Department of Neuroscience, The Scripps Research Institute, La Jolla, California, USA.
Department of Psychiatry, University of California San Diego, La Jolla, California, USA.
Br J Pharmacol. 2021 Sep;178(18):3797-3812. doi: 10.1111/bph.15520. Epub 2021 Jun 8.
The extra medical use of, and addiction to, prescription opioid analgesics is a growing health problem. To characterize how prescription opioid abuse develops, this study investigated the affective consequences of escalating prescription opioid use using intracranial self-stimulation (ICSS) reward and oxycodone intravenous self-administration (IVSA) models.
Male Wistar rats were given access to oxycodone IVSA (0.15 mg·kg per infusion, i.v.) in short-access (ShA; 1 h) or long-access (LgA; 12 h) sessions for five sessions per week followed by intermittent 60-h discontinuations from drug access, a novel explicit test of the negative reinforcement hypothesis. Separate groups were first trained in the ICSS procedure and then in oxycodone IVSA in 11-h LgA sessions.
Rats given LgA to oxycodone escalated their responding more than ShA rats, with further significant increases observed following each 60-h discontinuation. Presession brain reward thresholds increased with sequential daily LgA IVSA sessions, consistent with a growing negative affective state consequent to successive daily intoxication/abstinence cycles. A 1-h oxycodone IVSA interval was sufficient to normalize these elevated reward thresholds, as was, paradoxically, a 60-h weekend abstinence. The increase in ICSS thresholds was attenuated in a group treated with the long-acting κ-opioid antagonist norbinaltorphimine prior to IVSA training.
Changes in brain reward function during escalation of oxycodone self-administration are driven by an interplay between κ-opioid receptor-mediated negative affective state associated with escalated oxycodone intake and dynamic restoration of brain reward status during longer periods of abstinence.
处方类阿片类镇痛药的额外医疗用途和成瘾是一个日益严重的健康问题。为了描述处方类阿片滥用的发展过程，本研究使用颅内自我刺激（ICSS）奖励和羟考酮静脉自我给药（IVSA）模型，研究了递增使用处方类阿片的情感后果。
雄性 Wistar 大鼠每周接受五次短时长（ShA；1 小时）或长时长（LgA；12 小时）羟考酮 IVSA（0.15mg·kg 每剂量，静脉注射），随后有 60 小时的药物接触中断期，这是对负强化假说的一种新的明确测试。单独的一组大鼠首先接受 ICSS 程序训练，然后在 11 小时 LgA 时段接受羟考酮 IVSA 训练。
接受 LgA 羟考酮的大鼠比 ShA 大鼠的反应更多，在每次 60 小时的停药后观察到进一步的显著增加。随着连续每日 LgA IVSA 时段的进行，预先的大脑奖励阈值增加，这与连续每日中毒/戒断周期引起的负面情绪状态的增加相一致。1 小时羟考酮 IVSA 间隔足以使这些升高的奖励阈值正常化，就像周末 60 小时的戒断一样。在 IVSA 训练之前用长效 κ-阿片受体拮抗剂诺比那特罗米进行治疗的一组大鼠，ICSS 阈值的增加减弱。
在羟考酮自我给药增加期间，大脑奖励功能的变化是由 κ-阿片受体介导的与递增羟考酮摄入相关的负面情感状态与更长时间的禁欲期间大脑奖励状态的动态恢复之间的相互作用驱动的。
