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IMT504 provides analgesia by modulating cell infiltrate and cytokine milieu in rats with hindpaw inflammation

Candelaria Leiguarda

  • Derqui,
  • Argentina
  • Candelaria Leiguarda ¹
  • , Constanza Potilinski ¹
  • , Julia Rubione ¹
  • , Pablo Tate ¹
  • , Marcelo J Villar ¹
  • , Alejandro Montaner ²
  • , Veronica Bisagno ³
  • , Luis Constandil ⁴
  • 1 Instituto de Investigaciones en Medicina Traslacional (IIMT), Universidad Austral-CONICET, 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, Buenos Aires, Argentina
  • 4 Departamento de Biología, Laboratorio de Neurobiología, Facultad de Química y Biología, Universidad de Santiago de Chile, Santiago, Chile.

IMT504 is a non-CPG, non-coding synthetic ODN exerting long-lasting anti-allodynic effects in rats undergoing unilateral hindpaw inflammation. The purpose of the present study is to address cellular and molecular mechanisms at the site of injury potentially underlying the anti-nociceptive role of IMT504. Analysis of pain-like behavior, locomotor activity, histology, cell infiltration by flow-cytometry, secreted proteins by protein microarrays or ELISA (β-endorphins) in the inflamed hindpaws were employed to study the impact of a single subcutaneous administration of IMT504 in male adult rats undergoing complete Freund´s adjuvant-induced hindpaw inflammation. We show that a single subcutaneous dose of IMT504 results in a 6-week-long full reversal of mechanical and cold allodynia, compromising neither acute pain perception nor locomotor activity. The anti-nociceptive effects of systemic IMT504 correlated with reductions in hindpaw dorsoventral thickness, plasma extravasation, decreases in B-cell and macrophage counts, and an increase in CD8+ T-cell counts. Moreover, a profound downregulation in several pro-inflammatory cytokines as well as of β-endorphin, plus mild upregulation of IL-10, were also observed at the site of injury. Altogether, we provide new evidence demonstrating that the anti-nociceptive actions of IMT504 relate to modulation of the peripheral immune system at the site of injury, and support its use as a novel anti-inflammatory drug against chronic pain.