Rostral Anterior Cingulate Cortex–Ventrolateral Periaqueductal Gray Circuit Underlies Electroacupuncture to Alleviate Hyperalgesia but Not Anxiety-Like Behaviors in Mice With Spared Nerve Injury

Abstract

Neuropathic pain is a common cause of chronic pain and is often accompanied by negative emotions, making it complex and difficult to treat. However, the neural circuit mechanisms underlying these symptoms remain unclear. Herein, we present a novel pathway associated with comorbid chronic pain and anxiety. Using chemogenetic methods, we found that activation of glutamatergic projections from the rostral anterior cingulate cortex (rACCGlu) to the ventrolateral periaqueductal gray (vlPAG) induced both hyperalgesia and anxiety-like behaviors in sham mice. Inhibition of the rACCGlu-vlPAG pathway reduced anxiety-like behaviors and hyperalgesia in the spared nerve injury (SNI) mice model; moreover, electroacupuncture (EA) effectively alleviated these symptoms. Investigation of the related mechanisms revealed that the chemogenetic activation of the rACCGlu-vlPAG circuit effectively blocked the analgesic effect of EA in the SNI mice model but did not affect the chronic pain-induced negative emotions. This study revealed a novel pathway, the rACCGlu-vlPAG pathway, that mediates neuropathic pain and pain-induced anxiety.

Electroacupuncture alleviates mechanical allodynia and anxiety‐like behaviors induced by chronic neuropathic pain via regulating rostral anterior cingulate cortex‐dorsal raphe nucleus neural circuit

“…Anxiety‐like behaviors of mice were recorded and analyzed in the elevated plus maze (EPM) test and open‐field test (OFT) 8 . The timeline for anxiety‐like behavioral tests is shown in Figure 1.…”

“…Glutamatergic neurons in the rACC are necessary and sufficient to induce pain‐related negative emotions 5,6 . Our previous studies have demonstrated that glutamatergic neurons in the rACC (rACC Glu ) serve as part of the neural circuitry underlying anxiety‐like behaviors induced by chronic pain 7,8 . We hypothesized that glutamatergic transmission in the rACC might play a crucial role in processing the anxiety‐related aspects of chronic neuropathic pain.…”

Role of nerve signal transduction and neuroimmune crosstalk in mediating the analgesic effects of acupuncture for neuropathic pain

“…In an SNI model, EA at bilateral ST36 and SP6 significantly reduced the expression of Syt-1 in the L1–L2 spinal cord, further inhibited neurotransmitters (such as glutamate) release, mediating analgesic effects of EA ( 27 ). The 2-Hz EA at ST36 and SP6 reduced glutamate in the rostral anterior cingulate cortex (rACC)-ventral lateral periaqueductal gray (vlPAG) loop in SNI mice model and revealed anxiety-like behavior and nociceptive hypersensitivity ( 32 ). In GV20 and GV14 EA in the CCI rat's model, hippocampal glutamate reduction was observed which produced an analgesic effect on NP ( 23 ).…”

Knowledge Mapping of International Research on Acupuncture for Chronic Pain: A Bibliometric Analysis

“… 12–17 Animal and clinical trials related to the mechanism of acupuncture in treating pain have verified the effectiveness of acupuncture for pain. 18–22 More and more insurance companies in different countries or regions have incorporated acupuncture into medical insurance to treat pain and various diseases. 23–31 This also proves that acupuncture is widely accepted worldwide.…”