GRK2 in sensory neurons regulates epinephrine-induced signalling and duration of mechanical hyperalgesia

Abstract

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 21days in GRK2+/− mice, whereas it lasts only 3 to 4days 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 Cε PKCε inhibitor TAT-PKCεv1-2 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 PKCε-dependent pathway that ultimately mediates prolonged EPI-induced hyperalgesia.G protein-coupled receptor kinase 2 (GRK2) is a crucial regulator of hyperalgesia. Low GRK2 in sensory neurons markedly prolongs epinephrine (EPI)-induced hyperalgesia, by switching EPI signalling from protein kinase A-dependent toward PKCε-dependent pathways.