Toll-like receptors (TLRs) are mediators of the innate immune response to exogenous pathogens. They have also been implicated in sterile
inflammation associated with systemic injury and
non-infectious diseases via binding of endogenous
ligands, possibly released by damaged cells. Emerging evidence indicates that some TLRs play a role in
nervous system injury and especially in injury-elicited
pain and sterile
inflammation. However, no information is available about the contribution of TLR9, a member of the TLR family, to traumatic
spinal cord injury (SCI). Moreover, the therapeutic potential of TLR9
ligands in the functional outcomes of SCI, including
pain, has not been explored. We report, for the first time, that the intrathecal administration of a TLR9 antagonist,
cytidine-
phosphate-
guanosine oligodeoxynucleotide 2088 (
CpG ODN 2088), to mice sustaining a severe
contusion SCI, diminishes injury-induced heat
hypersensitivity. Investigations on the potential mechanisms underlying the reduction in
pain sensitivity indicated an attenuation of the inflammatory reaction manifested by a decrease in the number of CD11b-, CD45- and CD3-immunoreactive cells and a reduction in
tumor necrosis factor-α (TNF-α) expression at the epicenter. Conversely, intrathecal delivery of a TLR9 agonist,
CpG ODN 1826, increased inflammatory cell numbers and TNF-α expression in the epicenter. The
CpG ODN 2088 treatment did not appear to induce systemic adverse effects as shown by spleen histology and serum
cytokine levels. We propose that
CpG ODN 2088 dampens injury-induced heat
hypersensitivity by suppressing the inflammatory response and TNF-α expression. This investigation defines a previously unreported therapeutic role for
CpG ODN 2088 in SCI-induced
pain.