A µ-opioid receptor superagonist analgesic with minimal adverse effects

µ-opioid receptor (MOR) superagonists can produce analgesia but typically come with serious side effects tied to high intrinsic efficacy. This Nature study identifies N-desethyl-fluornitrazene (DFNZ), derived from nitazene chemistry, and reports that it produces effective analgesia in rodents while showing minimal adverse effects in preclinical tests. DFNZ has impaired brain penetrance, a distinct spatiotemporal MOR signaling profile, and reduced efficacy at the MOR-GAL1 heteromer. In repeated-exposure studies, DFNZ did not induce respiratory depression, tolerance, or MOR downregulation, and it also showed limited effects on dopamine neurotransmission and weaker reinforcing effects in drug self-administration compared with other MOR agonists. The findings challenge the idea that high-efficacy MOR agonists cannot be safe and effective therapeutics, with implications for treating pain and potentially opioid addiction.