Modulation of humoral immune responses in the rat by centrally applied Met–Enk and opioid receptor antagonists: functional interactions of brain OP1, OP2 and OP3 receptors

We have previously demonstrated that central application of leucine–enkephalin (Leu–Enk) elicits potentiation and suppression of humoral immune responses through OP₁ (δ) and OP₂ (κ) receptors, respectively. Interestingly, both effects were found to be additionally dependent on OP₃ (μ) receptor function. In the present study, we have further investigated whether opioid receptor interactions underlie the immunomodulatory effects of endogenous opioids as well as exogenously applied methionine–enkephalin (Met–Enk). For that purpose, the plaque-forming cell (PFC) response was determined in rats injected intracerebroventricularly (i.c.v.) with opioid receptor-selective antagonists and Met–Enk. Application of the OP₁ antagonist ICI 174864, but not naltrindole, resulted in suppression of the PFC response. In contrast, i.c.v. injection of the OP₂ selective antagonist nor-binaltorphimine (nor-BNI) significantly potentiated the PFC response. Both effects, presumably mediated by endogenous opioid peptides, were antagonized by the OP₃ receptor antagonist β-funaltrexamine (β-FNA) at a dose that was devoid of immunomodulatory activity. The immunopotentiation of the PFC response induced by Met–Enk was reversed by OP₁ receptor antagonists, naltrindole and ICI 174864, but not by β-FNA or nor-BNI.

On the basis of these and previous findings, it may be concluded that central OP₃ receptors are permissive for the central immunomodulatory action of endogenous opioid peptides and Leu–Enk. In contrast, the central immunoenhancing effect of Met–Enk appears to be mediated through OP₃-independent OP₁ receptors.