Neuronal GRK2 regulates microglial activation and contributes to electroacupuncture analgesia on inflammatory pain in mice

Abstract

Background G protein coupled receptor kinase 2 (GRK2) has been demonstrated to play a crucial role in the development of chronic pain. Acupuncture is an alternative therapy widely used for pain management. In this study, we investigated the role of spinal neuronal GRK2 in electroacupuncture (EA) analgesia. Methods The mice model of inflammatory pain was built by subcutaneous injection of Complete Freund’s Adjuvant (CFA) into the plantar surface of the hind paws. The mechanical allodynia of mice was examined by von Frey test. The mice were subjected to EA treatment (BL60 and ST36 acupuncture points) for 1 week. Overexpression and downregulation of spinal neuronal GRK2 were achieved by intraspinal injection of adeno associated virus (AAV) containing neuron-specific promoters, and microglial activation and neuroinflammation were evaluated by real-time PCR. Results Intraplantar injection with CFA in mice induced the decrease of GRK2 and microglial activation along with neuroinflammation in spinal cord. EA treatment increased the spinal GRK2, reduced neuroinflammation, and significantly decreased CFA-induced mechanical allodynia. The effects of EA were markedly weakened by non-cell-specific downregulation of spinal GRK2. Further, intraspinal injection of AAV containing neuron-specific promoters specifically downregulated neuronal GRK2, and weakened the regulatory effect of EA on CFA-induced mechanical allodynia and microglial activation. Meanwhile, overexpression of spinal neuronal GRK2 decreased mechanical allodynia. All these indicated that the neuronal GRK2 mediated microglial activation and neuroinflammation, and subsequently contributed to CFA-induced inflammatory pain. Conclusion The restoration of the spinal GRK2 and subsequent suppression of microglial activation and neuroinflammation might be an important mechanism for EA analgesia. Our findings further suggested that the spinal GRK2, especially neuronal GRK2, might be the potential target for EA analgesia and pain management, and we provided a new experimental basis for the EA treatment of pain.

Electroacupuncture alleviates orofacial allodynia and anxiety-like behaviors by regulating synaptic plasticity of the CA1 hippocampal region in a mouse model of trigeminal neuralgia

“…Studies have demonstrated that EA has an analgesic effect on chronic pain and can modulate mood changes and cognitive dysfunction through central and peripheral mechanisms ( Han, 2011 ; Chen et al, 2022 ; Zhou et al, 2022 ). In this study, EA had immediate alleviating effects on mechanical allodynia on postoperative day 7, and repeated EA alleviated the pT-ION-induced allodynia and anxiety-like behaviors on day 21 after nerve injury.…”

Electroacupuncture attenuates neuropathic pain via suppressing BIP-IRE-1α-mediated endoplasmic reticulum stress in the anterior cingulate cortex

“…Previous studies have confirmed that the mechanisms underlying the analgesic effect of EA are via the regulation of opioids, norepinephrine, or cholinergic activity in subcortical structures such as the spinal cord, periaqueductal gray matter, and hypothalamus pre-optic area [ 16 , 40 – 42 ]. However, whether the cerebral cortex is involved in the antihyperalgesic effects of EA remains unclear.…”

Global Trends and Hotspots on Microglia Associated with Pain from 2002 to 2022: A Bibliometric Analysis

“… 74 Recent research found that neuron GRK2 can specifically mediate the inhibitory effect of acupuncture on microglia activation and contribute to the analgesia of neuropathic pain 75 and inflammatory pain. 76 …”