ALPHA-MELANOCYTE-STIMULATING HORMONE ANTAGONIZES THE NEUROENDOCRINE EFFECTS OF CORTICOTROPIN-RELEASING FACTOR AND INTERLEUKIN-1-ALPHA IN THE PRIMATE

Alpha-Melanocyte stimulating hormone (alpha-MSH), a peptide derived from POMC has previously been shown to antagonize the action of exogenously administered beta-endorphin (beta-EP) on pituitary PRL and LH release in the primate. In this study, we have tested the ability of alpha-MSH to block some of the acute pituitary effects of CRF and interleukin-1-alpha (IL-1-alpha), effects which are thought in part to result from the release of endogenous beta-EP. Experiments were performed in ovariectomized rhesus monkeys bearing a chronically implanted lateral ventricular cannula for peptide infusion. Peripheral blood samples for LH, cortisol, and PRL RIA were obtained at 15-min intervals during a 3-h control period when saline was infused into the ventricle, followed by a 5-h experimental period. CRF (15-mu-g/h) infused alone for 5 h caused a significant suppression of pulsatile LH release; by the fifth hour, LH secretion was reduced to 32.5 +/- 2.4% of the control saline infusion. The CRF-induced suppression of LH was prevented by coinfusion of alpha-MSH (60-mu-g/h); by the fifth hour LH was 89.0 +/- 3.6% of the control (P < 0.05 vs. CRF alone). alpha-MSH also prevented the CRF-induced decrease in LH pulse frequency (P < 0.05). IL-1-alpha (4.2-mu-g) was infused alone for 30 min or in combination with alpha-MSH (120-mu-g/h for 2 h). After IL-1-alpha alone, LH decreased to 30.1 +/- 2.4%. of baseline at 5 h. This decrease was prevented by alpha-MSH; by 5 h LH was 101 +/- 5.1% of baseline (P < 0.005 vs. IL-1-alpha alone). IL-1-alpha did not affect LH pulse frequency but pulse amplitude was reduced; this reduction was prevented by alpha-MSH (P < 0.05). IL-1-alpha also stimulated PRL release. PRL rose from a mean baseline of 3.5 +/- 0.3 ng/ml to a peak of 13.8 +/- 2.7 ng/ml; after coinfusion of alpha-MSH the mean peak PRL response was only 4.4 +/- 1.5 ng/ml (P < 0.001 vs. IL-1-alpha alone). After CRF infusion, cortisol increased to 136 +/- 7.9% of the mean morning baseline concentration. This increase was not prevented by alpha-MSH coinfusion; after CRF plus alpha-MSH, cortisol increased to 121 +/- 6.0% of baseline. In contrast, alpha-MSH prevented the IL-1-alpha-induced increase in cortisol: 167 +/- 15.5% vs. 91.7 +/- 8.3% (P < 0.005). When gamma-3-MSH, an N-terminal fragment of POMC, was infused together with IL-1-alpha, it did not interfere with the actions of IL-1-alpha on LH, PRL, or cortisol. Thus, the antagonistic effects of alpha-MSH appear to be relatively specific. We conclude that alpha-MSH can effectively antagonize the CRF and IL-1-alpha-induced suppression of pituitary LH release as well as the IL-1-alpha-induced stimulation of PRL release. Since these pituitary effects of CRF and IL-1-alpha appear to involve the release of beta-EP, it is likely that alpha-MSH acts by antagonizing the effects of endogenously released beta-EP. alpha-MSH also blocked the stimulation of cortisol caused by IL-1-alpha; the mechanism by which this occurs is unclear but presumably results from blocking IL-1-alpha-induced CRF release since alpha-MSH does not block pituitary-adrenal activation by CRF infusion. These findings further support the concept that differential processing of POMC may be an important step in the processes that govern neuroendocrine control of anterior pituitary function.