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

Carlos Minoru Omura; Daniela Dero Lüdtke; Verônica Vargas Horewicz; Paula Franson Fernandes; Taynah de Oliveira Galassi; Afonso Shiguemi Inoue Salgado; Juliete Palandi; Heloiza Dos Santos Baldança; Edsel B Bittencourt; Josiel Mileno Mack; Lynsey A Seim; Daniel Fernandes Martins; Franciane Bobinski

doi:10.3389/fphys.2021.816624

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

Front Physiol. 2022 Jan 14:12:816624. doi: 10.3389/fphys.2021.816624. eCollection 2021.

Authors

Carlos Minoru Omura¹, Daniela Dero Lüdtke^{1

2}, Verônica Vargas Horewicz¹, Paula Franson Fernandes¹, Taynah de Oliveira Galassi¹, Afonso Shiguemi Inoue Salgado³, Juliete Palandi^{1

4}, Heloiza Dos Santos Baldança^{1

2}, Edsel B Bittencourt⁵, Josiel Mileno Mack^{1

6

7}, Lynsey A Seim⁸, Daniel Fernandes Martins¹, Franciane Bobinski¹

Affiliations

¹ Experimental Neuroscience Laboratory (LaNEx), Graduate Program in Health Sciences, University of Southern Santa Catarina, Palhoça, Brazil.
² Faculty of Physical Therapy, University of Southern Santa Catarina, Palhoça, Brazil.
³ Natural Quanta Wellness Center, Windermere, FL, United States.
⁴ Laboratory of Experimentation in Neuropathology (LEN), Graduate Program in Neuroscience, Department of Biochemistry, Federal University of Santa Catarina, Florianopolis, Brazil.
⁵ Coastal Health Institute, Jacksonville, FL, United States.
⁶ Graduate Program in Medical Sciences, Department of Medical Clinic, Federal University of Santa Catarina (UFSC), Florianopolis, Brazil.
⁷ Faculty of Medicine, University of Southern Santa Catarina, Palhoça, Brazil.
⁸ Department of Hospital Internal Medicine, Mayo Clinic, Jacksonville, FL, United States.

Abstract

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-1β) and anti-inflammatory cytokines (IL-4, IL-10, and TGF-β1) 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-1β 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-1β and TNF.

Keywords: inflammatory cytokines; joint mobilization; macrophages; manual therapy; neuroimmunomodulation.