Inflammatory
pain associates with spinal glial activation and central sensitization. Systemic administration of
IMT504, a non-CpG
oligodeoxynucleotide originally designed as an
immunomodulator, exerts remarkable anti-allodynic effects in rats with complete Freund´s adjuvant (CFA)-induced hindpaw
inflammation. However, the anti-nociceptive mechanisms of
IMT504 remain unknown. Here we evaluated whether
IMT504 blocks inflammatory
pain-like behavior by modulation of spinal glia and central sensitization. The study was performed in Sprague Dawley rats with intraplantar CFA, and a single lumbosacral intrathecal (i.t.) administration of
IMT504 or vehicle was chosen to address if changes in glial activation and spinal sensitization relate to the
pain-like behavior reducing effects of the ODN. Naïve rats were also included. Von Frey and Randall-Selitto tests, respectively, exposed significant reductions in
allodynia and mechanical
hypersensitivity, lasting at least 24 h after i.t.
IMT504. Analysis of electromyographic responses to electrical stimulation of C fibers showed progressive reductions in wind-up responses. Accordingly,
IMT504 significantly downregulated spinal glial activation, as shown by reductions in the
protein expression of
glial fibrillary acidic protein, CD11b/c,
Toll-like receptor 4 (TLR4) and the phosphorylated p65 subunit of NFκB, evaluated by immunohistochemistry and western blot. In vitro experiments using early post-natal cortical glial cultures provided further support to in vivo data and demonstrated
IMT504 internalization into microglia and astrocytes. Altogether, our study provides new evidence on the central mechanisms of anti-nociception by
IMT504 upon intrathecal application, and further supports its value as a novel anti-inflammatory ODN with actions upon glial cells and the TLR4/NFκB pathway. Intrathecal administration of the non-
CpG ODN IMT504 fully blocks CFA-induced
mechanical allodynia and
hypersensitivity, in association with reduced spinal sensitization. Administration of the ODN also results in downregulated
gliosis and reduced TLR4-NF-κB pathway activation.
IMT504 uptake into astrocytes and microglia support the concept of direct modulation of CFA-induced glial activation.