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Biomedical subjects

E R Meyer

Publications and source records attributed to E R Meyer.

At least 37 records · Page 2Linked to original sources
PubMed1989

Age-related differences in the sensitivity to opiate-induced perturbations in reproductive endocrinology in the developing and adult male rat.

The effects of a single morphine pellet (75 mg) implanted in developing male rats at 27 days of age on reproductive endocrine parameters were compared to those found in adult (65-day-old) animals after the same treatment. The pellets were left in place to provide the release of morphine during critical phases of puberty and sexual maturation and to prevent an abrupt withdrawal syndrome upon pellet removal which would confound our results. Developing rats were sacrificed at representative intervals after pellet insertion to assess the development of key indices of reproductive endocrinology; adult rats were sacrificed at the same time intervals to permit an evaluation of age-related differences in the sensitivity to opiate-induced endocrine disturbances. Our results showed that morphine markedly influenced a number of endocrine parameters associated with the maturation of the hypothalamic-pituitary-gonadal axis in developing rats for prolonged periods of time, whereas the effects of the opiate in the adult rat were relatively modest and transient. In the developing rat, serum luteinizing hormone (LH), testosterone, the wet tissue weights of the seminal vesicles and testes and hypothalamic LH-releasing hormone (LHRH) levels were substantially depressed immediately after pellet implantation and these effects persisted for up to 4 weeks when compared to placebo-implanted, age-matched controls. In contrast to these results, adult rats showed only transient effects (less than 1 week) of morphine on certain reproductive endocrine parameters (e.g., serum LH, testosterone and the weights of the seminal vesicles) and no effects on others (e.g., testes weights and hypothalamic LHRH).(ABSTRACT TRUNCATED AT 250 WORDS)

Age Factors↗
PubMed1988

Characterization and possible opioid modulation of N-methyl-D-aspartic acid induced increases in serum luteinizing hormone levels in the developing male rat.

It has been previously reported that the excitatory amino acid, N-methyl-D-aspartic acid (NMDA), elicits prompt increases in serum luteinizing hormone (LH) levels in young male rats. The present studies were carried out to determine whether the effects of NMDA on LH were mediated by the release of LHRH from the hypothalamus. We also examined whether NMDA-sensitive neuronal pathways interacted with the endogenous opioid system regulating LHRH release and the ontogeny of NMDA-evoked increases in serum LH. We found that the age-response curve for NMDA-induced increases in LH was an inverted U; at early ages (10 and 15 days) the amino acid was marginally effective in increasing LH levels, it became maximally effective from post-natal days 20-40 and thereafter rapidly lost its efficacy such that it was virtually inactive in adult animals. Dose-response curves revealed that adult animals were more than 10-fold less sensitive to NMDA than their younger counterparts. Our studies also demonstrated that NMDA increased LH via a direct effect on the hypothalamic release of LHRH since a potent LHRH antagonist competitively inhibited the effects of NMDA. Finally, we observed that morphine competitively inhibited the effects of NMDA on LH release, suggesting a relationship between NMDA-sensitive neuronal pathways and those endogenous opioid-containing systems which are known to regulate LH release.

Aging↗
PubMed1988

Oral melanoma with oral squamous carcinoma: report of a case.

A case of an oral melanoma occurring simultaneously with an oral squamous carcinoma has been presented. This combination is not thought to have been reported in the literature before. The histologic diagnosis is discussed as are the incidence, prognosis, and possible treatment of oral melanoma.

Carcinoma, Squamous Cell↗
PubMed1988

Age-related differences in the sensitivity of serum luteinizing hormone to prototypic mu, kappa and delta opiate agonists and antagonists.

It has been shown in developing male rats that morphine maximally depresses serum luteinizing hormone (LH) levels as early as postnatal day 15. In contrast, naloxone fails to increase serum LH in the prepubescent male rat but, coincident with the onset of puberty (30-35 days of age), the antagonist becomes increasingly more effective until adult appropriate responses are achieved at sexual maturation. The purpose of the present studies was to examine and characterize further the dichotomous response to naloxone and morphine in the prepubescent male rat. We found that the inability of naloxone to affect a release in LH-releasing hormone (LHRH) was not related to pharmacokinetic factors as the dose and time-response characteristics were identical in young and adult animals. In addition, our results indicated that the release of LHRH and its actions on the pituitary to promote LH release were equivalent in prepubescent and adult rats, indicating that if naloxone was capable of releasing LHRH then robust increases in LH should have occurred. Our results indicate further that the ineffectiveness of naloxone in prepubescent animals was not unique to this compound inasmuch as kappa antagonists also were devoid of activity in young animals but were highly effective in adults; delta opiate antagonists failed to increase LH either in young or adult animals. In contrast to these data, we observed that mu and kappa agonists were equipotent in depressing serum LH levels in both young and adult animals.(ABSTRACT TRUNCATED AT 250 WORDS)

Aging↗
PubMed1986

Ontogeny of the opioid-mediated control of reproductive endocrinology in the male and female rat.

Endogenous opioids (EOP) appear to inhibit the release of luteinizing hormone-releasing hormone and, subsequently, luteinizing hormone (LH). These observations have led to the hypothesis that EOP-containing neuronal systems may be involved in the onset of puberty. To examine this possibility, rats were challenged with naloxone and morphine, as probes to decrease or exaggerate, respectively, the effects of EOP on luteinizing hormone releasing hormone/LH release at intervals from birth to adulthood. Morphine had no effect on serum LH up to 15 days of age in males, but thereafter was maximally effective. On the other hand, the onset of adult-appropriate responses to morphine occurred much later in females (30-35 days) and the depressions in LH were consistently less pronounced than in comparably aged males. Naloxone produced large increases in LH in 10- and 25-day-old females, but was ineffective at 15 or 20 days. After day 25, the response to naloxone declined gradually, but was still significantly greater than control values in adults. In contrast, naloxone failed to increase serum LH from 10 to 30 days after birth in males. Beginning at 30 to 35 days of age, however, a sudden onset in the sensitivity to naloxone occurred which increased exponentially until 60 days. At this time, serum LH levels were 5 times greater in naloxone-treated males than in controls, and were twice those found in similarly treated females. These age- and sex-related differences in response to the opiates were not related to pharmacokinetic variables and also could not be attributed to gross maturational alternations in the hypothalamic-pituitary-gonadal axis.(ABSTRACT TRUNCATED AT 250 WORDS)

Age Factors↗
PubMed1986

Opiate withdrawal-induced hyposensitivity to naloxone's effects on serum luteinizing hormone in the male rat.

In previous studies, it was demonstrated that morphine pellet implantation markedly sensitized adult male rats to the subsequent elevations in serum luteinizing hormone (LH) levels produced by the opiate antagonist, naloxone. The present studies were carried out to examine the persistence of this phenomenon upon pellet removal and to characterize the relationship between naloxone-induced alterations in serum LH and the development and dissipation of precipitated withdrawal behavior. We found an excellent correlation between both the development and dissipation of naloxone-precipitated withdrawal behavior and hypersensitivity to naloxone's effects on serum LH. However, although there was no evidence of protracted effects of chronic morphine administration upon pellet removal as assessed by withdrawal behavior, the effects of naloxone on serum LH levels did not return to normal for nearly a week postwithdrawal. The markedly enhanced sensitivity to naloxone normally observed in the pellet-implanted animal dissipated immediately after pellet removal (6-24 hr), but, rather than exhibiting normal levels of responding, morphine-withdrawn animals were markedly hypo-sensitive to naloxone. The antagonist did not increase LH at all in pellet-withdrawn animals and, in fact, appeared to depress them at many doses in the acutely withdrawn animal; normal responses did not return until 4 to 7 days after pellet removal. The mechanisms underlying the striking withdrawal-induced reversal of naloxone's effects on serum LH levels are presently unclear, but our data are consistent with the hypothesis that chronic morphine administration induces a fundamental change in the sensitivity of the endogenous opioid-mediated control of LH, which takes some time to revert to normal upon abrupt termination of opiate administration.

Animals↗
PubMed1985

Luteinizing hormone releasing hormone mediates naloxone's effects on serum luteinizing hormone levels in normal and morphine-sensitized male rats.

Naloxone produces large increases in serum luteinizing hormone (LH) levels in normal males and females, supporting a role for endogenous opioids (EOP) in the tonic inhibition of LH. Since the antagonist apparently exerts no important effects on the pituitary, the reasonable assumption has been made that it elevates gonadotropin levels by affecting the release of LH-releasing hormone (LHRH) from the hypothalamus. However, at present there is no direct in vivo evidence supporting this widely-held view. In an attempt to directly demonstrate that naloxone increases the secretion of LHRH, and thereby elevates serum LH levels, we examined whether a potent synthetic antagonist of LHRH ( [D-p Glu1, D-Phe2, D-Trp3,6]-LHRH, GPT-LHRH) blocked the effects of naloxone in male rats with a normal response to naloxone and in those with a markedly enhanced sensitivity to the drug induced by a brief period of morphine pellet implantation. Our results demonstrated that GT-LHRH antagonized equipotent doses of LHRH (100 ng/kg) and naloxone (0.5 mg/kg) over a similar time course with approximately the same AD50. Most importantly, however, we showed that the GPT-LHRH produced equivalent, parallel shifts to the right in the dose-response curves for LHRH and naloxone, indicative of competitive inhibition. We also found that GPT-LHRH completely abolished the enhanced response to naloxone's effects on LH which occurs in morphine-pretreated rats. Since we observed no competition between LHRH and naloxone for their binding sites in pituitary or brain, the only viable interpretation of our results is that naloxone increases LH by inducing the release of LHRH.

Animals↗
PubMed1984

Exogenous and endogenous opioid-induced enhancements of naloxone's effects on serum luteinizing hormone levels in the male rat.

We have previously shown that brief periods of exposure to opiate alkaloid drugs markedly enhance the subsequent effects of the opiate antagonist, naloxone, on serum luteinizing hormone (LH) levels in the male rat. In the present studies, we have found that this phenomenon is not simply a property of opiate drugs, but can be produced by a metabolically stable analog of an endogenously occurring opioid peptide, methionine enkephalin (FK 33-824). These findings suggest that alterations in the sensitivity of those opioid receptors involved in LH-releasing hormone (LHRH) generated in our experimental paradigm may occur under in vivo conditions, particularly since it now appears that endogenous opioids are released in an episodic manner like most neurotransmitter/neuromodulators. We also attempted to more fully characterize the factors responsible for the development of opiate-induced enhancements of naloxone's effects on LH. We found that this effect was produced only by those doses of morphine which initially suppressed serum LH levels, followed by a "rebound" increase in the gonadotropin 6-8 h later. A modest facilitation of LHRH-evoked increases in serum LH was also observed, but our data suggest that this represents only a minor component of opiate-induced enhancements of naloxone's effects. These data indicate that hypothalamic or suprahypothalamic sites are the major loci involved, but no differences in the uptake or regional distribution of naloxone in brain have been previously found, as a function of morphine pretreatment, nor were we able to demonstrate any alterations in opiate binding sites in the hypothalamus or whole brain. Thus, the mechanisms involved in this effect remain unclear.

Animals↗
PubMed1984

Enhancement of opiate-induced depressions in serum luteinizing hormone levels by the prior administration of naloxone in the male rat.

The effects of naloxone pretreatment on opiate agonist-induced depressions in serum luteinizing hormone (LH) levels were examined in male rats. Our results demonstrated a pronounced enhancement of morphine's actions 6 hours after the administration of naloxone (0.5 mg/kg). This effect was characterized by a 10 fold reduction in the ED50 (1.26 mg/kg versus 0.13 mg/kg in saline- and naloxone-pretreated rats, respectively) and much greater depressions in serum LH levels at each dose of morphine. The actions of naloxone were not confined to morphine, since similar increased potencies were found for opioid agonists with selectivity for a variety of opioid receptor subtypes. Because naloxone did not alter the uptake of subsequently administered morphine into brain, our results cannot be explained on the basis of an increased availability of the agonist. Rather, it appears that naloxone pretreatment induces a change in the sensitivity of those receptors involved in the effects of opioid agonists on LH.

Animals↗
PubMed1983

Testosterone does not influence opiate binding sites in the male rat brain.

It has been reported previously that castration produces testosterone-reversible increases in the density of 3H-naltrexone binding sites in the male rat brain. Unfortunately, we were unable to replicate these observations in a comprehensive series of studies. Specifically, we found that castration failed to produce changes in the Kd or Bmax of opiate binding sites in whole male rat brain, or in the hypothalamus, utilizing 3H-dihydromorphine (a mu receptor ligand), 3H-D-alanine, D-leucine enkephalin (delta) or 3H-naltrexone (ubiquitous). Furthermore, we found that the relative proportion of mu and delta binding sites in brain was unchanged by castration. The reasons for the discrepancy between the present results and those previously reported are unclear, but it appears that the provocative hypothesis that testosterone influences opioid receptors in brain must be carefully reevaluated.

Alanine↗
PubMed1983

Opiate-induced enhancement of the effects of naloxone on serum luteinizing hormone levels in the male rat: specificity for Mu agonists.

We have shown previously that acute morphine administration markedly enhances naloxone-induced increases in serum luteinizing hormone (LH) levels in the male rat. The purposes of the present studies were to determine whether this effect was opiate-specific and, if so, whether it was mediated by mu, kappa or sigma opiate receptors. In agreement with our previous reports, we found that naloxone-induced increases in serum LH levels were markedly enhanced (greater than 400%) in morphine-pretreated rats, relative to controls, 6 to 8 hr after a single injection; furthermore, similar effects were observed with all mu agonists assessed with the order of potency being etorphine greater than levorphanol greater than morphine greater than methadone greater than codeine. In contrast, we were unable to demonstrate any enhancement of the effects of naloxone on serum LH levels by ketocyclazocine, cyclazocine or SKF 10,047, prototypic ligands for kappa and sigma binding sites in brain. Finally, we observed that neither ethanol nor Nembutal induced a period of supersensitivity to the effects of naloxone on LH, even though both compounds transiently depressed serum LH levels over a time course similar to that observed for the opiates. On the basis of these results, it appears that the phenomenon of opiate-induced enhancement of the effects of naloxone on serum LH levels is opiate specific and, most importantly, is a unique feature of mu opiate agonists. The mechanisms underlying this phenomenon are unclear, but our results suggest that as yet unidentified events occurring within the hypothalamus must be responsible.

Animals↗
PubMed1983

Morphine-induced supersensitivity to the effects of naloxone on luteinizing hormone secretion in the male rat.

The effects of morphine pretreatment on naloxone-induced increases in serum luteinizing hormone (LH) levels were examined in male rats. After a single morphine injection (10 mg/kg), naloxone (0.5 mg/kg)-induced increases in serum LH levels were initially suppressed (0-3 hr), but returned to normal by 4 hr. Five to 24 hr after morphine pretreatment, however, naloxone-precipitated increases in LH were markedly exaggerated with the peak effect occurring at 6 hr (4 times greater than saline-pretreated controls). In morphine-implanted rats (75-mg pellet, 48 hr earlier), the enhanced sensitivity to naloxone was considerably more dramatic than that found after acute administration. Naloxone-induced increases in serum LH levels were more than 40 to 50 times greater in morphine-implanted animals than they were in placebo-implanted rats at the respective ED50 dose. Naloxone dose-response curves revealed that the naloxone ED50 was reduced by either morphine pretreatment regimen, but was much more pronounced in pellet-implanted animals [181.6 micrograms/kg in controls; 116.4 micrograms/kg in acutely morphinized animals (P less than .05); and 4.39 micrograms/kg in morphine-implanted rats (P less than .001)]. The only distinction between acute and chronic morphine administration was in the magnitude of the shift in the naloxone ED50 as identical peak increases in LH were obtained in both groups. Finally, our data indicate that naloxone-induced increases in serum LH levels can serve as a useful and sensitive means to assess opiate dependence. The mechanisms underlying the morphine-induced enhancement of the effects of naloxone on serum LH levels are not fully understood, but we found no differences in the uptake of naloxone into brain as a function of morphine pretreatment.

Animals↗
PubMed1982

Development of tolerance to the effects of morphine on luteinizing hormone secretion as a function of castration in the male rat.

The effects of morphine on the secretion of luteinizing hormone (LH) were examined in male rats at intervals after castration. We found that morphine was extremely effective in suppressing serum LH levels in animals that had been castrated for periods of less than 7 days, but was considerably less potent in long-term castrates (13 + days). For example, the dose of morphine producing the half-maximal suppression of serum LH levels in 3-day castrates was 1.5 mg/kg, whereas in 31-day castrates the ED50 was 13.8 mg/kg. This insensitivity to morphine satisfied the two pharmacological criteria for tolerance: a parallel shift to the right in the morphine dose-response curve and a reduced effect of the drug at the same brain concentration. Hence, castration appeared to render male rats, never exposed to opiates, tolerant to the effects of morphine. Corresponding to the development of tolerance to morphine, 31-day castrates were also less responsive to the LH-depressing effects of testosterone than were 3-day castrates or sham-operated controls. In marked contrast to these results, castration did not significantly affect naloxone-induced increases in serum LH levels. The tolerance observed to morphine in the long-term castrated rat was selective to LH secretion because long- and short-term castrates and sham-operated controls were equally responsive to the antinociceptive effects of morphine (in fact, at a dose of 8 mg/kg long-term castrates were more sensitive to morphine than short-term castrates or sham-operated controls) and there was no apparent shift in the LD50. The mechanisms underlying the development of tolerance to morphine in castrated male rats are not clear at the present time.

Analgesics↗