Involvement of central mu- but not delta- or kappa-opioid receptors in immunomodulation

Studies completed in both humans and animals have shown that opioids have significant effects on the immune system via pharmacological interactions with the opioid receptor. However, the type of opioid receptor at which morphine binding produces changes in immune status has not been well characterized. To determine the type of opioid receptor involved in opioid-induced immune alterations, the present study assessed the effects of agonists selective for the mu-, delta-, and kappa-opioid receptors. The site of action (i.e., peripheral vs central) at which opioids produce immune changes was investigated by injecting the agonists directly into the left lateral ventricle of the brain. Specifically, Lewis rats received an intracerebroventricular administration of [d-Ala(2),N-Me-Phe(4), Gly-ol(5)]enkephalin (DAMGO), a mu-receptor selective agonist, [D-Pen(2,5)]enkephalin (DPDPE), a delta-opioid receptor agonist, or U69,593, a kappa-receptor agonist. Immune assessments completed 1 h following drug administration showed that the mu-receptor selective agonist DAMGO produced a dose-dependent decrease in natural killer cell activity and T-lymphocyte proliferation to the mitogen concanavalin A (Con A); no immunological changes were found following DPDPE or U69,593 treatment. Calculation of the number of white blood cells per sample showed no differences between rats treated with saline and rats treated with any of the selective agonists. Administration of the opioid antagonist N-methylnaltrexone prior to DAMGO treatment attenuated the DAMGO-induced changes in immune status. Results from the present study indicate that the immunomodulatory effects of opioids can be attributed to interactions with the mu-opioid receptor.