科研之友
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摘要
Epinephrine (EPI) contributes to hyperalgesia in inflammatory and stress conditions. EPI signals via adrenoceptors, which are regulated by G protein-coupled receptor kinase 2 (GRK2). We previously reported that GRK2 is decreased in nociceptors during chronic inflammation. Herein, we investigated whether GRK2 modulates EPI-induced mechanical and thermal hyperalgesia by using GRK2(+/) mice, which express 50% of the GRK2 protein. We demonstrate for the first time that EPI-induced mechanical as well as thermal hyperalgesia is prolonged to approximately 21 days in GRK2(+/) mice, whereas it lasts only 3 to 4 days in wild-type mice. Using cell-specific GRK2-deficient mice, we further show that a low level of GRK2 in primary sensory neurons is critical for this prolongation of EPI-induced hyperalgesia. Low GRK2 in microglia had only a small effect on EPI-induced hyperalgesia. Low GRK2 in astrocytes did not alter EPI-induced hyperalgesia. EPI-induced hyperalgesia was prolonged similarly in mice with tamoxifen-induced homozygous or heterozygous deletion of GRK2. In terms of EPI signalling pathways, the protein kinase A (PKA) inhibitor H-89 inhibited EPI-induced mechanical hyperalgesia in wild-type mice, whereas H-89 had no effect in mice with low GRK2 in sensory neurons (SNS-GRK2(+/) mice). Conversely, intraplantar injection of the protein kinase C epsilon PKC epsilon inhibitor TAT-PKC(epsilon v1-2) inhibited hyperalgesia in sensory neuron specific (SNS)-GRK2(+/) mice and not in wild-type mice. These results indicate that low GRK2 in primary sensory neurons switches EPI-induced signalling from a protein kinase A-dependent toward a PKC epsilon-dependent pathway that ultimately mediates prolonged EPI-induced hyperalgesia.
