Electrical stimulation of the auricular branch of the vagus nerve potentiates analgesia induced by physical exercise in mice with peripheral inflammation.

Objective: This study evaluated the antihyperalgesic and anti-inflammatory effects of percutaneous vagus nerve electrical stimulation (pVNS) associated with physical exercise, i.e., swimming, in mice with peripheral inflammation. Methods: The pain model was induced by intraplantar (i.pl.) injection of Freund's complete adjuvant (CFA). Sixty-four male Swiss mice (35-40 g) received an i.pl. of CFA and underwent behavioral tests, i.e., mechanical hyperalgesia, edema, and paw temperature tests. Additionally, cytokine levels, specifically interleukin-6 (IL-6) and interleukin-10 (IL-10), were determined by enzyme-linked immunosorbent assay. Mice were treated with swimming exercise for 30 min alone or associated with different time protocols (10, 20, or 30 min) of stimulation in the left ear with random frequency during four consecutive days. Results: pVNS for 20 min prolonged the antihyperalgesic effect for up to 2 h, 24 h after CFA injection. pVNS for 30 min prolonged the antihyperalgesic effect for up to 7 h, 96 h after CFA injection. However, it did not alter the edema or temperature at both analyzed times (24 and 96 h). Furthermore, the combination of pVNS plus swimming exercise, but not swimming exercise alone, reduced IL-6 levels in the paw and spinal cord, as well as IL-10 levels in the spinal cord. Conclusion: pVNS potentiates the analgesic effect induced by swimming, which may be, at least in part, mediated by the modulation of inflammatory cytokines in the periphery (paw) and central nervous system (spinal cord). Therefore, the combination of these therapies may serve as an important adjunctive treatment for persistent inflammatory pain.

Electrical Stimulation of the Auricular Branch Vagus Nerve Using Random and Alternating Frequencies Triggers a Rapid Onset and Pronounced Antihyperalgesia via Peripheral Annexin A1-Formyl Peptide Receptor 2/ALX Pathway in a Mouse Model of Persistent Inflammatory Pain.

This study evaluated the antihyperalgesic and anti-inflammatory effects of percutaneous vagus nerve electrical stimulation (pVNS) by comparing the effects of alternating and random frequencies in an animal model of persistent inflammatory hyperalgesia. The model was induced by Freund's complete adjuvant (CFA) intraplantar (i.pl.) injection. Mice were treated with different protocols of time (10, 20, or 30 min), ear laterality (right, left or both), and frequency (alternating or random). Mechanical hyperalgesia was evaluated, and some groups received i.pl. WRW4 (FPR2/ALX antagonist) to determine the involvement. Edema, paw surface temperature, and spontaneous locomotor activity were evaluated. Interleukin-1ß, IL-6, IL-10, and IL4 levels were verified by enzyme-linked immunosorbent assay. AnxA1, FPR2/ALX, neutrophil, M1 and M2 phenotype macrophage, and apoptotic cells markers were identified using western blotting. The antihyperalgesic effect pVNS with alternating and random frequency effect is depending on the type of frequency, time, and ear treated. The pVNS random frequency in the left ear for 10 min had a longer lasting antihyperalgesic effect, superior to classical stimulation using alternating frequency and the FPR2/ALX receptor was involved in this effect. There was a reduction in the levels of pro-inflammatory cytokines and an increase in the immunocontent of AnxA1 and CD86 in mice paw. pVNS with a random frequency in the left ear for 10 min showed to be optimal for inducing an antihyperalgesic effect. Thus, the random frequency was more effective than the alternating frequency. Therefore, pVNS may be an important adjunctive treatment for persistent inflammatory pain.

Sex differences in comorbidities associated with Sjögren's disease.

Background: Little is known about the association of comorbidities with sex and age at diagnosis in Sjögren's disease. We tested the hypothesis that sex differences occur in comorbidities in patients with Sjögren's disease. Methods: Patients with Sjögren's disease were identified from 11/1974 to 7/2018 in the Mayo Clinic electronic medical record and assessed for 22 comorbidities according to sex and age at diagnosis. Results: Of the 13,849 patients identified with Sjögren's disease, 11,969 (86%) were women and 1,880 (14%) men, primarily white (88%) with a sex ratio of 6.4:1 women to men. The mean age at diagnosis was 57 years for women and 59.7 years for men, and 5.6% had a diagnosis of fibromyalgia at Sjögren's diagnosis. Men with Sjögren's disease were more likely than women to be a current or past smoker. The average time to diagnosis of comorbidities after diagnosis of Sjögren's disease was 2.6 years. The top comorbidities in patients with Sjögren's disease were fibromyalgia (25%), depression (21.2%) and pain (16.4%). Comorbidities that occurred more often in women were hypermobile syndromes (31:1), CREST (29:1), migraine (23:1), Ehlers-Danlos syndrome (EDS) (22:1), Raynaud's syndrome (15:1), SLE (13:1), systemic sclerosis (SSc) (13:1), and fibromyalgia (12:1). Women with Sjögren's disease were at increased risk of developing hypermobile syndromes (RR 7.27, CI 1.00-52.71, p = 0.05), EDS (RR 4.43, CI 1.08-18.14, p = 0.039), CREST (RR 4.24, CI 1.56-11.50, p = 0.005), migraine (RR 3.67, CI 2.39-5.62, p < 0.001), fibromyalgia (RR 2.26, CI 1.92-2.66, p < 0.001), Raynaud's syndrome (RR 2.29, CI 1.77-2.96, p < 0.001), SLE (RR 2.13, CI 1.64-2.76, p < 0.001), and SSc (RR 2.05 CI 1.44-2.92; p < 0.001). In contrast, men with Sjögren's were at increased risk for developing myocardial infarction (RR 0.44, CI 0.35-0.55, p < 0.001), atherosclerosis/CAD (RR 0.44, CI 0.39-0.49, p < 0.001), cardiomyopathy (RR 0.63, CI 0.46-0.86, p = 0.003), stroke (RR 0.66 CI 0.51-0.85, p = 0.001), and congestive heart failure (RR 0.70, CI 0.57-0.85, p < 0.001). Conclusions: The top comorbidities in Sjögren's disease were fibromyalgia, depression, and pain. Women with Sjögren's disease had a higher relative risk of developing fibromyalgia, depression, pain, migraine, hypermobile syndrome, EDS and other rheumatic autoimmune diseases. Men with Sjögren's disease had higher risk of developing cardiovascular diseases.

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.

Immunoregulatory Effect of Preventive Supplementation of Omega-3 Fatty Acid in a Complex Regional Pain Syndrome Type I Model in Mice.

Objective: Complex regional pain syndrome (CRPS) is usually triggered by trauma or a surgical procedure, and it typically becomes an established one after an intense inflammatory process with chronic pain and edema as the main symptoms. Available treatments for CRPS have low efficacy. This study aimed to evaluate the clinical and immunoregulatory effects of omega-3 polyunsaturated fatty acid (PUFA) supplementation on paw edema and anti- and pro-inflammatory cytokines and macrophage phenotypes in the chronic post-ischemia pain (CPIP) preclinical model of CRPS-Type I. Methods: Female Swiss mice were supplemented with omega-3, corn oil, or saline and then submitted to the CPIP model of ischemia/reperfusion (I/R) injury. Supplementation was carried out for 30 days prior to and up to 2 or 15 days after the induction of CPIP, according to experimental protocols. The supplementation protocol included 1,500 mg/kg of omega-3 or corn oil through an intragastric route (gavage). Paw edema, interleukin- (IL-) 4, IL-10, transforming growth factor-ß1 (TGF-ß1), monocyte chemotactic protein-1 (MCP-1), and tumor necrosis factor (TNF) were then measured in the paw skin and muscle by enzyme-linked immunosorbent assay (ELISA), and macrophage phenotypes (M1 and M2) assessed in the paw muscle by Western blotting. Results: The CPIP model induced an increase in paw thickness up to 72 h post-I/R. Mice supplemented with omega-3 compared to the saline group displayed reduced edema but neither altered skin IL-4 or skin and muscle TGF-ß1, TNF, and MCP-1 concentrations, nor did they exhibit significantly altered muscle macrophage phenotype on the 2nd-day post-CPIP. However, omega-3 supplementation reversed the I/R-related reduction in IL-4 in the paw muscle compared to groups supplemented with saline and corn oil. Furthermore, omega-3 promoted the reduction of IL-10 levels in the paw skin, compared to animals with lesions supplemented with saline, until the 2nd-day post-CPIP. On the 15th day post-CPIP, IL-10 was significantly increased in the muscle of animals supplemented with omega-3 compared to the saline group. Conclusion: The results suggest that omega-3 PUFA supplementation has anti-inflammatory effects in the CPIP model of CRPS-Type I, significantly reducing paw edema and regulating concentrations of anti-inflammatory cytokines, including IL-4 and IL-10.

The role of the vagus nerve in fibromyalgia syndrome.

Fibromyalgia (FM) syndrome is a common illness characterized by chronic widespread pain, sleep problems, fatigue, and cognitive difficulties. Dysfunctional neurotransmitter systems that influence the body's endogenous stress response systems are thought to underlie many of the major FM-related symptoms. A model of FM pathogenesis suggests biological and psychosocial variables interact to influence the genetic predisposition, but the precise mechanisms remain unclear. The Polyvagal Theory provides a theoretical framework from which to investigate potential biological mechanisms. The vagus nerve (VN) has anti-inflammatory properties via its afferent and efferent fibers. A low vagal tone (as assessed by low heart rate variability), has been observed in painful and inflammatory diseases, including FM, while the ventral branch of the VN is linked to emotional expression and social engagement. These anti-inflammatory and psychological (limbic system) properties of the VN may possess therapeutic potential in treating FM. This review paper summarizes the scientific literature regarding the potential role of the VN in transducing and/or therapeutically managing FM signs and symptoms.

Decrease of IL-1ß and TNF in the Spinal Cord Mediates Analgesia Produced by Ankle Joint Mobilization in Complete Freund Adjuvant-Induced Inflammation Mice Model.

OBJECTIVE: This study aims to investigate the effects of ankle joint mobilization (AJM) on mechanical hyperalgesia and peripheral and central inflammatory biomarkers after intraplantar (i.pl.) Complete Freund's Adjuvant (CFA)-induced inflammation. METHODS: Male Swiss mice were randomly assigned to 3 groups (n = 7): Saline/Sham, CFA/Sham, and CFA/AJM. Five AJM sessions were carried out at 6, 24, 48, 72, and 96 h after CFA injection. von Frey test was used to assess mechanical hyperalgesia. Tissues from paw skin, paw muscle and spinal cord were collected to measure pro-inflammatory (TNF, IL-1ß) and anti-inflammatory cytokines (IL-4, IL-10, and TGF-ß1) by ELISA. The macrophage phenotype at the inflammation site was evaluated by Western blotting assay using the Nitric Oxide Synthase 2 (NOS 2) and Arginase-1 immunocontent to identify M1 and M2 macrophages, respectively. RESULTS: Our results confirm a consistent analgesic effect of AJM following the second treatment session. AJM did not change cytokines levels at the inflammatory site, although it promoted a reduction in M2 macrophages. Also, there was a reduction in the levels of pro-inflammatory cytokines IL-1ß and TNF in the spinal cord. CONCLUSION: Taken together, the results confirm the anti-hyperalgesic effect of AJM and suggest a central neuroimmunomodulatory effect in a model of persistent inflammation targeting the pro-inflammatory cytokines IL-1ß and TNF.