Biomedical subjects

J W Simpkins

Publications and source records attributed to J W Simpkins.

At least 73 records · Page 4Linked to original sources

PubMed1991

cAMP accumulation in opioid-sensitive SH-SY5Y neuroblastoma cells is modified by estradiol and progesterone.

We have recently demonstrated that acute and chronic treatments with estradiol and progesterone induce changes in the responsiveness of endogenous opioid systems to painful stimulation. In the present study the neuroblastoma SH-SY5Y subclone known to contain predominantly mu opioid receptors was used as a model to characterize the gonadal steroid effect on this opioid receptor system. The function of opioid receptors was assessed by measuring prostaglandin E1 (PGE1)-induced cyclic AMP accumulation after various treatments with estradiol and progesterone. Differentiated SH-SY5Y cells respond to PGE1 with a dramatic increase in cAMP level. Morphine (MOR) inhibits by about 75% the stimulatory effect of PGE1 on cAMP. Pretreatment with 5 nM of estradiol for 6 days resulted in a significant increase of PGE1-stimulated cAMP accumulation. Exposure of cells for 48 h to estradiol in doses of 5 nM or 50 nM did not affect cell sensitivity to the PGE1 effect on cAMP. Moreover, neither dose of estradiol changed the inhibitory effect of morphine on PGE1-induced cAMP response. There was a significant increase in PGE1-stimulated cAMP accumulation after treatment with 100 nM progesterone for 1 h or 15 min and a marked elevation of cAMP levels was also measured after 15 min treatment with 10 nM progesterone. Exposure to either dose of progesterone for 8 h, 48 h or 6 days did not affect basal or PGE1-induced cAMP in neuroblastoma cells. Progesterone-treated groups responded to MOR with 56-67% inhibition of PGE1-stimulated cAMP accumulation. The potency of MOR-induced inhibition was comparable to the MOR effect in cells not treated with the steroid.(ABSTRACT TRUNCATED AT 250 WORDS)

Alprostadil↗

PubMed1991

Effects of a brain-enhanced estrogen delivery system on tail-skin temperature of the rat: implications for menopausal hot flush.

The menopause results from the decreasing production of ovarian estrogens/progestins. This loss of ovarian hormones in 75-85% of women leads to a number of brain-mediated steroid-withdrawal symptoms, the most frequent being hot flushes. Thus, replacement therapy with a brain-enhanced estrogen delivery system (E2-CDS) with sustained release of estradiol (E2) in the brain may be more effective in the treatment of menopausal symptoms than currently used estrogens. The present study was designed to evaluate the effects of E2-CDS vs. E2, on the tail-skin temperature (TST) surge associated with administration of naloxone to morphine-dependent rats, an animal model for menopausal hot flush. Ovariectomized rats received a single or multiple doses of E2-CDS at 1.0 mg/kg body weight or E2 (0.5 mg pellet) weekly for 1 or 3 weeks before temperature recording. The mean maximal elevation in TST of the control animals was 6.4 +/- 0.2 degrees C. A single injection of E2-CDS attenuated the naloxone-induced rise in TST by 25%, while multiple injections resulted in significant attenuation of the rise in TST (3.4 +/- 0.6). By contrast, multiple implants of E2 pellet (3 pellets over 3 weeks) did not affect the surge of TST. Plasma E2 levels in animals treated with E2-CDS were slightly increased to 13 pg/ml for single-injected and to 44 pg/ml for multiple-injected rats. However, the E2-pellet treatment produced plasma E2 levels that were 2-fold greater than the E2 levels produced by multiple injections of E2-CDS. Plasma gonadotropins (LH and FSH) were significantly suppressed with the E2-pellet as well as the single and multiple E2-CDS treatment. Plasma prolactin levels were significantly elevated by E2 pellet and multiple injections of E2-CDS. The kinetic profiles of E2-CDS metabolites in plasma indicated an apparent t1/2 = 8 h for E2-Q+ and 3 h for E2. Collectively, these data support the view that E2-CDS may be potentially useful in the treatment of vasomotor hot flushes.

Animals↗

PubMed1991

Use of 2-hydroxypropyl-beta-cyclodextrin as a solubilizing and stabilizing excipient for protein drugs.

A chemically modified, amorphous beta-cyclodextrin, namely, 2-hydroxypropyl-beta-cyclodextrin (HPCD), was examined as a solubilizing and stabilizing agent for protein drugs. The aqueous solubility of ovine growth hormone at pH 7.4 was increased through the use of HPCD. This effect was manifested by higher UV transparency at 600 nm. Interleukin-2 (IL-2) is rendered insoluble upon lyophilization in the absence of stabilizers. Use of aqueous HPCD provides a clear solution, as indicated by fluorometric light scattering, and inhibits aggregate formation, as shown by ultracentrifugation and Western blot analyses. In addition, there were no major conformational changes of IL-2 in HPCD formulation as indicated by fourth-derivative ultraviolet spectroscopy. Finally, IL-2 retained 100% of its biopotency when prepared in HPCD solutions. Aggregation of insulin was also suppressed by HPCD. These data, as well as the i.v. safety of HPCD and its well-characterized chemical composition, suggest that this starch derivative may be a potentially useful excipient for protein drugs intended for parenteral use.

2-Hydroxypropyl-beta-cyclodextrin↗

PubMed1991

Evaluation of the sites of opioid influence on anterior pituitary hormone secretion using a quaternary opiate antagonist.

Studies were conducted to determine the effects of a potent narcotic antagonist, nalmefene methyliodide, which does not cross the blood-brain barrier (BBB), on the secretion of anterior pituitary hormones and on the anterior pituitary hormonal response to morphine sulfate. Since the localization of opiate receptor responses to inside or outside the BBB depended upon the relative ability of nalmefene HCl and nalmefene methyliodide to penetrate the BBB, initial studies were conducted to document that nalmefene methyliodide does not block opiate receptors inside the central nervous system. While nalmefene HCl blocked morphine-induced antinociceptive responses at doses as low as 10 micrograms/kg, nalmefene methyliodide was ineffective in this regard at doses as high as 500 micrograms/kg. The luteinizing hormone (LH) suppression and prolactin (PRL) secretion induced by morphine was blocked by both nalmefene HCl and its methyliodide analogue, indicating that the opioid receptor type which mediates both responses is located outside the BBB. We observed that basal PRL levels were reduced by nalmefene HCl but not by nalmefene methyliodide indicating that basal PRL secretion is influenced by opioid neurons inside the BBB. While nalmefene HCl blocked morphine-induced suppression of thyroid-stimulating hormone (TSH) release, nalmefene methyliodide was less effective, suggesting that opiate-induced TSH suppression may be mediated by receptors located both within and outside the BBB. Nalmefene HCl caused a growth hormone (GH)-secretory response by itself, but nalmefene HCl and nalmefene methyliodide were ineffective in blocking morphine-induced GH secretion.(ABSTRACT TRUNCATED AT 250 WORDS)

Analgesia↗

PubMed1991

Luteinizing hormone-releasing hormone alters the hypothalamic effects of morphine in the rat.

Female rats exhibit a generalized refractoriness to opiate stimulation during periods of steroid-induced LH secretion. In the present study we evaluated that role of LHRH in this steroid-induced effect on opiate-responsiveness. Central administration to ovariectomized rats of native LHRH or the LHRH agonist [Des-Gly10]LHRH ethylamide causes a dose-dependent refractoriness to the hypothermic effects of morphine. The potency relationship of these two LHRH agonists in antagonizing morphine's effect was consistent with their potency in inducing LH release. Treatment of ovariectomized rats with estradiol benzoate and progesterone in a regimen which induces a preovulatory-like LH surge, antagonized morphine-induced hypothermia, and the LHRH antagonist [D-Phe2, Pro3, D-Phe6] LHRH, reversed the effects of the gonadal steroids. These results indicate that the LHRH secretory dynamics associated with the preovulatory surge of LH may serve to modulate opiate responsiveness and thereby could serve to couple behavioral, sensory, and autonomic events with this neuroendocrine response to gonadal steroids.

Animals↗

PubMed1991

The effects of a brain-enhanced estradiol delivery system on testosterone and androgen-dependent tissues. I. Dose-response and time-course evaluation.

The primary objective underlying hormone treatment of prostatic adenocarcinoma is to induce an effective androgen deprivation, and high dose estrogen therapy is as effective as surgical castration in abolishing the growth-promoting effects of androgens on prostatic tissue. An estradiol-chemical delivery system (E2-CDS), with sustained release of E2 in the brain, may be potentially useful in the treatment of prostatic cancer by virtue of the need for lower or less frequent doses of the estrogen. In this study we evaluated the dose- and time-dependent effects of the E2-CDS vs. 17 beta-E2 on serum testosterone (T) and weights of androgen-dependent tissues in male rats. Rats received a single iv injection of E2-CDS (0.1, 0.5, or 1.0 mg/kg), equimolar doses of 17 beta-E2, or the drug's vehicle. Sera and tissues were collected 1, 7, 14, or 21 days later for determination of hormone levels and tissue weights. The E2-CDS exhibited a dose- and time-dependent suppression of serum T and weights of the ventral prostate and seminal vesicles. In contrast, 17 beta-E2 had no significant effect on serum T or growth of these androgen-dependent tissues. Serum T levels were significantly reduced by 98%, 82%, and 59% at 1, 7, and 14 days, respectively, with the 1.0 mg/kg dose of E2-CDS. The E2-CDS significantly reduced prostate weight by 45% and 50% (1.0- and 0.5-mg/kg doses, respectively) 7 days and by 27% (0.5 mg/kg dose) 14 days after treatment. Similarly, seminal vesicle weights were reduced by 14-20% on day 1, maximally reduced by 39-48% on day 7, and still reduced by 24-36% on day 14 compared with the control levels. Weights of these tissues returned to control levels by day 21. Serum E2 was elevated through 7 days by E2-CDS or on day 1 only by 17 beta-E2. PRL secretion was stimulated for 1 week by both forms of estrogen. Anterior pituitary weights were increased by the E2-CDS through 14 days, while 17 beta-E2 had no significant effect. These data indicate that the E2-CDS causes chronic suppression of serum T, which subsequently results in regression of androgen-dependent tissue weight.

2-Hydroxypropyl-beta-cyclodextrin↗

PubMed1991

The effects of a brain-enhanced estradiol delivery system on testosterone and androgen-dependent tissues. II. The role of testosterone.

The present study was undertaken to evaluate the efficacy of an estradiol-chemical delivery system (E2-CDS) for the brain vs. estradiol benzoate (E2-BNZ) in suppressing serum testosterone (T) and weights of the ventral prostate and seminal vesicle in male rats. Also, the role of serum T in the weight reduction of androgen-dependent tissues observed after E2-CDS treatment was further evaluated in these studies. Intact male rats received a single iv injection of either E2-CDS at a dose of 1.0 mg/kg or an equimolar dose of E2-BNZ (0.95 mg/kg). Sera and tissue samples were collected 1, 7, 14, or 21 days after injection for determination of hormones and tissue weights. A single injection of E2-CDS suppressed serum T levels by 96%, 83%, 46%, or 63% 1, 7, 14, or 21 days after treatment, respectively. In contrast, an equimolar dose of E2-BNZ had no significant effect on serum T at any sampling time examined. Prostate weight was maximally reduced by 53% at 7 days and remained significantly suppressed by more than 31% throughout the 21-day time course. Similarly, seminal vesicle weight was reduced by 14% on day 1, maximally reduced by 41% on day 7 and remained significantly suppressed through day 21. In contrast, E2-BNZ was ineffective in inducing weight changes in either of these tissues. Serum PRL was significantly elevated through day 14, while E2 was elevated through day 7 by E2-CDS. Both the anterior pituitary and adrenal gland weights were stimulated by E2-CDS treatment. Testis weight was moderately reduced by both esters. In a subsequent study serum T was reduced by 98% and 97% 1 and 7 days, respectively, after E2-CDS treatment, and weights of the ventral prostate and seminal vesicle were reduced by 47% and 40%, respectively, at 7 days. In contrast, in rats treated with Silastic capsules containing T, the expected E2-CDS-induced weight regression was prevented in both prostate and seminal vesicles. These data indicate that the prolonged effects of E2-CDS on weights of androgen-dependent tissues are caused by its ability to produce profound suppression of the serum T concentration.

Adrenal Glands↗

PubMed1990

Glucose modulation of skin temperature responses during morphine withdrawal in the rat.

Studies were undertaken to determine the effects of acute alterations in plasma glucose levels on the tail skin temperature (TST) response of morphine-dependent rats to naloxone-precipitated withdrawal. In morphine-dependent rats, treatment with dextrose at doses of 0.5 or 2.5 g/kg did not alter the normal 6.0 +/- 0.3 degrees C TST response to naloxone. However, treatment with 5, 10 or 20 g dextrose/kg, which increased plasma glucose to 250 mg/dl or greater, blocked the TST response during morphine withdrawal. In contrast, an IV injection of 2.5 IU insulin (Na-porcine)/kg, which reduced plasma glucose for 2 h, caused a delayed TST response of 4.7 +/- 0.4 degrees C in control rats and exaggerated the TST response normally observed in morphine-dependent rats treated with naloxone. Collectively, these data indicate that acute hyperglycemia can attenuate and hypoglycemia can enhance the skin vasodilation which accompanies precipitated morphine withdrawal. In view of our observation that naloxone-precipitated morphine withdrawal caused a marked increase in blood glucose, the sympathetic activation associated with opiate withdrawal may be intended to elevate blood glucose and thereby limit the manifestation of the withdrawal response.

Animals↗

PubMed1990

The effect of cellular glucoprivation on skin temperature regulation in the rat.

Studies were undertaken to determine the effects of cellular glucoprivation on temperature responses in morphine-addicted and placebo-treated rats and to compare these responses to those observed during naloxone-precipitated morphine withdrawal. Naloxone caused a tail skin temperature (TST) response of 5.7 +/- 0.5 degrees C in morphine-dependent rats. Intraperitoneal administration 2-deoxyglucose (2DG) caused TST responses in placebo-treated and morphine-dependent rats of 4.8 +/- 0.6 and 6.2 +/- 0.5 degrees C, respectively. These data indicate that the activation of the sympathetic nervous system by cellular glucoprivation causes a TST response which is equivalent in magnitude to that induced by precipitating withdrawal with naloxone. This effect of 2DG appears to be mediated by the brain, since icy administration of 2DG caused a TST response, similar to that induced by naloxone treatment of morphine-dependent rats. Collectively, these data suggest that a TST increase is a component of the response of rats to local brain glucoprivation induced by 2DG.

Animals↗

PubMed1990

The role of conditioned taste aversion in the suppression of food intake by estradiol.

In three experiments, ovariectomized rats were given a familiar or novel diet prior to treatment with a brain-enhanced estradiol-chemical delivery system (E2-CDS, 1 mg/kg). Experiment 1 showed that food intake was suppressed in subjects receiving either diet, but animals given a novel diet initially showed a profound anorexia which eventually recovered to the moderate suppression of animals given the familiar diet. In Experiment 2, rats showed an aversion to a novel diet paired with the E2-CDS in a two-choice preference test given on Day 2 after the injection, indicating that the initial large reduction in intake was mediated by a conditioned taste aversion. However, no aversion was observed seven days after the E2-CDS, suggesting that the residual intake suppression was mediated by unconditioned aversion or appetite suppression. Experiment 3 showed that lengthening the postovariectomy time resulted in a taste aversion that persisted for a longer duration.

Animals↗

PubMed1990

Dose and time-course evaluation of a redox-based estradiol-chemical delivery system for the brain. II. Pharmacodynamic responses.

Clinically, brain-enhanced delivery and sustained release of estradiol (E2) are desirable for effective treatments of menopausal hot flushes and prostatic adenocarcinoma and for fertility regulation. Thus, we conducted studies to determine the dose- and time-dependent effects of a brain-enhanced estradiol-chemical delivery system (E2-CDS) on anterior pituitary hormones secretion in ovariectomized (OVX) rats. The E2-CDS has consistently demonstrated preferential retention of its intermediate metabolite (E2-Q+), with slow release of E2 in the brain but rapid clearance from peripheral tissues. Animals received a single iv injection of E2-CDS at doses of 0.01, 0.1, or 1.0 mg/kg or an E2 dose of 0.7 mg/kg on day 0. The responses of plasma luteinizing hormone (LH), follicle-stimulating hormone (FSH), growth hormone (GH), and prolactin (PRL) were then evaluated at 1, 7, 14, 21, or 28 days after drug administration. The E2-CDS caused a dose- and time-dependent suppression of LH and FSH throughout the time course studied. The maximum LH and FSH reduction occurred at 7 days postinjection. Plasma LH and FSH were significantly suppressed by 86 and 58% on day 7, respectively, and were suppressed by 35% (LH) or were at preinjection levels (FSH) at 28 days following the single injection of a 1.0-mg E2-CDS dose. An equimolar E2 dose suppressed LH and FSH by only 29 and 20% on day 7, respectively which were not significantly different from time 0 values. Plasma PRL increased significantly on day 14 with the 1.0-mg E2-CDS dose but levels returned to preinjection values by 28 days after drug administration.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1990

Growth hormone (GH) secretory dynamics in animals administered estradiol utilizing a chemical delivery system.

We have utilized a redox chemical delivery system (CDS) for the brain targeting of estradiol (E2) to ascertain its effects on GH secretory patterns in adult intact male rats. The E2-CDS (1.0 mg/kg) dissolved in 20% hydroxypropyl-cyclodextrin (HPCD), E2 (1.0 mg/kg) alone in 20% HPCD, or 20% HPCD was administered intravenously. GH secretory profiles, plasma steroid levels, and anterior pituitary levels of hormones were determined 1 week following steroid injection. Whereas E2 in HPCD and HPCD treatment did not alter masculine GH secretory patterns, animals administered the E2-CDS displayed disrupted GH patterns with attenuated individual pulse amplitudes and significantly elevated GH baseline levels. Moderate pituitary hyperplasia was evident only in the E2-CDS group of animals. Plasma testosterone (T) concentrations were reduced in only the E2-CDS group. T replacement reduced E2-CDS-associated pituitary hyperplasia and preserved the masculine GH secretory profiles, with only a slight reduction in individual GH peak amplitudes being observed. T replacement did not prevent the increase in pituitary and plasma levels of PRL associated with E2-CDS treatment but did block both the increase in pituitary GH content and the hyperplasia associated with prolonged E2 exposure. E2 given alone induced a significant increase in both GH and PRL in the pituitary without establishment of pituitary hyperplasia or elevated plasma PRL levels. These data indicate that E2-CDS is an effective mode of steroid administration. Changes in GH secretory dynamics, pituitary levels of GH, and degree of hyperplasia are dependent upon the chemical design of the delivery system for E2. Concomitant T therapy can prevent some of the changes in GH secretion associated with high-dose E2 exposure.

2-Hydroxypropyl-beta-cyclodextrin↗

PubMed1990

Dose and time-course evaluation of a redox-based estradiol-chemical delivery system for the brain. I. Tissue distribution.

Brain-enhanced delivery and sustained release of estradiol (E2) may be potentially useful in the treatments of vasomotor hot flushes and prostatic adenocarcinoma and for fertility regulation. Therefore, we have evaluated a redox-based estradiol-chemical delivery system (E2-CDS) for the brain. The mechanism of this drug delivery is based on an interconvertible dihydropyridine in equilibrium pyridinium salt redox reaction. In this study, we investigated the dose- and time-dependent effects of E2-CDS on the tissue distribution of E2-Q+ and E2, the inactive (intermediate) and active metabolites, respectively, of the E2-CDS. Ovariectomized rats received a single iv injection of E2-CDS at 0.01, 0.1, or 1.0 mg/kg or an E2 dose of 0.7 mg/kg or the drug's vehicle, 2-hydroxypropyl-beta-cyclodextrin (HPCD), on day 0. Tissue samples including brain and peripheral tissues were then analyzed for both E2-Q+ and E2 at 1, 7, 14, 21, or 28 days following the E2-CDS administration. Initially, both E2-Q+ and E2 were detected in all tissues analyzed. The dose-distribution and time-course study demonstrates that (1) at 24 hr (1 day) after administration of E2-CDS, all tissues showed a dose-proportional increase in concentrations of E2-Q+ and E2; (2) the enzymatic oxidation of E2-CDS to E2-Q+ was dose dependent over the 100-fold dose range examined; and (3) the disappearance of E2-Q+ as well as E2 was slow in whole brain and hypothalamus, with an apparent t1/2 = 8-9 days, while both of these metabolites were rapidly cleared from plasma, liver, fat, anterior pituitary, kidney, lung, heart, and uterus.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1990

Dose-dependent effects of chronic treatment with estradiol or progesterone on LH secretion in ovariectomized rats.

Ovariectomized (OVX) Sprague-Dawley rats bearing atrial cannulae were implanted subcutaneously with fused pellets containing estradiol (E2) or progesterone (P4). Variable doses of E2 (0.1, 0.5, 1 and 5%) or P4 (10, 50, 75, 100%) were achieved by varying the ratio of the hormone to cholesterol (CHOL) in the pellet. Control groups were treated with CHOL containing pellets. Blood samples were collected in the morning and afternoon the day before and 1, 2, 5, 8, 11 and 14 days after pellet implantation. The concentrations of E2, P4 and LH were measured by RIA. Throughout the sampling period, plasma concentrations of both steroids were proportional to pellet composition. On days 1 and 2, high concentrations of E2 and P4 in plasma were obtained, but between days 5 and 14 stable levels at E2 and P4 were observed. The effectiveness of chronic replacement with E2 and P4 on the negative feedback on LH secretion was assessed from morning samples and positive feedback on LH from afternoon samples. E2 implants suppressed the morning LH levels in plasma in a time and dose-dependent manner. The afternoon concentrations of LH were significantly elevated on each sampling day, except for day 1. P4 pellets had no effect on morning-afternoon difference in LH level, but low doses suppressed LH shortly after the implantation and high doses suppressed LH level after the 8th day of implantation. These results indicate that fused pellets of E2 and P4 are effective in chronically maintaining plasma E2 and P4 at levels observed during various normal and pathological reproductive states. Further, these studies indicate that E2 can stimulate afternoon hypersecretion of LH for at least 14 days in ovariectomized rats.

Animals↗

PubMed1990

Opiate-thyroid hormone interactions in the regulation of thyrotropin secretion in the rat.

Studies were performed to determine the role of thyroid hormone in the suppression of thyrotropin (TSH) by opiates. Serum samples were collected by decapitation 1, 3, 6, 12, 24, or 48 h after rats were implanted with 1 sustained-release morphine (75 mg) or placebo pellet. Morphine decreased TSH by 44% at 1 h and by 83% at 3 h, and TSH remained significantly depressed by 38% through 48 h. Thyroxine (T4) levels were significantly reduced from 12 to 24 h after morphine, but triiodothyronine (T3) levels were not affected. When control or thyroidectomized (THX) rats were implanted with morphine or placebo 24 h before serum collection, morphine significantly decreased TSH, T3 and T4 in controls but had no effect on TSH in THX rats. Thus, it appears that the morphine-induced suppression of TSH release requires circulating thyroid hormone. When THX rats were chronically treated with morphine or placebo, then injected subcutaneously with saline or 1, 10 or 100 micrograms T4/kg body weight 24 h prior to serum collection, morphine treatment alone did not affect TSH in THX rats. T4 replacement caused a dose-dependent decrease in serum TSH in both morphine and placebo rats; however, TSH was suppressed significantly more in morphine than in placebo rats. Thus, while chronic morphine treatment is ineffective in suppressing in TSH in THX rats, morphine interacts with thyroid hormone to reduce TSH release. These data suggest that morphine may exert its inhibitory effect on TSH secretion by increasing the negative feedback sensitivity to thyroid hormones.

Animals↗

PubMed1990

A modulatory role for luteinizing hormone-releasing hormone in nociceptive responses of female rats.

We have shown that responsiveness to noxious stimuli change after gonadal steroid treatment and during the estrous cycle. In the present study, we evaluate the role of LHRH in modulating nociceptive responses in female rats. In ovariectomized (OVX) rats, an LHRH agonist ([ Des-Gly10] LHRH ethyl amide; 1 ng/rat/microliters), given intraventricularly (icv) at either 90, 60, or 30 min before a hot-plate test caused a time-dependent, significant increase in sensitivity to the noxious thermal stimulus (hyperalgesia) vs. saline-treated controls. Further, the LHRH agonist (1 ng/rat/microliters; icv) attenuated morphine (5 mg/kg, sc)-induced antinociception. The injection of an LHRH antagonist, [D-Phe2,Pro3,D-Phe6] LHRH, to OVX rats in doses of 0.1, 1, or 10 ng/rat 30 min prior to morphine, enhanced and prolonged morphine-induced antinociception in a dose-dependent manner. Moreover, the hyperalgesia observed in OVX rats treated with naloxone (1 mg/kg, sc) was reversed by preinjection of either the LHRH antagonist (0.1 ng/rat, icv) or LHRH antiserum. OVX rats primed with estradiol benzoate (EB) and progesterone (P) were less sensitive to the antinociceptive effect of morphine than OVX rats. When EBP-treated rats received the LHRH antagonist prior to morphine, a twofold increase in morphine-induced antinociception was observed. A similar effect was observed in EBP-treated rats after the injection of LHRH antiserum. In conclusion, LHRH may interact with central opioid systems causing an increased sensitivity to nociceptive stimulation (hyperalgesia) and reduction of the antinociceptive effect of morphine.

Analgesia↗

PubMed1990

Tissue distribution of a brain-enhanced chemical delivery system for estradiol.

Enhanced delivery and sustained release of estradiol (E2) in the brain could have potential clinical applications in the effective treatment of vasomotor "hot flushes" and prostatic cancer. We have, therefore, evaluated a brain-enhanced E2-chemical delivery system (E2-CDS), which is based upon the interconvertible dihydropyridine in equilibrium with pyridinium salt redox reaction. In this study, we evaluated the tissue distributions of E2-Q+ and E2--the inactive and active metabolites of the E2-CDS. Both E2-Q+ and E2 were detected in all tissues analyzed. In peripheral tissues, E2-Q+ and E2 were rapidly cleared, but in brain, concentrations of both compounds exhibited a slow decline with a t1/2 = 8 days. 14 Days after the E2-CDS administration, brain levels of E2-Q+ exceeded plasma levels by 170-fold, fat levels by 20-fold, and liver levels by 8-fold. Similarly, brain-E2 levels exceeded plasma levels by 38-fold, fat levels by 11-fold, and liver levels by 7-fold. Furthermore, levels of E2-Q+ In anterior pituitary, kidney, heart, and lung were initially 2- to 6-fold higher than brain levels, but 14 days after the E2-CDS administration, brain levels of E2-Q+ exceeded E2-Q+ levels in these peripheral tissues by 1.5- to 3-fold. The increased brain/peripheral tissues ratios of E2-Q+ and E2 in rats treated with the E2-CDS support brain-enhanced delivery and sustained release of E2 from this delivery system.

Animals↗

PubMed1989

Effects of acute central LH-RH administration of the skin temperature response in morphine dependent rats.

There are numerous reports of a temporal relationship between LH secretion and a subsequent flushing response in menopausal women. We have developed a morphine-dependent animal model to study the mechanisms of the hot flush. Administration of naloxone to these animals results in a surge in LH secretion which precedes the elevation in tail skin temperature (TST). In the present study, we utilized central administration of an LH-RH agonist and antagonist to evaluate the skin temperature response in our animal model. Ovariectomized female rats were fitted with unilateral cannula in the lateral ventricle (LV). One week later these animals were midly restrained to allow for continuous measurement of tail skin temperatures (TST). Central administration of naloxone was without effect in controls but produced a 5-6 degree C rise of TST in the morphine-dependent rat while central administration of 10 microliters of the saline vehicle produced no changes in TST in either group. A similar increased sensitivity to LH-RH was observed in morphine-dependent rats. Administration of 5 or 10 micrograms of the LH-RH agonist (Des-Gly10, [im-Bzl-D-His6]LH-RH ethylamide) into the LV produced a significantly greater elevation in TST (4 degrees C) in the morphine-dependent rats compared to a negligible rise in TST in the control rats; however, administration of a larger dose of 20 micrograms of the LH-RH agonist produced similar TST responses of about 4 degrees C in both groups. Intravenous administration of the LH-RH agonist (10 micrograms) was ineffective in producing any temperature effect in morphine-dependent rats. Thus, it appears that the morphine-dependent rat is more sensitive to the LH-RH agonist and the temperature response is mediated by a central mechanism which is similar to that observed following administration of a dose of naloxone. In a subsequent study central administration of the LH-RH agonist (5 micrograms/10 microliters) resulted in a similar rise in serum LH in both control and morphine-dependent rats, suggesting that the elevation in TST is not closely associated with LH secretion. Further support for a role of LH-RH in our animal model was obtained following central administration of an LH-RH antagonist [( D-Phe2.6, Pro3]LH-RH) which blocked the rise in TST associated with systemic administration of naloxone (1 mg/kg, s.c.) in morphine-dependent rats.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗