Burgess Gwendolyn E, Traynor John R, Jutkiewicz Emily M
Department of Pharmacology, University of Michigan, Ann Arbor Michigan, 48109.
bioRxiv. 2024 Nov 21:2024.11.19.624329. doi: 10.1101/2024.11.19.624329.
Pleasant subjective effects of drugs (e.g., euphoria) have been demonstrated to contribute to their abuse potential. In humans, there is some evidence that acute pain states may decrease the positive subjective effects of opioids; however, no studies have directly tested the impact of a long-lasting pain state. Therefore, the goal of this study was to directly evaluate the discriminative stimulus of mu opioid receptor (MOR) agonist, fentanyl, or the non-opioid drug of abuse, cocaine, in the presence or absence of spared nerve injury (SNI) induced chronic neuropathic pain. Prior to surgery, MOR agonists (fentanyl, morphine, nalbuphine) dose-dependently increased % fentanyl-like responding, as expected; surprisingly, after surgery, we saw small, significant rightward shifts in the fentanyl and morphine dose response curves in sham and SNI groups suggesting that the observed shifts were not due to chronic pain. In both sham and SNI groups, there was an increase in the generalization of nalbuphine to the fentanyl-discriminative stimulus. There was no change in the discriminative stimulus of cocaine (or amphetamine substitutions) over 4 months of SNI-induced chronic neuropathic pain or sham states, suggesting that the SNI model failed to alter the discriminative stimuli of fentanyl and cocaine. Following induction of chronic neuropathic pain, there was an observed increase in quinpirole-induced generalization to the cocaine discriminative stimulus. In the future, studies should directly examine the abuse potential of low efficacy MOR agonists and dopaminergic agonists in the presence and absence of chronic pain states.
药物的愉悦主观效应（如欣快感）已被证明会导致其滥用可能性。在人类中，有一些证据表明急性疼痛状态可能会降低阿片类药物的积极主观效应；然而，尚无研究直接测试持久疼痛状态的影响。因此，本研究的目的是直接评估在存在或不存在 spared nerve injury（SNI）诱导的慢性神经性疼痛的情况下，μ阿片受体（MOR）激动剂芬太尼或非阿片类滥用药物可卡因的辨别刺激。手术前，正如预期的那样，MOR激动剂（芬太尼、吗啡、纳布啡）剂量依赖性地增加了芬太尼样反应的百分比；令人惊讶的是，手术后，我们在假手术组和SNI组中看到芬太尼和吗啡剂量反应曲线有小的、显著的右移，这表明观察到的变化不是由于慢性疼痛。在假手术组和SNI组中，纳布啡对芬太尼辨别刺激的泛化均增加。在SNI诱导的慢性神经性疼痛或假手术状态的4个月期间，可卡因（或苯丙胺替代物）的辨别刺激没有变化，这表明SNI模型未能改变芬太尼和可卡因的辨别刺激。在诱导慢性神经性疼痛后，观察到喹吡罗对可卡因辨别刺激的泛化增加。未来，研究应直接检查在存在和不存在慢性疼痛状态的情况下低效MOR激动剂和多巴胺能激动剂的滥用可能性。
