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Title: 1755 - Microneedles-coated with Tramadol Induces Pain Relief in the Temporomandibular Joint

Authors:

Henrique Abdalla (Presenter)
Piracicaba Dental School, State University of Campinas

Cristina Macedo, São Leopoldo Mandic Institute and Research Cente
Marcelo Napimoga, Sao Leopoldo Mandic Institute and Research Center
Alexandre Hashimoto Pereira Lopes, Ribeirão Preto Medical School, University of Sao Paulo
Alexandre Gomes de Macedo Maganin, Ribeirão Preto Medical School, University of Sao Paulo
Thiago Mattar Cunha, Ribeirão Preto Medical School, University of Sao Paulo
Harvinder Singh Gill, Texas Tech University
Juliana Clemente-Napimoga, São Leopoldo Mandic Institute and Research Cente

Abstract:

Objectives: Tramadol delivery directly in to the temporomandibular joint (TMJ) of rats induces a potential anti-inflammatory effect. The present study tested the hypothesis that in the periarticular tissues, tramadol activates the adenosine-1 receptor to promote an anti-inflammatory effect and that tramadol induces macrophage polarization leading to a resolution process of inflammation. We additionally proposed that instead of painful injections for tramadol delivery, microneedles coated with tramadol can offer a convenient and painless platform to treat pain.

Methods: Male Wistar rats were treated with an intra-TMJ injection of tramadol (90µg/TMJ) or microneedles-coated with tramadol (0, 20, or 30%) followed by 1.5% formalin challenge. The nociceptive behavior was evaluated and then they were euthanized and their periarticular tissues removed for analysis by ELISA and Western Blot methods. In addition, an in vitro assay of BMDM (Bone Marrow Derived Macrophages) was performed to investigate the macrophage polarization induced by tramadol. Macrophages were cultured under LPS or IL-4 conditions, acquiring either M1 or M2 phenotype respectively. The supernatant was collected for analysis by ELISA.

Results: The intra-TMJ injection of tramadol was found to ameliorate inflammatory hypernociception through activation of adenosine-1 receptor located in macrophages in the periarticular tissues by activation of intracellular IL-10/pSTAT3 pathway (p<0.05:ANOVA, Tukey's test). In BMDM cell culture, tramadol significantly decreased the M1 markers while increasing M2 markers. Microneedles-coated with tramadol (30%) replicated the local anti-inflammatory effect induced by intra-TMJ injection of tramadol, and surprisingly, the effect lasted 6 days.

Conclusions: In conclusion, tramadol-induced local anti-inflammatory effect mediated by adenosine-1 receptor located in macrophages M2 by activation of IL-10/pSTAT3 pathway. Microneedles-coated with tramadol can offer a potentially safe, painless and easy to use therapeutic option for pain control of inflammatory disorders in the TMJ.

This abstract is based on research that was funded entirely or partially by an outside source:
This study was supported by grants from Brazilian governmental financial support CAPES (PDSE #88881.133786/2016-01) and CNPq (#169381/2017-0). Texas Tech University internal funds, and by endowment funds of Whitacre Endowed Chair in Science and Engineering (Dr. Harvinder Singh Gill).

Disclosure Statement:
The submitter must disclose the names of the organizations with which any author have a relationship, the nature of the relationship, and the clinical or research area involved. The following is submitted: The author(s) report no conflict of interest.