Abstract
Comorbidity of chronic pain and major depression disorder (MDD) are common diseases. However, the mechanisms of electroacupuncture (EA) and the responses of N-methyl-D-aspartate receptors in the brain remain unclear. Three injections of complete Freund's adjuvant (CFA) were administered to induce chronic inflammatory pain (CIP). EA was then performed once every other day from days 14 to 28. Behavior tests of chronic pain and depression were evaluated to make sure of the successful induction of comorbidity. We used Western blotting to analyze brain tissue from the prefrontal cortex (PFC), hippocampus, and hypothalamus for levels of phosphorylated N-methyl-D-aspartate receptor subunit 1 (pNR1), NR1, pNR2B, NR2B, and calcium/calmodulin-dependent protein kinase type II alpha isoform (pCaMKIIα). The mechanical hyperalgesia, thermal hyperalgesia, and depression were observed in the CIP group. Furthermore, decreased levels of N-methyl-D-aspartate receptors (NMDARs) were also noted. Not Sham EA but EA reversed chronic pain and depression as well as the decreased levels of NMDA in the signaling pathway. The CFA injections successfully induced a significant comorbidity model. EA treated the comorbidity by upregulating the NMDA signaling pathway in the PFC, hippocampus, and hypothalamus. Our results indicated significant mechanisms of comorbidity of chronic pain and MDD and EA-analgesia that involves the regulation of the NMDAR signaling pathway. These findings may be relevant to the evaluation and treatment of comorbidity of chronic pain and MDD.
Highlights
Chronic pain and major depression disorder are common diseases among medical outpatients [1, 2]
To further uncover the mechanisms linking EA, comorbidity, and N-methyl-D-aspartate receptors (NMDARs), we established a chronic pain and depression comorbidity model and used EA as the intervention. is study improves our understanding of how acupuncture treats comorbidities, using findings obtained through behavioral observation and the measurement of biomarkers in different brain cores
A total of 4 subjects, from the Con, chronic inflammatory pain (CIP), EA, and sham EA groups, were anesthetized using 1% isoflurane through inhalation and intracardially perfused with saline followed by 4% paraformaldehyde. e brain was immediately dissected and postfixed with 4% paraformaldehyde at 4°C overnight. e postfixed tissues were placed overnight in 30% sucrose for cryoprotection at 4°C. e brain was embedded in OCT and instantaneously frozen using liquid nitrogen prior to storage at −80°C. e coronal sections containing the medial prefrontal cortex (PFC), hippocampal CA1, and hypothalamus were cut into 16 μm thick slices through cryosectioning. e samples were incubated with blocking solution, which consisted of 3% bovine serum albumin (BSA), 0.1% Triton X-100, and 0.02% sodium azide, for 2 h at room temperature
Summary
Chronic pain and major depression disorder are common diseases among medical outpatients [1, 2]. One study indicated that patients with chronic pain had a significantly higher chance of developing depression (30%–54%) than the general population (5%–8%) [6]. Another study showed that patients with MDD had a different prevalence and intensity of pain compared to healthy controls [8]. MDD and pain share biological pathways and neurotransmitters, which suggests that simultaneous treatment of both conditions may be effective [9]. Our previous animal model studies have illustrated the therapeutic effects of EA against inflammatory pain via neuronal and nonneuronal pathways [10, 11]. By blocking the NMDAR-dependent burst firing of lateral habenula, Ketamine could reverse the suppression of reward center and caused rapid antidepressant effects. To further uncover the mechanisms linking EA, comorbidity, and NMDARs, we established a chronic pain and depression comorbidity model and used EA as the intervention. is study improves our understanding of how acupuncture treats comorbidities, using findings obtained through behavioral observation and the measurement of biomarkers in different brain cores
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