Anti-inflammatory effects of opioids.

In summary, therapy with opioids is an exciting new development for arthritis especially since there is the potential for fewer side effects from molecules which act outside the CNS. We found kappa-opioid drugs to be powerfully anti-inflammatory, reducing disease severity by as much as 80%; attenuating arthritis in a dose-dependent, stereoselective, antagonist-reversible manner. By contrast opioids acting at other receptors were only therapeutic at near toxic doses. The HPA-axis was found to be only partially involved, thus we investigated other neural and immune mechanisms. Results showed that the kappa-opioid anti-inflammatory actions were exerted via (i) reduced adhesion molecule expression; (ii) inhibition of cell trafficking; (iii) reduced TNF release and expression and (iv) alterations in mRNA expression and protein levels of SP and CGRP in joint tissue (Fig. 2). The ability of kappa-opioids to act at multiple sites in the inflammatory cascade, as suggested by the presence of opioid receptors at various locations throughout the cascade, may explain their powerful actions (Fig. 2). It is also relevant that during inflammatory states that enhanced peripherally directed axonal transport leads to receptor upregulation on peripheral nerve terminals in the joint. Neuropeptides (SP and CGRP) were found to be involved in the later phases of adjuvant arthritis suggesting that they are involved in the maintenance or persistence of the disease. The involvement of SP and the efficacy of neurokinin-1 (SP receptors) antagonists predicts that combined opioid- neurokinin-1 therapy has promise. Kappa-opioids are, however, powerfully therapeutic during disease onset. Thus, they most likely exert their anti-inflammatory effects via changes in cellular activation and cytokine expression. The mechanisms involved are summarized in Fig. 2. The increased potency of kappa-opioids in females is likely to be a significant advantage for treatment of inflammatory disease with these agents. Thus our work supports the findings of Stein's group, that opioids do indeed have powerful actions in the periphery via specific receptors at that site. Peripherally acting opioids may prove to be a potent new treatment for rheumatoid arthritis sufferers in the future.