Do inhalation general anesthetic drugs induce the neuronal release of endogenous opioid peptides?

The antagonism of some effects of inhalation general anesthetic agents by naloxone suggests that there may be an opioid component to anesthetic action. There is evidence that this opioid action component is due to neuronal release of endogenous opioid peptides. The strongest evidence is provided by studies that monitor changes in the concentration of opioid peptides in the perfused brain following inhalation of the anesthetic. Indirect or circumstantial evidence also comes from studies of anesthetic effects on regional brain levels of opioid peptides, antagonism of selected anesthetic effects by antisera to opioid peptides and anesthetic-induced changes radioligand binding to opioid receptors. It is likely that some inhalation general anesthetics (e.g., nitrous oxide) can induce neuronal release of opioid peptides and that this may contribute to certain components of general anesthesia (e.g., analgesia). More definitive studies utilizing in vivo microdialysis or autoradiography in selected areas of the brain during induction and successive states of general anesthesia have yet to be conducted.     

Site of action for β-endorphin-induced changes in plasma luteinizing hormone and prolactin in the ovariectomized rat

A number of sites have been hypothesized as loci at which opioid substances act to alter the secretion of luteinizing hormone (LH) and prolactin (PRL) (1–8). The aim of the present study was to determine the site(s) at which the opioid peptide β-endorphin (β-END) acts to influence plasma LH and PRL levels in the ovariectomized (OVX) rat. β-END, administered into the third ventricle of conscious OVX rats fitted with jugular catheters, significantly decreased plasma LH in doses ? 50 ng and increased PRL levels at all doses administered (10, 50, 100 and 250 ng) in a dose dependent fashion. To identify possible central nervous system sites of action, 250 ng β-END was unilaterally infused into various brain sites. Plasma LH was significantly decreased and plasma PRL significantly increased by infusions into the ventromedial hypothalamic area, the anterior hypothalamic area, and the preoptic-septal area. There was no significant effect of β-END infusions into the lateral hypothalamic area, amygdala, midbrain central gray, or caudate nucleus. When hemipituitaries of OVX rats were incubated $\text{in}$$\text{vitro}$ with β-END (10^?7M to 10^?5M), there was no suppression of basal or LHRH-induced LH release, nor was there any alteration of basal PRL release. It is concluded that β-END acts at a medial hypothalamic and/or preoptic-septal site and not the pituitary, to alter secretion of LH and PRL.     

The effect of β-endorphin on arginine-induced growth hormone and prolactin release

β-endorphin administration via constant infusion inhibited the release of growth hormone (GH) and augmented the release of prolactin (PRL) induced by arginine in normal female subjects. Although β-endorphin infusion also induced hyperglycemia, the increment in plasma glucose was insufficient to account for the observed suppression of arginine-initiated GH release. These studies demonstrate that β-endorphin influences, in opposed directions, the secretion of PRL and GH in women.     

Does leptin mediate the effect of photoperiod on immune function in mice?

Seasonal fluctuations in immune status have been documented for avian and mammalian populations. During the late summer and early fall, immune function is bolstered to help animals cope with the more physiologically demanding winter. The environmental cue for these seasonal changes is apparently decreasing photoperiod. In the present study, we determined the potential role of leptin in mediating the effect of photoperiod on cell-mediated immune responses in male mice. Leptin-deficient (ob/ob) and littermate control mice were housed for 10 wk in either a short (8L:16D) or a long (16L:8D) photoperiod beginning at 6 wk of age. After the mice were killed, immune and reproductive organs were weighed and splenocytes isolated. The proliferative and cytokine responses (interleukin [IL]-2 and IL-4) of splenocytes to the T-cell mitogen, concanavalin A (Con A; 0-40 microg/ml), were determined. Body weights were elevated and both testes and seminal vesicle weights subnormal in ob/ob mice (by ANOVA, main effect of leptin deficiency), but thymuses and spleens were of normal size. Serum leptin levels were at minimum detection limits in ob/ob mice, but leptin levels in control mice housed at 8L:16D were higher than in control mice housed at 16L:8D. The proliferative response of splenocytes from ob/ob mice to Con A was subnormal (by ANOVA, main effect of leptin deficiency), but photoperiod had no effect on this response. Production of IL-2 in splenocytes of ob/ob mice was subnormal (by ANOVA, main effect of leptin deficiency) irrespective of photoperiod, but cells from mice housed at 8L:16D (by ANOVA, main effect of photoperiod) produced more IL-2 than cells from animals housed at 16L:8D. In contrast, a leptin deficiency did not alter IL-4 production, but cells from animals (ob/ob and controls) housed at 16L:8D produced less IL-4 than cells from animals housed at 8L:16D (by ANOVA, main effect of photoperiod). The present study suggests that both photoperiod and leptin have mutually independent effects on the proliferation of lymphocytes and cytokine production profiles. The data do not provide definitive support for the hypothesis that photoperiod-induced changes in leptin secretion mediate the effects of season on immune status.     

The effect of Λ9-tetrahydrocannabinol on the positive and negative feedback control of luteinizing hormone release

The principal psychoactive component of marihuana, Λ⁹-Tetrahydrocannabinol (THC), decreases serum LH levels when given to ovariectomized rats at a dose of 10 mg/kg. This same dose of THC blocks both the estrogen and progesterone mediated positive feed-back release of LH. The steroid-induced LH surge, when blocked by THC, reappears 24 h later. The positive feedback release of LH should serve as a suitable model to study the mechanism of action by which THC blocks the ovulatory LH surge.     

Effect of β-endorphin on pulsatile luteinizing hormone release in conscious castrated rats

The effect of intraventricular administration of β-endorphin on pulsatile LH release in castrated conscious rats was studied. The administration of 1 μg of β-endorphin into the lateral ventricle inhibited pulsatile discharge of LH secretion. Intravenous administration of naloxone blocked the suppressive effect of β-endorphin on LH release. These results suggest a possible role of β-endorphin, in addition to Met⁵-enkephalin, in the control of LH release in male rats.     

Opioid regulation of luteinising hormone and prolactin release in the horse—identical or independent endocrine pathways?

In order to determine if endogenous opioids regulate luteinising hormone (LH) and prolactin secretion via a common, gonadotropin-releasing hormone (GnRH) dependent pathway in the horse, effects of the opioid antagonist naloxone (300 mg) and the GnRH agonist buserelin (20 μg) on prolactin and LH secretion were investigated in stallions (n = 22), long-term castrated geldings (n = 15) and non-lactating mares during the luteal phase of the oestrous cycle (n = 16). Blood samples for determination of LH and prolactin concentrations were withdrawn at 15 min intervals for 120 min. After 60 min of sampling, animals were treated with either naloxone, buserelin or saline. In stallions, naloxone significantly increased LH as well as prolactin release (P < 0.05), indicating an opioid inhibition of both hormones, whereas in mares, naloxone stimulated only LH secretion (P < 0.05). No changes in plasma LH or prolactin concentrations after injection of naloxone were found in geldings. In all animal groups, buserelin induced a significant release of LH (P < 0.05) without affecting prolactin. We conclude that endogenous opioids inhibit LH and prolactin release in the horse but the regulation of these two hormones involves independent opioid pathways. These are activated differentially in stallions, geldings and mares. The opioid regulation of prolactin secretion is not mediated via GnRH.     

Endogenous opioid peptides: do they mediate the acute antihypertensive action of clonidine in humans?

The involvement of endogenous opioid peptides in the antihypertensive action of acutely administered clonidine, a centrally acting adrenergic agonist, was studied in humans. Eight hypertensive subjects received clonidine 0.2 mg orally, naloxone 8 mg i.v. followed by a 0.13 mg/min infusion, and both drugs together on separate days. Clonidine resulted in a significant decrease in mean blood pressure, which was not affected by concomitant treatment with naloxone. Naloxone alone or with clonidine caused significant elevations in plasma aldosterone, not mediated by increased plasma renin activity. Plasma beta-endorphin was not increased after clonidine administration. In humans, the antihypertensive effects of acute clonidine administration do not appear to be mediated by the release or action of endogenous opioids.     

Effects of 2-bromo-α-ergocryptine on β-endorphin-induced growth hormone,prolactin and luteining hormone release in urethane anesthetized rats

Adult male rats were injected intraperitoneally either with saline or 2-Br- α-ergocryptine(CB-154)(10 ng/0.5 ml/rat) 30 min prior to an intraventricular injection of saline or β-endorphin (1 μg/10 μl or 5 μg/10 μl) and 30 min after β-endorphin, they were sacrificed by decapitation. Intraventricular injection of β-endorphin elicited significant increases in serum GH, prolactin and LH levels in a dose-related manner. Pretreatment with CB-154 inhibited the release of GH, prolactin and LH induced by β-endorphin. These results indicate that the stimulatory effects of β-endorphin on GH, prolactin and LH may be involved in an inhibition of dopaminergic mechanism in the central nervous system.     

Differential regulation of estrous behavior and luteinizing hormone secretion by estradiol-17β in ovariectomized dairy cows

Holstein cows (n = 9) were used in an experiment to characterize the behavioral and endocrine responses to estradiol-17β when administered at rates designed to maintain peripheral concentrations within a physiological range. Cows were pretreated with progesterone for 3 d. Three days after progesterone treatment was completed, each cow was assigned to one of five estradiol-17β treatment groups (Doses 0 to 4), calculated to produce and maintain 0, 3, 6, 9, or 12 pg/mL in peripheral blood for 8 h. The experiment was conducted in eight replicates (with 3 to 7 cows each), with no dose repeated in any replicate. In each replicate, at least one additional cow was given an injection of estradiol-17β (500 μg im, in a corn oil vehicle) to facilitate estrus detection. Estrus was detected by visual observation for 30 min at 4 h intervals. Estrus was defined as a cow that stood to be mounted at least twice during the 50 h interval over which estrus was observed. Jugular venous blood samples were collected at 2 h intervals throughout the infusion and observation periods for quantification of luteinizing hormone (LH). Cows that received the highest dose (Dose 4, n = 7) all showed estrus, whereas those that received the two lowest doses (Dose 0, n = 5; Dose 1, n = 6) did not. Over the course of the experiment, five cows received each dose at least once. Of these, three showed estrus at Doses 2, 3, and 4, whereas the other two showed estrus only at Dose 4. Therefore, individual cows differed in the amount of estradiol-17β needed to induce estrus. There was a linear effect of dose on duration of estrus (P < 0.01). Estrus was shorter for Dose 2 (8.0 h) than for Dose 4 (18.4 h). The onset of estrus (after start of infusion) tended to be later for Dose 2 (20.0 h) than for Doses 3 and 4 (14.0 and 13.4 h, respectively; P = 0.15). Preovulatory-like surges of LH were induced in all cows at Doses 2, 3, and 4. Surges also were detected in 3 of 5 cows receiving Dose 1. The magnitude of the LH surge was less for Doses 1, 2, and 3 than for Dose 4 (P = 0.06). In contrast to the timing of estrus, the timing of the LH surge (after start of infusion) was not different among doses (P = 0.88). Thus, the hypothalamic centers responsible for regulating expression of estrus and secretion of LH responded differently to estradiol-17β.     

Does prolactin influence the hypothalamo-pituitary GnRH-LH system in preovulatory-phase ewes?

The effects of prolonged infusions of prolactin (PRL) into the third ventricle of the brain of cycling ewes on the secretory activity of hypothalamic GnRH neurons and pituitary LH cells in the pars distalis during the proestrous day were studied. Mature Blackhead ewes were infused with vehicle (control, n=5) or with prolactin (200 mug/day, n=5) during 4 consecutive days prior to the next spontaneous ovulation. The dose of PRL was infused each day in 4 series of 50 mug/100 mul/h at 30-min. intervals, from 8.30 to 14.00 h. The animals were slaughtered on the 16th (proestrous) day of the estrous cycle immediately after the last infusion and their brains were fixed in situ. Plasma samples were collected for 6 h at 10 min. intervals, on days 12 (before the infusions) and 16 of the cycle. The distribution pattern, number and morphology of GnRH neurons in vehicle- and PRL-infused ewes were found to be similar and typical for the proestrous phase of the cycle. The immunoreactive (ir) GnRH stores in the median eminence were high and similar in both groups. There were no differences between control and PRL-treated ewes in the number or features of irLH cells. The area fraction and optical density for irLH cells and mRNA LHbeta-expressing cells did not differ between control and experimental groups. Irrespective of the kind of infusion, changes in LH secretion during the estrous cycle were similar in control and PRL-infused ewes. Mean plasma LH concentrations were higher (p<0.001) on day 16 compared to day 12 of the cycle. There were no differences in plasma LH concentrations or in the parameters of pulsatile LH secretion between groups. In conclusion, repeated, several-hour-long infusions of PRL into the CNS prior to the next spontaneous ovulation in ewes has no direct effect on the secretory activity of GnRH neurons, and/or the synthesis, accumulation, or tonic release of LH from the pituitary gonadotrophs.     

Interactive effects of α-NAA and UV-B radiation on the endogenous hormone contents and growth of Trichosanthes kirilowii Maxim seedlings

The impact of UV-B radiation on endogenous hormones in plants has recently drawn attention from researchers. The mechanism for reduced stem elongation by UV-B might be due to changes in the phytohormone levels, especially IAA, which plays a role in stem elongation. In this study, effects of UV-B radiation on Trichosanthes kirilowii Maxim (T. kirilowii) seedlings in greenhouse-grown plants were investigated. The results indicated that: (1) In comparison to controls, exposure to 0.029 Jm^?2 s^?1. UV-B radiation led to accumulation of endogenous abscisic acid (ABA) and zeatinriboside (ZR) in the plant contents, and decreased contents of endogenous indole-3-acetic acid (IAA) and gibberellic acid (GA_1/3). Exposure to UV-B radiation reduced the height and leaf area of plants. As a result, total biomass (plant dry weight) was lower. (2) In comparison to controls, addition of 2 mg l^?1 α-naphthaleneacetic acid (α-NAA) slightly increased the contents of IAA, GA_1/3 and ZR, and decreased the content of ABA in leaves. This addition of α-NAA significantly increased plant height and leaf area, but only slightly increased total biomass. (3) Addition of α-NAA to UV-B-exposed plants: increased the content of endogenous IAA, GA_1/3 and ZR; decreased accumulation of endogenous ABA; and increased plant height and leaf area in comparison to plants that only were exposed to UV-B. Moreover, total biomass increased slightly. This suggests that addition of α-NAA may compensate to a certain extent for the lack of IAA resulting from UV-B radiation; it also increases the content of GA_1/3 and ZR, decreases the accumulation of ABA, and promotes the growth of plants.     

Does the seasonal increase in estradiol negative feedback prevent luteinizing hormone surges in anestrous ewes by suppressing hypothalamic gonadotropin-releasing hormone pulse frequency?

To test the hypothesis that the anestrous increase in estradiol negative feedback prevents estrous cycles by suppressing hypothalamic gonadotropin-releasing hormone (GnRH) pulse frequency, a variety of regimens of increasing GnRH pulse frequency were administered to anestrous ewes for 3 days. A luteinizing hormone (LH) surge was induced in 45 of 46 ewes regardless of amplitude or frequency of GnRH pulses, but only 19 had luteal phases. Estradiol administration induced LH surges in 6 of 6 ewes, only 3 having luteal phases. Anestrous luteal phase progesterone profiles were similar in incidence, time course, and amplitude to those of the first luteal phases of the breeding season, which in turn had lower progesterone maxima than late breeding season luteal phases. In the remaining ewes, progesterone increased briefly or not at all, the increases being similar to the transient rises in progesterone occurring in most ewes at the onset of the breeding season. These results demonstrate that increasing GnRH pulse frequency induces LH surges in anestrus and that the subsequent events are similar to those at the beginning of the breeding season. Finally, they support the hypothesis that the negative feedback action of estradiol prevents cycles in anestrus by suppressing the frequency of the hypothalamic pulse generator.     

Suppressive effect of dynorphin-(1–13) on luteinizing hormone release in conscious castrated rats

The effect of intraventricular administration of dynorphin-(1–13) of luteinizing hormone (LH) release was studied in castrated conscious rats. The administration of 5 μg of dynorphin-(1–13) into the lateral ventricle inhibited LH secretion. Intravenous administration of naloxone blocked this suppressive effect of dynorphin on LH release. These results suggest a possible role of dynorphin, in addition to β-endorphin and Met⁵-enkephalin, in the control of LH release in male rats.     

Does the hypothalamic tyrosine-hydroxylase inhibition mediate the positive feedback of progesterone on gonadotropin release in women?

Neuropharmacological studies suggest a common inhibitory role for the hypothalamic dopaminergic pathway on gonadotropin and prolactin pituitary release, in humans. As a consequence, it has been hypothesized that the inhibition of hypothalamic tyrosine-hydroxylase and the subsequent fall in dopamine synthesis is involved in the positive feedback of progesterone on LH and PRL pituitary release in estrogen-primed hypogonadal women. The aim of our study was to verify whether an inhibition of tyrosine-hydroxylase may really account for the progesterone action on gonadotropin and prolactin secretion. For this purpose, we compared the effect of a specific tyrosine-hydroxylase inhibitor (alpha-methyl-p-tyrosine, AMPT) with the effect of progesterone on gonadotropin and prolactin release in estrogen-primed postmenopausal women. Progesterone induced a marked release of LH (delta: 129.7 +/- 16.5 mlU/ml, mean +/- SE) and a slight increase in FSH (delta: 39.4 +/- 11.6 mlU/ml) and PRL (delta: 15.3 +/- 2.8 ng/ml) serum levels. Acute or two-day administration of AMPT was followed by a marked rise in PRL serum levels (delta: 82.9 +/- 13.8 and 88.3 +/- 8.2 ng/ml, respectively) while there were no significant increases in serum LH (delta: 5.4 +/- 2.6 and 3.3 +/- 4.6 mlU/ml) and FSH (delta: 3.4 +/- 0.9 and -0.4 +/- 2.9) concentrations. The ineffectiveness of a specific tyrosine-hydroxylase inhibitor in simulating the progesterone effect on gonadotropin secretion seems to negate the hypothesis that a reduction in hypothalamic dopaminergic activity mediates the positive feedback of progesterone on gonadotropin release.     

Theoretical prediction of antigenic sites in the Β-subunits of human choriogonadotropin and luteinizing hormone

Using hydrophilicity and recognition values of amino acids, the antigenic sites of theΒ-subunits of human choriogonadotropin and luteinizing hormone were computed from their amino acid sequences. Six antigenic sites were calculated for human choriogonadotropinΒ-subunits: residues 3–8, 17–22, 59–65,100–106,110–116 and 134–139. For luteinizing hormoneΒ-chain three antigenic sites were calculated: residues 17–22,59–65, and 100–106; all these three sites of luteinizing hormoneΒ being identical to the corresponding sites in human choriogonadotropinΒ. There was no antigenic site in luteinizing hormone that was also not found in human choriogonadotropin. On the other hand, there were unique determinants in human choriogonadotropin that were not found in luteinizing hormone; these determinants were residues 3–8, 110–116 and 134–139     

Long-term effects of the rhapontic rhubarb extract ERr 731® on estrogen-regulated targets in the uterus and on the bone in ovariectomized rats

The efficacy of ERr 731(?), a commercially available extract isolated from Rheum rhaponticum, in terms of menopausal complaints like hot flushes, depression, anxiety and vaginal dryness has been proven in a two-year clinical study. Further a recent preclinical study excluded unwanted side effects on the endometrium by showing a lack of stimulation of proliferation marker genes by ERr 731(?) or its constituents in the 3-day uterotrophic assay. The present study aimed at further substantiating the safety of ERr 731(?) in terms of endometrial hyperplasia and at the same time test for potential estrogenic effects in the bone. Therefore, ovariectomized (ovx) rats were treated in a dietary long-term administration for 90 days. Hence, the modulation of proliferation in the uterus was investigated by examining the effects on the mRNA expression of proliferation marker genes (Mki67, Pcna), on the estrogen-responsive gene C3 and on the estrogen receptors ERα and ERβ. We additionally performed densitometry analysis of the proximal tibia metaphysis using peripheral computed tomography (pQCT) and quantified bone homeostasis markers in the serum to examine potential effects on the bone. In this study design, neither an uterotrophic response nor a modulation of proliferation marker genes on mRNA level has been observed as response to the long-term application of the rhapontic extract. Furthermore, no impact of the two administered ERr 731(?) doses on the E2 deprivation-induced bone loss has been evident at the end of the study. In conclusion, the observations from previous trials regarding the endometrial safety of ERr 731(?) have been supported by our experimental findings that exclude a stimulatory activity on proliferation in the uterus in a long-term administration in the young adult rat but no effect on the bone mineral density could be observed.     

Interactive effects of α-NAA and UV-B radiation on the endogenous hormone contents and growth of Trichosanthes kirilowii Maxim seedlings

The impact of UV-B radiation on endogenous hormones in plants has recently drawn attention from researchers. The mechanism for reduced stem elongation by UV-B might be due to changes in the phytohormone levels, especially IAA, which plays a role in stem elongation. In this study, effects of UV-B radiation on Trichosanthes kirilowii Maxim (T. kirilowii) seedlings in greenhouse-grown plants were investigated. The results indicated that: (1) In comparison to controls, exposure to 0.029 Jm^?2 s^?1. UV-B radiation led to accumulation of endogenous abscisic acid (ABA) and zeatinriboside (ZR) in the plant contents, and decreased contents of endogenous indole-3-acetic acid (IAA) and gibberellic acid (GA_1/3). Exposure to UV-B radiation reduced the height and leaf area of plants. As a result, total biomass (plant dry weight) was lower. (2) In comparison to controls, addition of 2 mg l^?1 α-naphthaleneacetic acid (α-NAA) slightly increased the contents of IAA, GA_1/3 and ZR, and decreased the content of ABA in leaves. This addition of α-NAA significantly increased plant height and leaf area, but only slightly increased total biomass. (3) Addition of α-NAA to UV-B-exposed plants: increased the content of endogenous IAA, GA_1/3 and ZR; decreased accumulation of endogenous ABA; and increased plant height and leaf area in comparison to plants that only were exposed to UV-B. Moreover, total biomass increased slightly. This suggests that addition of α-NAA may compensate to a certain extent for the lack of IAA resulting from UV-B radiation; it also increases the content of GA_1/3 and ZR, decreases the accumulation of ABA, and promotes the growth of plants.     

Do testosterone and estradiol-17 beta enforce inhibition or stimulation of luteinizing hormone-releasing hormone secretion?

The effects of gonadectomy and gonadal steroid replacement on hypothalamic luteinizing hormone-releasing hormone (LHRH) secretion in vivo and in vitroi in the rat are reviewed. The evidence revealed that the part played by testosterone or estradiol-17 beta in regulation of LHRH signals to pituitary gonadotropes is more complex than that which has been surmised from measurements of steroidal effects on luteinizing hormone (LH) release. There is little evidence to date to corroborate the assumptions that the rate of hypothalamic LHRH drive is enhanced to sustain the post-gonadectomy LH response and that gonadal steroids inhibit LHRH secretion in gonadectomized rats. There is a dire need to develop newer techniques not only to characterize the LHRH pulsatility pattern reaching the pituitary gonadotropes on a moment-to-moment basis but also to fully explain the existing evidence that suggests a facilitatory influence of gonadal steroids and invokes participation of newer neural and steroidal and nonsteroidal gonadal factors in regulating the communication between LHRH secreting neurons and pituitary gonadotropes. Plainly, further studies will be necessary to provide a unified view on the exchange of information between the gonads and hypothalamus for control of reproduction.     

Does season alter responsiveness of the reproductive neuroendocrine axis to the suppressive actions of cortisol in ovariectomized ewes?

Season can profoundly influence activity of the hypothalamic-pituitary-adrenal axis and alter reproductive neuroendocrine responsiveness to stress and gonadal steroids. Here we tested the hypothesis that the inhibitory effect of a stress-like increment in plasma concentration of the adrenal steroid cortisol on pulsatile LH secretion varies with season. LH pulse patterns were monitored prior to and during the administration of cortisol in the same seven ovariectomized ewes during three stages of the yearly breeding cycle: breeding season, transition to anestrus, and midanestrus. The elevation in cortisol mimicked the rise in plasma level of cortisol in response to an immune/inflammatory stress. During all three seasons, cortisol acutely suppressed the pulsatile release of LH. This inhibition reflected a marked reduction of LH pulse amplitude and a minimal suppression of LH pulse frequency. Of interest, the suppressive effect of this physiologic increment in cortisol did not vary across seasons. This provides initial evidence that, in ovariectomized ewes, cortisol-induced suppression of pulsatile LH secretion differs from that of gonadal steroids in that it is not profoundly influenced by season.