IMT504 Provides Analgesia by Modulating Cell Infiltrate and Inflammatory Milieu in a Chronic Pain Model
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ORIGINAL ARTICLE
IMT504 Provides Analgesia by Modulating Cell Infiltrate and Inflammatory Milieu in a Chronic Pain Model Candelaria Leiguarda 1 & Constanza Potilinski 1 & Julia Rubione 1 & Pablo Tate 1 & Marcelo J. Villar 1 & Alejandro Montaner 2 & Verónica Bisagno 3 & Luis Constandil 4 & Pablo R. Brumovsky 1 Received: 2 September 2020 / Accepted: 11 November 2020 # Springer Science+Business Media, LLC, part of Springer Nature 2020
Abstract IMT504 is a non-CPG, non-coding synthetic oligodeoxinucleotide (ODN) with immunomodulatory properties and a novel inhibitory role in pain transmission, exerting long-lasting analgesic effects upon multiple systemic administrations. However, its mechanisms of anti-nociceptive action are still poorly understood. In the present study in male adult rats undergoing complete Freund’s adjuvant-induced hindpaw inflammation, we focused in the analysis of the immunomodulatory role of IMT504 over the cellular infiltrate, the impact on the inflammatory milieu, and the correlation with its anti-allodynic role. By means of behavioral analysis, we determined that a single subcutaneous administration of 6 mg/kg of IMT504 is sufficient to exert a 6-week-long full reversal of mechanical and cold allodynia, compromising neither acute pain perception nor locomotor activity. Importantly, we found that the anti-nociceptive effects of systemic IMT504, plus quick reductions in hindpaw edema, were associated with a modulatory action upon cellular infiltrate of B-cells, macrophages and CD8+ T-cells populations. Accordingly, we observed a profound downregulation of several inflammatory leukocyte adhesion proteins, chemokines and cytokines, as well as of βendorphin and an increase in the anti-inflammatory cytokine, interleukin-10. Altogether, we demonstrate that at least part of the anti-nociceptive actions of IMT504 relate to the modulation of the peripheral immune system at the site of injury, favoring a switch from pro- to anti-inflammatory conditions, and provide further support to its use against chronic inflammatory pain. Keywords Complete Freund’s adjuvant (CFA) . Cytokines . IMT504 . Lymphocytes . Oligonucleotide . Pain
Introduction Pain due to peripheral inflammation naturally depends on nociceptors activation. Nociceptors respond to a variety of stimuli, including pathogen-associated molecular patterns detected after barrier interface breaching, damage-associated molecular patterns resulting from tissue injury-dependent cell
* Pablo R. Brumovsky [email protected] 1
Instituto de Investigaciones en Medicina Traslacional (IIMT), CONICET-Universidad Austral, Av. Juan D. Perón 1500 B1629AHJ, Pilar, Buenos Aires, Argentina
2
Instituto de Ciencia y Tecnología “Dr. César Milstein”, CONICET-Fundación Pablo Cassará, Buenos Aires, Argentina
3
Instituto de Investigaciones Farmacológicas, CONICET-Universidad de Buenos Aires, Buenos Aires, Argentina
4
Laboratorio de Neurobiología, Facultad de Química y Biología, Universidad de Santiago de Chile, Santiago, Chile
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