Beta1 subunits enable fentanyl-induced BK channel activation and opioid regulation of cerebral artery diameter

Ultra-potent synthetic opioids are powerful analgesics but also a leading cause of drug overdose deaths. Calcium-/voltage-gated potassium channels of large conductance (BK) control vital physiological processes, with their accessory β1 (encoded by Kcnmb1 in mice) subunit being predominantly expressed in smooth muscle. Thus, we hypothesize that BK β1 determines the effect of fentanyl on cerebral artery diameter. Here we report that fentanyl (0.001-10 μm) activates BK heteromers consisting of slo1 + β1 subunits in CHO cells, but not homomers of slo1. In ex vivo pressurized mouse cerebral arteries, pharmacological inhibition of BK or β1 genetic deletion (Kcnmb1-/-) led to fentanyl-induced vasoconstriction. Naloxone, an opioid receptor antagonist, ablates the fentanyl response in wild-type cerebral arteries whereas mild constriction persists in Kcnmb1-/- arteries. Therefore, we identify BK β1 as a functional fentanyl target which acts independently of opioid receptors to regulate fentanyl action on cerebral artery diameter.