Spinal adenosine receptor activation inhibits inflammation and joint destruction in rat adjuvant-induced arthritis

Abstract

Objective: To examine the effect of spinal cord adenosine (Ado) receptor stimulation on rat adjuvant-induced arthritis (AIA).

Methods: Long-term intrathecal (IT) catheters were implanted into rats to provide spinal access for drug delivery. Animals were immunized with complete Freund's adjuvant at the tail base. Eight days later and every other day thereafter until day 20, rats were treated IT with the selective Ado A1 receptor agonist cyclohexyladenosine (CHA) or vehicle. In some experiments, animals received an additional daily intraperitoneal injection of the nonselective Ado antagonist theophylline. Paw swelling was measured by water displacement plethysmometry. The effect of IT CHA on the activation of activator protein 1 (AP-1) was determined by electromobility shift assay. Spinal cord c-Fos expression was determined by immunohistochemistry.

Results: Spinal CHA significantly inhibited inflammation in AIA, with a mean +/- SEM 20.9 +/- 16.9% increase in paw swelling in the IT CHA group compared with 81.3 +/- 10.6% in the saline group. The antiinflammatory effect of CHA was mediated through Ado receptors since the effect was reversed by coadministration of systemic theophylline. In addition, radiographs showed significantly less bone and cartilage destruction in the CHA-treated animals. Synovial expression of AP-1, which is a key regulator of metalloproteinase expression, was lower in IT CHA-treated animals. C-Fos expression was localized to spinal laminae I-VI, with a modest decrease observed in the superficial laminae in IT CHA-treated rats.

Conclusion: These data demonstrate that the spinal cord can regulate peripheral inflammation. Therapeutic strategies that target the central nervous system might be useful in arthritis.