Interaction of morphine with the cholinergic system on prolactin release.
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Biomedical subjects
Publications and source records attributed to J Meites.
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Seven days prior to 7,12-dimethylbenz(a)anthracene (DMBA) administration, virgin 50-day-old female Sprague-Dawley rats were placed on a food-restricted diet and continued on this regimen until 30 days after DMBA injection. One day prior to and 7 days after DMBA administration, animals were given daily 0.1-ml s.c. injections of 0.9% NaCl solution (controls), haloperidol (HAL; 0.5 mg/kg) to increase prolactin secretion, growth hormone (GH; 0.5 mg/kg), estradiol benzoate (EB; 1 microgram/rat), or a combination of HAL, EB, and GH. Drug and hormone treatments were terminated after 8 days, but underfeeding continued for 30 days after DMBA administration, after which time all animals were placed on ad libitum feeding for the remainder of the 26-week experiment. Food restriction for 7 days prior to and 30 days after DMBA administration resulted in a significant reduction in average tumor number and size by the end of the 26-week experiment. Treatment for 8 days with EB produced a significant increase in mammary tumor incidence despite underfeeding, whereas underfed rats given the combination of HAL EB, and GH showed development and growth of mammary tumors equal to that of full-fed controls. Both EB and HAL significantly raised blood prolactin levels. GH alone had no apparent effect on mammary tumor incidence. These results indicate that reduced food intake during the "critical period" for induction of mammary tumors in rats by DMBA can produce inhibition of mammary tumor development throughout the 6-month period of this experiment and that administration of EB or the combination of EB, HAL, and GH for only 8 days can counteract the inhibition by underfeeding.
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The regulation of hormonal influences on mammary tumor development and growth resides in the hypothalamus. The two major hormones essential for mammary tumor development in the rat and mouse, and also for mammary tumor growth in the rat, are prolactin and estrogen. Prolactin secretion is directly controlled by the hypothalamus, and estrogen indirectly via the pituitary gonadotropins. Treatments that increase prolactin secretion in the rat and mouse increase the incidence of spontaneous mammary tumors, whereas treatments that decrease prolactin or estrogen secretion decrease the incidence of spontaneous mammary tumors in these species. In carcinogen treated rats, either an increase or decrease in prolactin or ovarian hormones inhibits development of mammary cancers. After the appearance of mammary tumors in rats, spontaneous or carcinogen-induced, a reduction in prolactin results in reduced mammary tumor growth, and an increase in prolactin in enhanced mammary tumor growth. Either a reduction in estrogen or an excess of estrogen inhibits mammary tumor growth in rats. Large doses of estrogen inhibit mammary tumor growth by preventing prolactin from stimulating tumor growth. In mice with well established mammary tumors, prolactin or estrogen have relatively little effect since these tumors are largely autonomous.
Serum TSH, T4 and T3 were measured by radioimmunoassay (RIA) in 20-24 month old and 6-8 month old Long-Evans male rats during basal conditions, and upon exposure to cold temperature (4 degrees C), injection of ovine TSH, thyroidectomy, and T4 or T3 treatment. Basal serum TSH values in the old and young rats were similar, but serum T4 and T3 levels in the old rats were significantly lower than in the young rats. No differences were observed in TSH release between old and young rats in response to cold temperature, but old rats whowed no rise in serum T4, TSH administration produced a significantly smaller increase in serum T4 in old rats, but similar increases in serum T3 in old and young rats. No differences were observed between old and young rats in the rise of serum TSH after thyroidectomy, or in the fall of serum TSH after T4 or T3 administration. These results are believed to indicate that the primary cause for reduced thyroid function in old rats lies in the thyroid gland itself.
A study was made of the effects of increasing age on uterine histology, follicular development and steroidogenesis within the ovary of the white-footed mouse (Peromyscus leucopus). The animals were autopsied on each day of the estrous cycle and ranged from 14 to 49 mos. of age. The data indicated that the animals maintained estrous cycles throughout their lifespan as judged by cyclic changes in uterine histology. In addition these studies showed that aging (1) did not alter ovarian concentrations of testosterone, 17 beta-estradiol or progesterone, (2) resulted in a decrease in the number of primary and preantral follicles during metestrus, proestrus and estrus, (3) increased the percentage of atretic preantral follicles during metestrus only, and (4) did not reduce the number of antral (preovulatory) follicles that develop by proestrus. These observations suggest that in P. leucopus the "rescue" of preantral follicles constitutes the mechanism which compensates for the decrease in the number of smaller follicles and allows the normal number of preovulatory follicles to develop and ovulate. It is also possible that this mechanism exists in the laboratory mouse and rat since species-specific numbers of preovulatory follicles develop in aged cycling animals despite an age-related decrease in the total follicular populations.
Peromyscus leucopus, with an average lifespan of 48 months, showed unchanged levels of serum luteinizing hormone (LH), estradiol, progesterone, and pituitary LH and prolactin, between the ages of 12 and 48 months. Hypothalamic LH-releasing hormone (LHRH), norepinephrine and dopamine also remained unchanged with advancing age. Ovarian and uterine weight decreased with age, although the changes in uterine weight were not statistically significant. These data indicate that the hypothalamic-pituitary-ovarian axis remains intact with increasing age, accounting for the maintenance of fertility in these animals. The lack of significant changes in these parameters is in very marked contrast to those in the aging laboratory mouse and rat, which show derangements in their reproductive systems midway through their lifespans.
Nineteen, non-cycling female rats, 13-15 months of age, were fed 125 mg L-DOPA/15 g feed daily, and nineteen control rats of the same age were provided feed without L-DOPA. Sixteen of the L-DOPA fed rats each demonstrated 1-7 (average = 3) vaginal estrous cycles during the 75-day period of treatment, whereas no cycles were observed in the untreated controls. All animals were then ovariectomized and the post-castration rise in LH was monitored. Four weeks after ovariectomy, serum LH levels in the L-DOPA treated old female rats were significantly higher than in the non-treated old female rats. A single injection of 20 micrograms of estradiol benzoate (EB) significantly lowered serum LH in the L-DOPA treated rats, but no effect was observed in the non-treated controls. A second injection of EB three days later produced a significantly greater LH surge in the old rats given L-DOPA than in the non-L-DOPA treated controls. These results indicate that prolonged L-DOPA administration can partially prevent the decline in function of the hypothalamo-pituitary-ovarian system in aging female rats.
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The effects of naloxone hydrochloride and morphine sulfate on the proestrous surge of PRL and gonadotropins (LH and FSH) were investigated in normal cycling Sprague-Dawley rats. Blood samples (0.45-0.50 ml) were withdrawn without anesthesia every 20 min from 1400-2000 h through an atrial cannula implanted the same morning. RIA revealed that a single iv injection of naloxone (0.2 mg/kg) at 1400 h completely suppressed the surge of PRL, and this was reversed by a concomitant injection of morphine (10 mg/kg). Morphine itself did not alter the peak of the PRL surge. Morphine suppressed only the early phase of the LH surge, and this was reversed by naloxone. Naloxone alone did not change the peak of the LH surge but maintained higher levels than controls during the declining phase. The FSH surge was not altered by either morphine or naloxone. These results suggest that endogenous opioid peptides may have a role in regulating the PRL and LH surges during proestrus in the rat.
Pulsatile release of GH was compared in young (4-5 months old) and old (18-20 months old) male Sprague-Dawley rats using indwelling atrial cannulae. More than 57% of the young rats exhibited GH pulses greater than 300 ng/ml plasma, whereas only 7% of the old animals had GH pulses of similar amplitude. Trough GH values were not different between young and old rats, but during the 10.5-h sampling period, mean GH concentrations in young male rats were significantly greater than those in old male rats (175.3 +/- 20.9 vs. 70.2 +/- 7.6 ng/ml; P < 0.01). In another experiment, pituitary GH and hypothalamic somatostatin content were measured in young and old rats. The pituitary GH content was significantly greater in young than in old males (1187 +/- 95 vs. 670 +/- 93 microgram; P < 0.01). The immunoreactive somatostatin content in caudal areas of the hypothalamus was also greater in young than in old male rats (100.2 +/- 4.2 vs. 79.0 +/- 5.1 ng; P < 0.01). These observations demonstrate that GH secretion is depressed in old male rats, and this is associated with diminished pulsatile release of GH. The results also suggest that a relationship exists among the reduction in somatostatin content, pituitary GH content, and attenuated GH secretion in old male rats.
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