4.7 Article

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

期刊

JCI INSIGHT
卷 7, 期 3, 页码 -

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AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/jci.insight.153191

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资金

  1. National Natural Science Foundation of China [31930042, 82021002, 82130032, 81971043]
  2. innovative research team of high-level local uni-versities in Shanghai
  3. Shanghai Municipal Science and Technology Major Project [2018SHZDZX01]
  4. ZJLab
  5. Shanghai Center for Brain Science and Brain-Inspired Technology

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This study reveals the important role of peripheral adenylyl cyclase isoform AC3 in nociceptive transmission and regulation of opioid receptor signaling. The conditional knockout of AC3 in mouse DRGs led to increased nociceptive responses, decreased Kv channel currents, and increased neuronal excitability. Furthermore, AC3 knockout abolished the analgesic effect of KOR agonist and its inhibition on Kv channel, suggesting the involvement of AC3 in KOR opioid analgesia through classical G alpha(i/o) signaling or direct interaction with KOR. Additionally, the upregulation of AC1 and cAMP levels in AC3-deficient DRGs highlights the compensatory role of AC1 in the absence of AC3.
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 remains elusive. Here, we report that conditional KO of AC3 (AC3 CKO) in L3 and L4 DRGs robustly facilitated the mouse nociceptive responses, decreased voltage-gated potassium (Kv) channel currents, and increased neuronal excitability. Furthermore, we report AC3 CKO eliminated the analgesic effect of kappa-opioid receptor (KOR) agonist and its inhibition on Kv channel by classical G alpha(i/o) signaling or nonclassical direct interaction of KOR and AC3 proteins. Interestingly, significantly upregulated AC1 level and cAMP concentration were detected in AC3deficient DRGs. Inhibition of AC1 completely reversed cAMP upregulation, neuronal excitability enhancement, and nociceptive behavioral hypersensitivity in AC3-CKO mice. Our findings suggest a crucial role of peripheral AC3 in nociceptive modulation and KOR opioid analgesia.

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