Anti-inè ammatory effects of k-opioids: relevance to rheumatoid arthritis

Abstract

Therapy with opioids is an exciting new development for arthritis, especially since there is the potential for fewer side effects from molecules that act outside the central nervous system. We have found k-opioid drugs to be powerfully anti-in eammatory, reducing disease severity by as much as 80% and attenuating arthritis in a dose-dependent, stereoselective, antagonist-reversible manner. In contrast, opioids acting at other receptors were therapeutic only at near toxic doses. Currently, however, no pure k-opioids are available for clinical use. The hypothalamic-pituitary-adrenal axis was found to be only partially involved; thus we investigated other neural and immune mechanisms. The results showed that the k-opioid anti-in eammatory actions were exerted via: (1) reduced adhesion molecule expression; (2) inhibition of cell trafecking; (3) reduced tumour necrosis factor release; and (4) alterations in mRNA expression and substance P (SP) and calcitonin gene-related peptide protein in joint tissue. The ability of k-opioids to act at multiple sites in the in eammatory cascade, as suggested by the presence of opioid receptors at various locations throughout the cascade, may explain their powerful actions. k-Opioids are, however, most therapeutic during disease onset; thus it is likely they exert their anti-in eammatory effects predominantly via changes in cellular activation and cytokine expression rather than via the nervous system. The involvement of SP and the efecacy of neurokinin 1 (NK1) antagonists predicts that combined opioid ‐NK1 regimens have therapeutic promise. Peripherally acting opioids may prove to be a potent new treatment for rheumatoid arthritis sufferers in the future.