Hypothalamic processing of β-endrophin in female C57BL/6J mice is altered at middle age

Abstract

Abstract β-Endorphin (β-endo) (1–31) is the active opioid peptide product of pro-opiomelanocortin processing. Further post-translational modifications of β-endo(1–31) yield β-endo(1–27), (1–26) and their acetylated forms which are considered to be opiate receptor antagonists. Mechanistically, alteration in opiatergic properties is likely to result in the loss of a number of physiological functions including reproductive capacity. The purpose of this study was to determine whether there are changes in the way β-endo neurones process the peptide with age in female C57BL/6J mice. Pooled extracts of arcuate nucleus (ARC) and preoptic area (POA) of 3- to 4-month-old normally cycling (4–5 days at dioestrus), 12- to 13-month-old irregularly cycling (5–7 days at dioestrus), 23- to 24-month-old acyclic (in persistent dioestrus) animals were subjected to reversed-phase HPLC (n=4 experiments). Column fractions were assayed for β-endo-like-immunoreactivity by sequence-specific RIAs. The opiate receptor active as well as opiate receptor antagonist forms of β-endo were present in both ARC and POA at all three age groups although their ratios varied. β-Endo(1–31), the active opiate, was the predominant form in young animals. At middle age there was a threefold (P<0·05, ANOVA) increase in the antagonist forms of β-endo and this was associated with a significant (P<0·05, ANOVA) increase in the ratio of antagonist to active forms. This was accompanied by a trend toward an increase in acetylated forms of β-endo in middle-aged mice. HPLC profiles from hypothalami of old animals more closely resembled those of young females. The increase in the antagonist forms of β-endo at middle age may contribute to a decline of opiatergic influences in the female C57BL/6J mouse and suggest a mechanism whereby alterations in opiate influence over gonadotrophin control may occur. Journal of Endocrinology (1995) 144, 405–415