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Papers of the Week


Papers: 11 Dec 2021 - 17 Dec 2021


Animal Studies, Pharmacology/Drug Development


2021 Dec 16


JCI Insight

Peripheral ablation of type Ⅲ adenylyl cyclase induces hyperalgesia and eliminates KOR-mediated analgesia in mice.

Authors

Abstract

Ca2+/calmodulin-stimulated group Ⅰ adenylyl cyclase (AC) isoforms AC1 and AC8 have been involved in nociceptive processing and morphine responses. However, whether AC3, another member of group I ACs, is involved in nociceptive transmission and regulates opioid receptor signaling remain elusive. Here we report that conditional knockout of AC3 (AC3CKO) in L3 and L4 DRGs robustly facilitates the mouse nociceptive responses, decreases voltage-gated potassium (Kv) channel currents and increases neuronal excitability. Also, AC3CKO eliminates the analgesic effect of κ opioid receptor (KOR) agonist and its inhibition on Kv channel by classical Gαi/o signaling or nonclassical direct interaction of KOR and AC3 proteins. Interestingly, significantly upregulated AC1 level and cAMP concentration are detected in AC3 deficient DRGs. Inhibition of AC1 completely reversed cAMP upregulation, neuronal excitability enhancement and nociceptive behavioral hypersensitivity in AC3CKO mice. Our findings suggest a crucial role of peripheral AC3 in nociceptive modulation and KOR opioid analgesia.