A top-down neural circuit for affective-motivational responses of pain relief induced by electroacupuncture.

BACKGROUND: Peripheral neuromodulation, which can be considered as a flow of signals from the body to the brain, influences mental and psychological states. However, whether peripheral neuromodulation, particularly electroacupuncture (EA), may regulate specific neural circuits and evoke affective‒motivational responses remains elusive. Here, we investigate the affective-motivational responses of pain relief following the application of EA in human and animal models in the context of pain. METHODS: The conditioned place preference (CPP), open field test and elevated plus maze tests were used to examine the affective‒motivational responses of pain relief induced by EA in different animal models of pain. EA at acupoint ST36 (2 Hz) was administered. Multi‒electrode array recording, optogenetics, retrograde neuronal tracing, chemogenetics and immunohistochemistry were used to explore the neural circuit mechanisms involved. rAAV virus were used to identify the target projection neurons. A battery of self-report questionnaire was used to assess affective‒motivational responses after EA in patients with chronic low back pain. RESULTS: EA analgesia induced CPP only in pain states in different animal models of pain. Chronic pain induced negative affective valence of pain. EA attenuated anxious- or depressive-like behaviors in spared nerve injury (SNI) rats. EA robustly activated glutamatergic neurons in the infralimbic cortex (IL) in a pain-dependent manner. The optogenetic activation of IL glutamatergic (IL(Glu)) neurons mimicked EA-induced analgesia and CPP whereas their inhibition reversed the effects promoted by EA. Furthermore, the IL-nucleus accumbens (NAc) shell pathway was activated by EA in SNI rats. Inhibition of IL(Glu) to the NAc shell reversed EA-induced analgesia, CPP and anxiolytic-like behaviors. In addition, we identified that activation of IL(Glu) to nucleus accumbens shell(GABA) projection is necessary for EA induced analgesia, CPP and anxiolytic-like behaviors. CONCLUSIONS: These results illustrate an example in which the emotional dimension of pain is directly influenced through the peripheral neuromodulation and provide the basis for the use of EA to target top down neural circuits to relieve chronic pain in psychological and clinical situations. TRIAL REGISTRATION: ChiCTR1800020029.