Huang Q H, Hruby V J, Tatro J B
Department of Medicine and the Tupper Research Institute, Tufts University School of Medicine and New England Medical Center Hospitals, Boston, Massachusetts 02111, USA.
Am J Physiol. 1998 Aug;275(2):R524-30. doi: 10.1152/ajpregu.1998.275.2.R524.
Systemically administered alpha-melanocyte-stimulating hormone (alpha-MSH) inhibits endotoxin (lipopolysaccharide; LPS)- or interleukin (IL)-1-induced fever and adrenocortical activation, but the sites of these actions and the mechanisms involved are unknown. The aims of this study were, first, to determine whether melanocortin receptors (MCR) located within the central nervous system mediate the suppressive effects of peripherally administered alpha-MSH on LPS-induced fever and activation of the pituitary-adrenal axis and, second, to determine whether systemic alpha-MSH suppresses the LPS-induced rise in plasma IL-6 levels, potentially contributing to its antipyretic effect. Male rats received Escherichia coli LPS (25 microg/kg ip). Core body temperatures (Tb) were determined hourly by radiotelemetry (0-8 h), and blood was withdrawn via venous catheters for plasma hormone immunoassays (0-2 h) and IL-6 bioassay (0-8 h). alpha-MSH (100 microg/kg ip) completely prevented the onset of LPS-induced fever during the first 3-4 h after LPS and suppressed fever throughout the next 4 h but did not affect Tb in afebrile rats treated with intraperitoneal saline rather than LPS. Intraperitoneal alpha-MSH also suppressed the LPS-induced rise in plasma IL-6, ACTH, and corticosterone (CS) levels. Intracerebroventricular injection of SHU-9119, a potent melanocortin-4 receptor (MC4-R)/MC3-R antagonist, completely blocked the antipyretic effect of intraperitoneal alpha-MSH during the first 4 h after LPS but had no effect on alpha-MSH-induced suppression of LPS-stimulated plasma IL-6 and CS levels. Taken together, the results indicate that the antipyretic effect of peripherally administered alpha-MSH during the early phase of fever is mediated by MCR within the brain. In contrast, the inhibition of LPS-induced increases in plasma CS and IL-6 levels by intraperitoneal alpha-MSH appears to be mediated by a different mechanism(s), and these effects do not contribute to its antipyretic action.
全身给药的α-黑素细胞刺激素（α-MSH）可抑制内毒素（脂多糖；LPS）或白细胞介素（IL）-1诱导的发热和肾上腺皮质激活，但其作用部位及相关机制尚不清楚。本研究的目的，一是确定位于中枢神经系统内的黑素皮质素受体（MCR）是否介导外周给予α-MSH对LPS诱导的发热及垂体-肾上腺轴激活的抑制作用，二是确定全身给予α-MSH是否抑制LPS诱导的血浆IL-6水平升高，这可能有助于其解热作用。雄性大鼠腹腔注射大肠杆菌LPS（25μg/kg）。通过无线电遥测每小时测定一次核心体温（Tb）（0 - 8小时），并通过静脉导管采血进行血浆激素免疫测定（0 - 2小时）和IL-6生物测定（0 - 8小时）。α-MSH（100μg/kg腹腔注射）在LPS注射后的最初3 - 4小时内完全阻止了LPS诱导的发热发作，并在接下来的4小时内抑制了发热，但对腹腔注射生理盐水而非LPS的无热大鼠的Tb没有影响。腹腔注射α-MSH还抑制了LPS诱导的血浆IL-6、促肾上腺皮质激素（ACTH）和皮质酮（CS）水平升高。脑室内注射强效黑素皮质素-4受体（MC4-R）/MC3-R拮抗剂SHU-9119，在LPS注射后的最初4小时内完全阻断了腹腔注射α-MSH的解热作用，但对α-MSH诱导的LPS刺激的血浆IL-6和CS水平的抑制没有影响。综上所述，结果表明外周给予α-MSH在发热早期的解热作用是由脑内的MCR介导的。相反，腹腔注射α-MSH对LPS诱导的血浆CS和IL-6水平升高的抑制作用似乎是由不同机制介导的，且这些作用对其解热作用没有贡献。
