The importance of timing of adrenergic drug delivery in relation to the induction and onset of adjuvant-induced arthritis

Stressful events often precede onset and exacerbate established rheumatic diseases. There are numerous reports of abnormal autonomic function in rheumatoid arthritis (RA) patients. Targeting the sympathetic nervous system (SNS) with adrenergic receptor (AR) drugs in RA patients and animal models of the disease have revealed mixed results, with treatments inhibiting and exacerbating disease pathology. We tested the hypothesis that variability in disease outcome following adrenergic drug treatment is due to different roles played by the SNS at different disease stages. The contribution of β₂- and α-AR subtypes to disease pathology was studied at different disease stages in adjuvant-induced arthritis (AA), an animal model of RA. Lewis rats were given twice-daily intraperitoneal (i.p.) injections of an α-AR antagonist (phentolamine: 500μg/kg) or a β₂-AR agonist (terbutaline: 1200μg/day), initiated at adjuvant challenge or disease onset, and continued through severe disease. Both adrenergic therapies, when initiated at adjuvant challenge exacerbated disease pathology. In contrast, SH1293, an adrenergic drug that targets both α- and β-AR (300μg/day; twice-daily), initiated at adjuvant challenge did not exacerbate disease severity. Additionally, the same treatment regimen of phentolamine, terbutaline or SH1293 initiated at disease onset attenuated joint-inflammation and dramatically reduced bone destruction in the arthritic hind limbs. These data support the SNS playing different roles in disease pathology preclinically and after disease onset. Given current drug therapies are not effective in preventing bone destruction, these data support using adrenergic drugs as bone sparing treatments in RA.