Biased Opioid Antagonists as Modulators of Opioid Dependence: Opportunities to Improve Pain Therapy and Opioid Use Management.
Molecules
; 25(18)2020 Sep 11.
Article
em En
| MEDLINE
| ID: mdl-32932935
ABSTRACT
Opioid analgesics are effective pain therapeutics but they cause various adverse effects and addiction. For safer pain therapy, biased opioid agonists selectively target distinct µ opioid receptor (MOR) conformations, while the potential of biased opioid antagonists has been neglected. Agonists convert a dormant receptor form (MOR-µ) to a ligand-free active form (MOR-µ*), which mediates MOR signaling. Moreover, MOR-µ converts spontaneously to MOR-µ* (basal signaling). Persistent upregulation of MOR-µ* has been invoked as a hallmark of opioid dependence. Contrasting interactions with both MOR-µ and MOR-µ* can account for distinct pharmacological characteristics of inverse agonists (naltrexone), neutral antagonists (6ß-naltrexol), and mixed opioid agonist-antagonists (buprenorphine). Upon binding to MOR-µ*, naltrexone but not 6ß-naltrexol suppresses MOR-µ*signaling. Naltrexone blocks opioid analgesia non-competitively at MOR-µ*with high potency, whereas 6ß-naltrexol must compete with agonists at MOR-µ, accounting for ~100-fold lower in vivo potency. Buprenorphine's bell-shaped dose-response curve may also result from opposing effects on MOR-µ and MOR-µ*. In contrast, we find that 6ß-naltrexol potently prevents dependence, below doses affecting analgesia or causing withdrawal, possibly binding to MOR conformations relevant to opioid dependence. We propose that 6ß-naltrexol is a biased opioid antagonist modulating opioid dependence at low doses, opening novel avenues for opioid pain therapy and use management.
Palavras-chave
Texto completo:
1
Bases de dados:
MEDLINE
Assunto principal:
Receptores Opioides mu
/
Manejo da Dor
/
Analgésicos Opioides
/
Antagonistas de Entorpecentes
Tipo de estudo:
Prognostic_studies
Limite:
Animals
/
Humans
Idioma:
En
Revista:
Molecules
Assunto da revista:
BIOLOGIA
Ano de publicação:
2020
Tipo de documento:
Article
País de afiliação:
Estados Unidos