Immunomodulatory activity of mu- and kappa-selective opioid agonists

Opioids and opioid peptides have been shown by numerous laboratories to modulate various parameters of the immune response, but little attention has been given to the type of opioid receptor that might be involved. This study focuses on the in vitro influences of morphine and DAMGE (Tyr-D-Ala-Gly-N-Me-Phe-Gly-ol), mu-selective agonists, and U50,488H and U69,593, kappa-selective agonists, on the generation of antibody to sheep erythrocytes in vitro. It was found that the mu and kappa opioid agonists were able to inhibit the capacity of murine lymphoid cells to generate antibody at concentrations as low as 10(-10) M. The effects were almost completely blocked by pretreatment with naloxone or naltrexone, opioid-specific antagonists. Only the kappa-agonist activity was abrogated by pretreatment with norbinaltorphimine, a kappa-specific antagonist. The stereospecificity of the kappa effect was demonstrated using isomers of U50,488H, with the (-) form possessing significantly greater immunomodulatory activity. Additional studies, using a mu receptor-deficient mouse strain, demonstrated that only the kappa agonists were capable of suppressing antibody responses, whereas mu- and kappa-selective agonists suppressed the parent mu-responsive strain. Our results clearly indicate that mu and kappa opioid receptors are involved in regulation of lymphoid cell production of antibodies.