Neuraxial TNF and IFN-beta co-modulate persistent allodynia in arthritic mice.

ABSTRACT

In rheumatoid arthritis, joint pain can persist despite resolution of swelling. Similarly, in the murine K/BxN serum transfer model, a persistent tactile allodynia is observed after the resolution of joint inflammation (post-inflammatory pain) in male mice. Here, we found female wild type (WT) mice show inflammatory, but reduced post-inflammatory tactile allodynia. The transition to the post-inflammatory phenotype is dependent on TLR4 signaling. At the spinal level, we found differences in TNF and IFNß mRNA expression in WT and TLR4 deficient males. In wild type male and female mice, there is differential temporal spinal expression of TNF and IFNß. In WT males, blockade of TNF or administration of IFNß was insufficient to affect the persistent allodynia. However, co-administration of intrathecal (IT) IFNß and anti-TNF antibodies in male WT mice permanently reversed tactile allodynia. IT IFNß treatment induces expression of anti-inflammatory proteins, contributing to the beneficial effect. Together, these experiments illustrated differences in the transition to chronic tactile allodynia in male and female animals and the complexities of effective pharmacologic interventions.