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Effect of Electro-Acupuncture at ST36 and SP6 on the cAMP -CREB Pathway and mRNA Expression Profile in the Brainstem of Morphine Tolerant Mice.

ABSTRACT: Undoubtedly, opioid drugs have been the most popular treatment for refractory pain since found, such as morphine. However, tolerance to the analgesic effects caused by repeated use is inevitable, which greatly limits the clinical application of these drugs. Nowadays, it has become the focus of the world that further development of non-opioid-based treatment along with efficient strategies to circumvent opioid tolerance are urgently needed clinically. Fortunately, electro-acupuncture (EA) provides an alternative to pharmaceutic treatment, remaining its potential mechanisms unclear although. This study was aimed to observe the effects of EA on morphine-induced tolerance in mice and discover its underlying mechanism. Tail-flick assay and hot-plate test were conducted to assess the development of tolerance to morphine-induced analgesia effect. As a result of repeated administration scheme (10 mg/kg, twice per day, for 7 days), approximately a two-fold increase was observed in the effective dose of 50% (ED50) of morphine-induced antinociceptive effect. Interestingly, by EA treatment (2/100Hz, 0.5, 1.0, and 1.5 mA, 30 min/day for 7 days) at the acupoints Zusanli (ST36) and Sanyinjiao (SP6), morphine ED50 curves was remarkably leftward shifted on day 8. In addition, the RNA sequencing strategy was used to reveal the potential mechanisms. Due to the well described relevance of cyclic adenosine monophosphate (cAMP), protein kinase A (PKA), extracellular regulated protein kinases (ERK), and cAMP response element-binding (CREB) in brainstem (BS) to analgesia tolerance, the cAMP-PKA/ERK-CREB signaling was deeply concerned in this study. Based upon Enzyme-Linked Immunosorbent Assay, the up-regulation of the cAMP level was observed, whereas reversed with EA treatment. Similarly, western blot revealed the phosphorylation levels of PKA, ERK, and CREB were up-regulated in morphine tolerant mice, whereas the EA group showed a significantly reduced expression level instead. This study observed an attenuating effect of the EA at ST36 and SP6 on morphine tolerance in mice, and suggested several potential biological targets by RNA-seq, which include the cAMP-PKA/ERK-CREB signaling pathway, strongly supporting a useful treatment for combatting the opioid epidemic, and opioid-tolerant patients.

SUBMITTER: Wang Q

PROVIDER: S-EPMC8431970 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Background Acupuncture is one of the most popular complementary and alternative treatments for knee osteoarthritis (KOA). There are many methods of acupuncture in the treatment of KOA, and the effects are different. According to our clinical observations and researches, it is found that manual acupuncture (MA), electro-acupuncture (EA), and warm acupuncture (WA) are used more frequently in the treatment of KOA, and the curative effects are satisfactory. However, there is currently a lack of efficacy comparison of efficacy between different acupuncture treatments, as well as a lack of standardized clinical research on the acupuncture treatment of KOA. Therefore, we will carry out a high-quality clinical randomized controlled trial to research the effect laws of MA, EA, and WA on KOA. Methods/design A total of 200 eligible participants with KOA will be randomly assigned to group A, B, C, or D in a ratio of 1:1:1:1. Patients in group A will receive MA, while those in group B, group C, and group D will be treated with EA, WA, and sham acupuncture (SA), respectively. Patients will be treated with acupuncture once a day, 30 min per session, 5 sessions per week for 4 weeks. The primary outcome is the change of Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) at week 4. The secondary outcomes include WOMAC, visual analog scale (VAS), Arthritis Quality of Life Measurement Scale Simplified Scale (AIMS2-SF), Beck Anxiety Inventory (BAI), Beck Depression Inventory (BDI), and Credibility/Expectancy Questionnaire. The evaluation will be performed at baseline and weeks 4, 8, and 12 respectively after randomization. Discussion This is a randomized controlled trial. We will observe the clinical effect of MA, EA, and WA on KOA to research the effect laws of these three acupuncture treatments on KOA and set up standardized treatment programs for acupuncture for KOA. Trial registration China Clinical Trials Registry ChiCTR2100049526. Registered on August 2, 2021 Supplementary Information The online version contains supplementary material available at 10.1186/s13063-022-06653-7.

Project description:BackgroundInflammation plays a significant role in the pathogenesis of knee osteoarthritis (KOA). Although both electro-acupuncture (EA) and manual acupuncture (MA) are known to influence systemic inflammation, little is known about the potential changes in inflammation as a working mechanism of EA and MA in KOA.MethodsData from the Acupuncture for Knee Osteoarthritis Trial (ATKOA) were used. Serum concentrations of inflammatory factors (tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), IL-6, IL-8, IL-18, IL-4, IL-10, IL-13, IL-15, IL-17, monocyte chemotactic protein-1 (MCP-1), CC-chemokine ligand 5 (CCL5), and cartilage degradation biomarkers (matrix metalloproteinase-1 MMP-1, MMP-3, MMP-13 and cartilage oligomeric matrix protein COMP)) were measured at baseline and after 8 weeks of treatment. Clinical outcomes were valid and reliable self-reported pain and function measures for osteoarthritis using the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) and visual analogue scale (VAS) at baseline and post-treatment.ResultsBoth 8-weeks EA and MA significantly reduced pro-inflammatory cytokines (TNFα, IL-1β), and cartilage degradation biomarkers (MMP-3, MMP-13) significantly increased the anti-inflammatory cytokine IL-13 compared with pre-treatment (p<0.05). Further, the reduction of TNF-α was more significant in EA when compared to MA (p=0.046). While there was no significant difference between groups in cytokines IL-1β (p=0.102), MMP-3 (p=0.113), MMP-13 (p=0.623) or IL-13 (p=0.935). Moreover, in both EA and MA, the effect of acupuncture on the VAS and WOMAC function scale after 8 weeks is clinically important, although no significant differences were found between groups.ConclusionEight weeks of both EA and MA seem to provide improvement in pain relief and function among individuals with mild to moderate knee OA. This benefit is partly mediated by changes of major inflammatory factors TNF-α, IL-1β and IL-13.Trial registrationControlled-Trials.com Identifier: NCT03274713.

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Effect of Electro-Acupuncture at ST36 and SP6 on the cAMP -CREB Pathway and mRNA Expression Profile in the Brainstem of Morphine Tolerant Mice.

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