Enkephalinase-inhibitors modulate immune responses.

Exogenous opioid peptides, and enkephalins in particular, modulate a variety of immune performances in vivo and in vitro. In this study, the immunomodulatory role of endogenous opioids was investigated by means of central and peripheral administration of four peptidase inhibitors in the rat. Animals sensitized with sheep red blood cells (SRBC) were daily treated intraperitoneally (i.p.) with 0.2 mg/kg or 1 mg/kg of each inhibitor, or intracerebroventricularly (i.c.v.) with 0.02 mg/kg and 0.2 mg/kg of bestatin, des-tyrosine-methionine-enkephalin, (Des-Tyr1)Met-Enk; and actinonin, and 0.005 and 0.5 mg/kg of N-Carboxymethyl-phenilalanine-leucine,(N-C)Phe-Leu. Controls were injected i.p. and i.c.v. with saline. The results revealed that in animals treated i.p. with 0.2 mg/kg of bestatin and (N-C)Phe-Leu potentiated the plaque-forming cell (PFC) response and hemagglutinin production. In contrast, these immune responses were suppressed by 1 mg/kg. On the other hand, i.p. doses of 0.2 and 1 mg/kg of actinonin and (Des-Tyr1)Met-Enk potentiated humoral immune responses. When given i.c.v., all of the inhibitors used exerted clear dose-dependent immunomodulatory effects, i.e. increase in the PFC response and hemagglutinin production when given at lower doses (0.005-0.02 mg/kg), and decrease when injected with higher doses (0.2-0.5 mg/kg). These effects of enkephalin-related peptidase inhibitors, applied i.p. and i.c.v., suggest the involvement of endogenous enkephalins in immune mechanisms.