，在之前的研究中也未产生其他作用（如抗抑郁作用）。作为比较，单胺释放剂d-苯丙胺（腹腔注射0.1 - 1.0mg/kg）和κ激动剂U69,593（腹腔注射0.1 - 0.56mg/kg）分别使ICSS频率-率曲线产生剂量依赖性的向左和向右移动，证实了该程序对药物作用的敏感性。ICSS频率-率曲线也因两种非药理学操作（刺激强度降低和反应要求增加）而发生移动。因此，在其他药理学和非药理学操作有效的条件下，SNC80未能促进或减弱ICSS维持的反应。这些结果表明，非肽类δ阿片受体激动剂在大鼠中与滥用相关的作用可忽略不计。
