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IMT504 Provides Analgesia by Modulating Cell Infiltrate and Inflammatory Milieu in a Chronic Pain Model

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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 β-endorphin 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.

GA short description - IMT504 systemic Administration. Systemic administration of the non-CpG ODN IMT504 results in a 6-week long blockade of pain-like behavior in association with anti-inflammatory responses at the site of injury. These include modulation of lymphoid and myeloid populations plus downregulated expression levels of multiple pro-inflammatory cytokines and β-endorphin. Nocifensive responses and locomotion remain unaltered.

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Acknowledgements

We would like to thank Mrs. Gabriela Periz, Mr. Guillermo Gastón, Mr. Franco Puebla and Mr. Santiago Cabrera, for animal care and manipulation.

Funding

This work was supported by Argentinean National Agency for the Promotion of Science and Technology (PICTO-Startup 2016–0091 and PICT 2017–0969 (PRB)), Austral University (grant n° 80020160200010UA01, CL), International Brain Research Organization (IBRO, CL), Fondecyt (grant n°1181622) and CEDENNA AFB180001 Projects (LC).

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All authors state to have discussed the results and commented on the manuscript. Candelaria Leiguarda and Drs. Luis Constandil, Alejandro Montaner, Marcelo J. Villar and Pablo R. Brumovsky discussed and designed the project. Candelaria Leiguarda performed most experimental and analytical work, in collaboration with Drs. Constanza Potiliski (molecular array), Julia Rubione (flow cytometry), Pablo Tate (histology) and Veronica Bisagno (open-field test). The manuscript was written by Candelaria Leiguarda and Pablo Brumovsky, with assistance from all other authors (through discussion of all results and the strategy for its presentation in manuscript format).

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Correspondence to Pablo R. Brumovsky.

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Supplementary Information

Fig. S1

Single s.c. IMT504 results in long-lasting reductions in mechanical allodynia. (A) A single s.c. administration of IMT504 (6 mg/kg; n = 6) blocks mechanical allodynia during 6 full weeks before returning to values comparable to CFA-VEH rats. (B) AUC of data in (A) (P = 0.0006, t = 4.95, df = 10; Hedges’g CFA-VEH: vs CFA-IMT504: 2.86). (PPTX 1.66 mb)

Fig. S2

Flow cytometry gating strategy for the isolation of myeloid and lymphoid populations. Cell surface antibodies were used to identify myeloid and lymphoid populations and subpopulations for B and T cells, T cytotoxic cells, monocytes and macrophages. All samples were first gated on a forward scatter (FS)/ side scatter (SS) plot and selected accordingly. (A) Flow cytometry shows myeloid (CD45+CD11b/c+; line outlines) and lymphoid (CD45+CD11b/c; dotted lines outlines) cells recruitment into the hindpaw after CFA injection and IMT504 treatment. Myeloid cells were selected for their higher complexity and size as compared with lymphocytes at the FS/SS plot. (B) Monocytes were first gated for CD45+CD11b/c+ population and further phenotyped for CD172a+. (C) Macrophages population was selected by gating CD4+CD3 subset and further gating HIS36+ cells. (D) B-cells were gated for CD45+CD45RA+ population while (E) T-cells were then gated for CD45+CD3+ population and further gated for the subset of interest (CD4+CD8 and CD4CD8+). Data was analyzed using FlowJo software. Myeloid and lymphoid population counts are expressed as percentage values, while subpopulations counts are expressed in absolute values. (PPTX 251 kb)

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Leiguarda, C., Potilinski, C., Rubione, J. et al. IMT504 Provides Analgesia by Modulating Cell Infiltrate and Inflammatory Milieu in a Chronic Pain Model. J Neuroimmune Pharmacol 16, 651–666 (2021). https://doi.org/10.1007/s11481-020-09971-2

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  • DOI: https://doi.org/10.1007/s11481-020-09971-2

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