KOR and B2R form heterodimers that function as a novel pharmacological entity. KOR/B2R heteromers mediate the Gαs/cAMP/CREB signaling pathway. Dyn A(1–13) enhances proliferation of HEK293-KOR/B2R and SH-SY5Y cells. We reveal the molecular mechanism underlying neuroprotection mediated by KOR/B2R heterodimers.