Induction of precocious puberty in the female rat after chronic naloxone administration during the neonatal period: the opiate 'brake' on prepubertal gonadotrophin secretion
ABSTRACT Studies were undertaken using the opiate receptor antagonist naloxone to examine the hypothesis that endogenous opiates may have a restraining effect on prepubertal gonadotrophin secretion and may be involved in the maturation of the central nervous system mechanisms regulating the onset of puberty in the female rat. Naloxone (2·5 mg/kg) administered intraperitoneally every 6 h to female rats from day 1 to day 10 of postnatal life significantly (P <0·001) advanced the age of onset of puberty assessed in terms of the day of vaginal opening and first oestrus (32·3 ± 0·2 vs 40·8 ± 0·4 days in control saline-treated animals). Animals so treated with naloxone showed significantly (P < 0·001) higher levels of FSH (761·4 ± 87·6 vs 483·8± 57·2 μg/l in control animals) and LH (562·8 ± 57·4 vs 351·3 ± 43·3 μg/l in control animals) at the first late pro-oestrus and a significantly (P < 0·001) higher number of ova released at first oestrus (12·4 ± 0·4 vs 8·1±0·3 in controls). Body weight at first oestrus was significantly (P <0·001) lower in the naloxone-treated animals, an indication that these animals were much younger. The weights (per 100 g body wt) of the ovaries and uteri at the first oestrus were significantly (P <0·01) higher in the naloxone-treated rats than in the controls. However, there were no significant differences in the weights of the adrenals and anterior pituitary glands between the two groups of animals. A study of the cyclic patterns of the neonatally naloxone-treated animals performed for 15 consecutive cycles after the first oestrus showed normal 4- or 5-day cycles similar to those occurring in the saline-treated animals. The lengths of the first and second cycles in the naloxone-treated animals were not significantly different from controls. No significant differences in body weight or in organ weights at oestrus or in the levels of LH and FSH determined during the various stages of the oestrous cycle were found between naloxone- and saline-treated animals when these parameters were examined at 3 months of age. Naloxone had no effect on onset of puberty when administered during the other stages of prepubertal life. The mechanisms by which naloxone acts specifically during the neonatal period to induce precocious puberty are at present not known but are being investigated; they may be related to naloxone-induced alterations in the inhibitory synaptic arrangements between opiatergic and gonadotrophin-releasing hormone (GnRH) neurones, with a resulting decrease in the inhibitory influence exerted by endogenous opioids on GnRH neurones during this period of intense neurological development. The results suggest that the endogenous opiate peptides could play a key role in the central mechanisms which trigger the onset of puberty in the female rat. J. Endocr. (1985) 104, 299–307