Do gabapentin or pregabalin directly modulate the µ receptor?

PeerJ

article

Preeti Manandhar¹  Bridin Patricia Murnion²  Natasha L. Grimsey⁴  Mark Connor¹  Marina Santiago¹ 

[1] Department of Biomedical Sciences, Macquarie University;Drug and Alcohol Services, Central Coast Local Health District;School of Medicine and Public Health, University of Newcastle;Department of Pharmacology and Clinical Pharmacology, University of Auckland

关键词: Pregabalin;    Gabapentin;    Opioid;    µ receptor;    Overdose;    Gabapentinoids;    Morphine;    Opioid-related harm;    Opioid receptor signaling;   

DOI  :  10.7717/peerj.11175

学科分类：社会科学、人文和艺术（综合）

来源: Inra

【 摘 要 】

Background Pregabalin and gabapentin improve neuropathic pain symptoms but there are emerging concerns regarding their misuse. This is more pronounced among patients with substance use disorder, particularly involving opioids. Co-ingestion of gabapentinoids with opioids is increasingly identified in opioid related deaths, however, the molecular mechanism behind this is still unclear. We have sought to determine whether pregabalin or gabapentin directly modulates acute μ receptor signaling, or μ receptor activation by morphine. Methods The effects of pregabalin and gabapentin were assessed in HEK 293 cells stably transfected with the human μ receptor. Their effect on morphine induced hyperpolarization, cAMP production and ERK phosphorylation were studied using fluorescent-based membrane potential assay, bioluminescence based CAMYEL assay and ELISA assay, respectively. Pregabalin/gabapentin effects on morphine-induced hyperpolarization were also investigated in AtT20 cells. Results Pregabalin or gabapentin (1 µM, 100 µM each) did not activate the µ receptor or affect K channel activation or ERK phosphorylation produced by morphine. Neither drug affected the desensitization of K channel activation produced by prolonged (30 min) application of morphine. Gabapentin (1 µM, 100 µM) and pregabalin (1 µM) did not affect inhibition of forskolin-stimulated cAMP production by morphine. However, pregabalin (100 µM) potentiated forskolin mediated cAMP production, although morphine still inhibited cAMP levels with a similar potency to control. Discussion Pregabalin or gabapentin did not activate or modulate µ receptor signaling in three different assays. Our data do not support the hypothesis that gabapentin or pregabalin augment opioid effects through direct or allosteric modulation of the µ receptor. Pregabalin at a high concentration increases cAMP production independent of morphine. The mechanism of enhanced opioid-related harms from co-ingestion of pregabalin or gabapentin with opioids needs further investigation.

【 授权许可】

CC BY