cAMP signaling through protein kinase A and Epac2 induces substance P release in the rat spinal cord

NEUROPHARMACOLOGY

卷:189

Article

Chen, Wenling^1,2  McRoberts, James A.¹  Ennes, Helena S.¹  Marvizon, Juan Carlos^1,2 

[1] Univ Calif Los Angeles, Dept Med, David Geffen Sch Med, Vatche & Tamar Manoukian Div Digest Dis, Los Angeles, CA 90095 USA

[2] Vet Affairs Greater Los Angeles Healthcare Syst, Los Angeles, CA 90073 USA

关键词: Cyclic-AMP;    Hyperalgesia;    Neurokinin-1 receptor;    NMDA receptor;    Primary afferent;    Protein kinase A;    Substance P;    Voltage-gated calcium channel;   

DOI  :  10.1016/j.neuropharm.2021.108533

来源: Elsevier

【 摘 要 】

Using neurokinin 1 receptor (NK1R) internalization to measure of substance P release in rat spinal cord slices, we found that it was induced by the adenylyl cyclase (AC) activator forskolin, by the protein kinase A (PKA) activators 6-Bnz-cAMP and 8-Br-cAMP, and by the activator of exchange protein activated by cAMP (Epac) 8-pCPT2-O-Me-cAMP (CPTOMe-cAMP). Conversely, AC and PKA inhibitors decreased substance P release induced by electrical stimulation of the dorsal root. Therefore, the cAMP signaling pathway mediates substance P release in the dorsal horn. The effects of forskolin and 6-Bnz-cAMP were not additive with NMDA-induced substance P release and were decreased by the NMDA receptor blocker MK-801. In cultured dorsal horn neurons, forskolin increased NMDA-induced Ca2+ entry and the phosphorylation of the NR1 and NR2B subunits of the NMDA receptor. Therefore, cAMP-induced substance P release is mediated by the activating phosphorylation by PKA of NMDA receptors. Voltage-gated Ca2+ channels, but not by TRPV1 or TRPA1, also contributed to cAMP-induced substance P release. Activation of PKA was required for the effects of forskolin and the three cAMP analogs. Epac2 contributed to the effects of forskolin and CPTOMe-cAMP, signaling through a Raf - mitogen-activated protein kinase pathway to activate Ca2+ channels. Epac1 inhibitors induced NK1R internalization independently of substance P release. In rats with latent sensitization to pain, the effect of 6-Bnz-cAMP was unchanged, whereas the effect of forskolin was decreased due to the loss of the stimulatory effect of Epac2. Hence, substance P release induced by cAMP decreases during pain hypersensitivity.

【 授权许可】

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