Peripheral ablation of type III adenylyl cyclase induces hyperalgesia and eliminates KOR-mediated analgesia in mice
Wen-Wen Zhang, Hong Cao, Yang Li, Xian-Jun Fu, Yu-Qiu Zhang
Wen-Wen Zhang, Hong Cao, Yang Li, Xian-Jun Fu, Yu-Qiu Zhang
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Research Article Neuroscience

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

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 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 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 were detected in AC3-deficient 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.

Authors

Wen-Wen Zhang, Hong Cao, Yang Li, Xian-Jun Fu, Yu-Qiu Zhang

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Figure 4

AC3 CKO alters excitatory synaptic transmission in spinal cord slices.

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AC3 CKO alters excitatory synaptic transmission in spinal cord slices. ...
(A–C) Patch clamp recording of sEPSC showing an increase in the frequency of sEPSCs in spinal lamina IIo neurons (A and B) and a left-shifted the cumulative fraction of interevent interval (C) AC3-CKO mice. *P < 0.05; 2-tailed Student’s t test; n = 35 Ctrl and 35 CKO (cells). (D–F) AC3 CKO did not affect the amplitude (D and E) and corresponding cumulative fraction (D and F) of sEPSCs. (G–L) Patch clamp recording of sIPSC showing no difference in the frequency (G–I) and amplitude (J–L) of sIPSCs in spinal lamina IIo neurons between control and AC3-CKO mice. 2-tailed Student’s t test; n = 10 Ctrl and 10 CKO (cells).