Effects of a Sustained-Release Naloxone Pellet on Luteinizing Hormone Secretion in Female Rats

Abstract

Studies were undertaken to develop a naloxone implant capable of chronically blocking opioid receptors for several weeks in an effort to evaluate the effect of this prolonged narcotic antagonism on luteinizing hormone (LH) secretion in female rats. Antagonism of opiate receptors was achieved with a tablet formulation which contained 75 mg naloxone free base and a high content of the insoluble binding material, Mg stearate. Subcutaneous placement of this implant prevented morphine-induced analgesia for 2 weeks and antagonized the LH suppressory effects of morphine (15 or 30 mg/kg) administration. Thus, this naloxone delivery system is capable of chronically occupying the opioid receptors which mediate morphine’s effects on analgesia and LH secretion. Despite this, the naloxone pellet only moderately enhanced the initial rate of increase in LH secretion following ovariectomy (day 1) and was ineffective in further augmenting LH secretion at 3 and 7 days after implantation. In rats which were ovariectomized and implanted immediately with estradiol-containing Silastic capsules, the naloxone pellet was ineffective in altering LH secretion 1, 3 or 7 days later. Thus, while chronic exposure to naloxone persistently antagonizes the pharmacologic actions of morphine, the naloxone pellet only transiently blocked the tonic inhibitory effect of endogenous opioid peptides. The mechanism by which the LH secretory effects of naloxone are lost following chronic exposure to the antagonist are at present unknown, but may involve the activation of compensatory mechanisms which are inhibitory to LH secretion.

Endogenous opioids and the control of seasonal LH secretion in Soay rams

“…Loss of response to chronic naloxone treatment has been observed previously in male rats (Owens & Cicero, 1981) and in ovariectomized female rats whether reimplanted with oestrogen or not (Gabriel & Simpkins, 1983). The loss of response to naloxone may limit its usefulness in long-term studies on the physio¬ logical role of endogenous opioids, though a recent study in Syrian hamsters suggests that if naloxone is given once daily it can partially reverse the inhibitory effects of short-day photoperiods on testicular func¬ tion (Chen, Targovnik, McMillan & Randall, 1984) and that naloxone given at 6-hourly intervals to young rats can advance the age of the onset of puberty (Sirinathsinghji, Motta & Martini, 1985).…”

Induction of LH hypersecretion in cyclic rats during the afternoon of oestrus by oestrogen in conjunction with progesterone antagonism or opioidergic blockade

“…Chronic opioidergic antagonism using an s.c. naloxone pellet was ineffective in inducing spon¬ taneous LH surges in acutely ovariectomized rats (Gabriel & Simpkins, 1983). This study similarly demonstrates that blockade of opiate receptors by nalmefene from the afternoon of pro-oestrus through oestrus was itself ineffective in inducing spontaneous LH hypersécrétion (group D), although LH micropulse amplitude may have been increased (data not shown).…”