Peripheral Activation of Formyl Peptide Receptor 2/ALX by Electroacupuncture Alleviates Inflammatory Pain by Increasing Interleukin-10 Levels and Catalase Activity in Mice.

In the context of the electroacupuncture (EA) neurobiological mechanisms, we have previously demonstrated the involvement of formyl peptide receptor 2 (FPR2/ALX) in the antihyperalgesic effect of EA. The present study investigated the involvement of peripheral FPR2/ALX in the antihyperalgesic effect of EA on inflammatory cytokines levels, oxidative stress markers and antioxidant enzymes in an animal model of persistent inflammatory pain. Male Swiss mice underwent intraplantar (i.pl.) injection with complete Freund's adjuvant (CFA). Mechanical hyperalgesia was assessed with von Frey monofilaments. Animals were treated with EA (2/10 Hz, ST36-SP6, 20 minutes) for 4 consecutive days. From the first to the fourth day after CFA injection, animals received i.pl. WRW4 (FPR2/ALX antagonist) or saline before EA. Levels of inflammatory cytokines (TNF, IL-6, IL-4 and IL-10), antioxidant enzymes (catalase and superoxide dismutase), oxidative stress markers (TBARS, protein carbonyl, nitrite/nitrate ratio), and myeloperoxidase activity were measured in paw tissue samples. As previously demonstrated, i.pl. injection of the FPR2/ALX antagonist prevented the antihyperalgesic effect induced by EA. Furthermore, animals treated with EA showed higher levels of IL-10 and catalase activity in the inflamed paw, and these effects were prevented by the antagonist WRW4. EA did not change levels of TNF and IL-6, SOD and MPO activity, and oxidative stress markers. Our work demonstrates that the antihyperalgesic effect of EA on CFA-induced inflammatory pain could be partially associated with higher IL-10 levels and catalase activity, and that these effects may be dependent, at least in part, on the activation of peripheral FPR2/ALX.

Gentle Touch Therapy, Pain Relief and Neuroplasticity at Baseline in Fibromyalgia Syndrome: A Randomized, Multicenter Trial with Six-Month Follow-Up.

BACKGROUND: Fibromyalgia (FM) is considered a stress-related disorder characterized mainly by chronic widespread pain. Its pathogenesis is unknown, but cumulative evidence points at dysfunctional transmitter systems and inflammatory biomarkers that may underlie the major symptoms of the condition. This study aimed to evaluate pain scores (primary outcome), quality of life, inflammatory biomarkers and neurotransmitter systems in women with FM (secondary outcomes) subjected to gentle touch therapy (GTT) or placebo. METHODS: A total of 64 female patients with FM were randomly assigned to two groups, namely GTT (n = 32) or Placebo (n = 32). Clinical assessments were conducted at baseline and post-intervention with six-month follow-up. We measured serum catecholamines (dopamine), indolamines and intermediary metabolites (serotonin or 5-hydroxyindolacetic acid (5-HIAA)), as well as tetrahydrobiopterin (BH4), which is a cofactor for the synthesis of neurotransmitters and inflammatory biomarkers in women with FM. A group of healthy individuals with no intervention (control group) was used to compare biochemical measurements. Intervention effects were analyzed using repeated measures (RM) two-way ANOVA followed by Bonferroni post hoc test and mixed ANCOVA model with intention to treat. RESULTS: Compared to placebo, the GTT group presented lower pain scores and brain-derived neurotrophic factor (BDNF) levels without altering the quality of life of women with FM. Changes in BDNF had a mediating role in pain. Higher baseline serum BDNF and 5-HIAA or those with a history of anxiety disorder showed a higher reduction in pain scores across time. However, women with higher serum dopamine levels at baseline showed a lower effect of the intervention across the observation period revealed by an ANCOVA mixed model. CONCLUSIONS: In conclusion, lower pain scores were observed in the GTT group compared to the placebo group without altering the quality of life in women with FM. Reductions in BDNF levels could be a mechanism of FM pain status improvement. In this sense, the present study encourages the use of these GTT techniques as an integrative and complementary treatment of FM.

Electroacupuncture decreases inflammatory pain through a pro-resolving mechanism involving the peripheral annexin A1-formyl peptide receptor 2/ALX-opioid receptor pathway.

The pro-resolving mechanism is a recently described endogenous process that controls inflammation. The present study evaluated components of this mechanism, including annexin 1 (ANXA1) and the formyl peptide receptor 2/ALX (FPR2/ALX) receptor, in the antihyperalgesic effect induced by electroacupuncture (EA) in an animal model of persistent peripheral inflammation. Male Swiss mice underwent intraplantar (i.pl.) injection with complete Freund's adjuvant (CFA). Mechanical hyperalgesia was assessed with von Frey monofilaments. Animals were treated with EA (2-10 Hz, ST36-SP6) or subcutaneous BML-111 injection (FPR2/ALX agonist) for 5 consecutive days. In a separate set of experiments, on the first and fifth days after CFA injection, animals received i.pl. WRW4 (FPR2/ALX antagonist) or naloxone (non-selective opioid receptor antagonist) before EA or BML-111 injection. Paw protein levels of FPR2/ALX and ANXA1 were evaluated on the second day after CFA injection by western blotting technique. EA and BML-111 reduced mechanical hyperalgesia. I.pl. naloxone or WRW4 prevented the antihyperalgesic effect induced by either EA or BML-111. EA increased ANXA1 but did not alter FPR2/ALX receptor levels in the paw. Furthermore, i.pl. pretreatment with WRW4 prevented the increase of ANXA1 levels induced by EA. This work demonstrates that the EA antihyperalgesic effect on inflammatory pain involves the ANXA1/FPR2/ALX pro-resolution pathway. This effect appears to be triggered by the activation of FPR2/ALX receptors and crosstalk communication with the opioid system.