A µ-opioid receptor superagonist analgesic with minimal adverse effects
Abstract
Abstract Developing safe and effective pain medications is an ongoing challenge for human health. Agonists for the µ-opioid receptor (MOR) are essential pain medications, but their high intrinsic efficacy also induces adverse side effects, including respiratory depression, constipation, tolerance, dependence, withdrawal and addiction 1–7 . Strategies to limit adverse effects traditionally include developing MOR agonists that have low intrinsic efficacy or that preferentially activate G-protein signalling over β-arrestin signalling 8 . Here we identify a novel MOR agonist with supramaximal intrinsic efficacy and a unique pharmacological profile that produced effective analgesia in rodents with minimal adverse effects. N -desethyl-fluornitrazene (DFNZ) was derived from a class of synthetic benzimidazole opioids called nitazenes. DFNZ has impaired brain penetrance, a unique spatiotemporal MOR cellular signalling profile, and diminished efficacy at the MOR–galanin 1 receptor (GAL1) heteromer. DFNZ does not induce respiratory depression, tolerance or MOR downregulation after repeated exposure. Compared with other MOR agonists, DFNZ has limited effects on dopamine neurotransmission in nucleus accumbens and weaker reinforcing effects in the drug self-administration procedure. These results provide novel insights about MOR and nitazene pharmacology, have important implications for pain and addiction treatment, and challenge the prevailing dogma that high-efficacy MOR agonists cannot constitute safe and effective therapeutic agents.
Article Details
Authors (44)
Juan L. Gomez
Emilya N. Ventriglia
Zachary J. Frangos
Agnieszka Sulima
Michael J. Robertson
Michael D. Sacco
Reece C. Budinich
Ilinca M. Giosan
Tongzhen Xie
Oscar Solis
Anna E. Tischer
Jennifer M. Bossert
Kiera E. Caldwell
Hannah Bonbrest
Amelie Essmann
Zelai M. Garçon-Poca
Shinbe Choi
Michael R. Noya
Feonil Limiac
Ali Arce
Grant C. Glatfelter
Margaret Robinson
Li Chen
Angelina A. Mullarkey
Dain R. Brademan
Garrett Enten
William Dunne
César Quiroz
Ingrid Schoenborn
Chae Bin Lee
Rana Rais
Daniel P. Holt
Robert F. Dannals
Lei Shi
School of Health Management Guangzhou Medical University Guangzhou China
Ruth Hüttenhain
Sergi Ferré
Eugene Kiyatkin
Jordi Bonaventura
Yavin Shaham
Venetia Zachariou
Michael H. Baumann
Georgios Skiniotis
Kenner C. Rice
Michael Michaelides