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At least 127 records · Page 7Linked to original sources
PubMed2004

Ghrelin effects on gonadotropin secretion in male and female rats.

Ghrelin is a 28-amino acid peptide primarily involved in the control of food intake and growth hormone secretion. The present experiments were carried out to analyze the potential involvement of ghrelin in the control of gonadotropin secretion. Prepubertal intact and gonadectomized female and male rats, cyclic rats in diestrus, lactating rats and aged female rats were i.c.v. injected with ghrelin (3 nmol/rat) and blood samples were obtained by decapitation 15 min later. In addition, we analyzed the effects of ghrelin on in vitro basal and luteinizing hormone-releasing hormone (LHRH)-stimulated gonadotropin secretion. Our present results indicate that ghrelin inhibited luteinizing hormone (LH) secretion in vivo in prepubertal males as well as gonadectomized males and females, whereas follicle-stimulating hormone (FSH) remained unaffected. In vitro, ghrelin stimulated the secretion of both gonadotropins, and differentially modulated the response to LHRH; the LH response was inhibited, while the FSH response was enhanced. Overall, our current data open up the possibility that ghrelin may be involved in the control of LH secretion, and in the dissociation of both gonadotropins that takes place in many physiological, pathological and experimental situations.

Animals↗
PubMed2005

Effect of streptozotocin-induced diabetes on the gene expression and biological activity of 3beta-hydroxysteroid dehydrogenase in the rat spinal cord.

Abnormal secretion of steroids by the adrenals and gonads is one of the disturbances occurring in diabetics but the impact of diabetes on steroid formation in the nervous system has never been studied. However, it is well known that numerous actions of peripheral steroids on the nervous system require their conversion into neuroactive metabolites within the neural tissue. As this in situ steroid synthesis/metabolism is crucial for the control of several neurobiological functions, we investigated the effects of streptozotocin-induced diabetes on the gene expression and activity of 3beta-hydroxysteroid dehydrogenase in the spinal cord, a pivotal structure involved in sensorimotor and neurovegetative mechanisms. 3beta-Hydroxysteroid dehydrogenase is a key enzyme which participates to the biosynthesis of all classes of steroids by converting delta5-3beta-hydroxysteroids such as pregnenolone and dehydroepiandrosterone into delta4-3-ketosteroids as progesterone and androstenedione, respectively. Reverse transcription coupled with quantitative real-time polymerase chain reaction revealed that 3beta-hydroxysteroid dehydrogenase gene was over-expressed in the spinal cord of streptozotocin-treated rats compared with controls. Pulse-chase experiments combined with high performance liquid chromatography and continuous flow detection of newly-synthesized steroids showed an increase of 3beta-hydroxysteroid dehydrogenase activity responsible for a hyper-production of progesterone in the spinal cord of diabetic rats. This up-regulation of progesterone biosynthesis was concomitant with a decrease of its transformation into tetrahydroprogesterone, a process which facilitated progesterone accumulation in the spinal cord of streptozotocin-treated rats. Since progesterone is a potent neuroprotective steroid, increase of its production appeared as an endogenous molecular and biochemical mechanism triggered by spinal nerve cells to cope with degenerative effects of streptozotocin-induced diabetes. Our results constitute the first direct evidence showing an impact of diabetes on steroid biosynthetic and metabolic pathways in the nervous system. The data open new perspectives for the modulation of deleterious effects of diabetes by neuroprotective steroids.

3-Hydroxysteroid Dehydrogenases↗
PubMed2005

The agouti-related protein and its role in energy homeostasis.

The melanocortin system plays an important role in the regulation of energy homeostasis. The Agouti-related protein (AGRP) is a natural antagonist of the action of alpha-melanocyte stimulating hormone (alpha-MSH) at the melanocortin receptors (MCR). AGRP is upregulated by fasting while intracerebroventricular injections of synthetic AGRP lead to increased appetite and food intake. Transgenic mice overexpressing AGRP are also hyperphagic and eventually become obese. AGRP is, therefore, a significant regulator of energy balance and a candidate gene for human fatness. Indeed, humans with common single nucleotide polymorphisms (SNPs) in the promoter or the coding region are leaner and resistant to late-onset obesity than wild-type individuals. AGRP is also expressed in the periphery. Recent studies show that AGRP in the adrenal gland is upregulated by fasting as much as it is in the hypothalamus. These data open up the possibility for a wider role by AGRP not only in food intake but also in the regulation of energy balance through its actions on peripheral tissues. This review summarizes recent advances in the biochemical and physiological properties of AGRP in an effort to enhance our understanding of the role this powerful neuropeptide plays in mammalian energy homeostasis.

Agouti-Related Protein↗
PubMed2004

Intracellular signaling triggered by antiphospholipid antibodies in platelets and endothelial cells: a pathway to targeted therapies.

Understanding the intracellular events triggered by antiphospholipid (aPL) antibodies in platelets and endothelial cells (ECs) is important in designing new modalities of targeted therapies for the treatment of thrombosis in Antiphospholipid Syndrome (APS). A recent study showed a significant increase in the expression of GPIIb/IIIa on platelets treated with aPL antibodies and a thrombin receptor peptide agonist (TRAP), and these effects were abrogated by hydroxychloroquine (HQ). Hydroxychloroquine has also been shown to reduce in vivo aPL-induced thrombus formation. Furthermore, aPL-enhanced thrombosis in vivo can be abrogated by infusions of a GPIIb/IIIa antagonist (1B5) monoclonal antibody, and aPL-mediated thrombophilia is not observed in GPIIb/IIIa-deficient mice. Treatment of platelets with aPL antibodies has resulted in a significant increase in p38 mitogen-activated protein kinase (p38MAPK) phosphorylation and aPL-induced platelet aggregation and thromboxane B2 (TXB2) production was abrogated by SB203580 (a p38MAPK inhibitor). aPL antibodies induce increased expression, function and transcription of tissue factor (TF) on EC. Activation of ECs and thrombogenicity of aPL in vivo can be reversed by treatment of the animals with statins. Upregulation of TF on ECs can also be abrogated by treatment of the cells with fluvastatin. There is also indication of activation of nuclear factor kappa B (NFkappaB), increase in phosphorylation of p38MAPK in ECs by aPL antibodies that can be reversed by specific inhibitors MG132 and SB203580, respectively. The data open the possibility to new treatment modalities that may include the use of hydroxychloroquine, statins, specific antagonists of GPIIb/IIIa (such as abciximab or equivalent) and specific p38MAPK inhibitors, after the completion of well-designed clinical studies.

Animals↗
PubMed2006

B5-deficient vaccinia virus as a vaccine vector for the expression of a foreign antigen in vaccinia immune animals.

Recombinant vaccinia viruses have shown promise as vaccine vectors. However, their effectiveness is markedly reduced by pre-existing anti-vaccinia immunity. The possibility of new vaccinia immunizations in the event of a bioterror-related smallpox release poses an additional negative impact on the utility of vaccinia-based vectors. Thus, we aimed to design a vaccinia vector that would enhance the immune response to an expressed foreign protein in a pre-immune animal model. To do this, we made use of the finding that most neutralizing antibodies against the extracellular form of vaccinia virus are directed against the B5 protein. We found that mice immunized with vaccinia, primed with Gag plasmid DNA, and boosted with a recombinant vaccinia virus lacking the majority of the B5 ectodomain expressing a test antigen, HIV Gag, had stronger anti-Gag immune responses than mice that were boosted with a wild-type virus-expressing Gag. These findings are particularly striking given the more attenuated phenotype of this virus, as compared to its wild-type counterpart. Importantly, we found that vaccination with a B5R deletion virus, followed by boosting with the Gag-expressing virus lacking the majority of the B5 ectodomain, resulted in poorer anti-Gag immune responses. Thus, recombinant vaccinia viruses lacking the B5 ectodomain may serve as vaccine vectors in DNA prime-vaccinia boost vaccinations of individuals with pre-existing immunity against vaccinia. These data open the possibility of extending the potential benefit of replication competent recombinant vaccinia virus vectors to a larger population.

AIDS Vaccines↗
PubMed2004

Selective inhibition of polysialyltransferase ST8SiaII by unnatural sialic acids.

Polysialic acid (polySia) is a unique and highly regulated posttranslational modification of the neural cell adhesion molecule (NCAM). The presence of polySia affects NCAM-dependent cell adhesion and plays an important role during brain development, neural regeneration and plastic processes including learning and memory. Polysialylated NCAM is expressed on several neuroendocrine tumors of high malignancy and correlates with poor prognosis. Two closely related enzymes, the polysialyltransferases ST8SiaII and ST8SiaIV, catalyze the biosynthesis of polySia. However, the impact of each enzyme in NCAM polysialylation is not understood. Here, we describe the selective cell-based in vitro inhibition of ST8SiaII using synthetic sialic acid precursors. We provide evidence for different substrate affinities of ST8SiaII and ST8SiaIV. These data open the possibility to study the individual role of the two enzymes during various aspects of brain development and function and in tumorigenesis.

Animals↗
PubMed1992

Morphological and biochemical evidence for partial nuclear localization of annexin 1 in endothelial cells.

Using immunofluorescence, an affinity-purified anti-annexin-1 polyclonal antibody showed both cytoplasmic and nuclear staining, whereas antibodies against annexins 2, 5 and 6 labelled almost exclusively the cytoplasm of cultured endothelial cells. This was further confirmed by immunogold labelling and electron microscopy using a monoclonal antibody, annexin 1 being detected close to the plasma membrane, in the cytoplasm, as well as inside the nucleus. Finally, using immunoblotting, purified nuclei were shown to contain annexin 1, which was not removed by EDTA treatment. These data open some new perspectives in the understanding of annexin function, including possible involvement in nucleoskeleton dynamics and regulation of proliferation through cell signalling.

Animals↗
PubMed1992

Partial remission of hemiplegia and somatoparaphrenia through vestibular stimulation in a case of unilateral neglect.

In a case of long lasting severe neglect resulting from a large right parieto-temporo-occipital infarct, vestibular stimulation produced a temporary reduction of the motor deficit and disappearance of the somatoparaphrenic delusion, in addition to the already reported improvement of extrapersonal and personal neglect and anosognosia. These data open new perspectives in the understanding of the neglect syndrome and of functional involvement of the parietal lobe in space representation.

Aged↗
PubMedDate not supplied

Wistar rat palpebral conjunctiva contains more slow-cycling stem cells that have larger proliferative capacity: implication for conjunctival epithelial homeostasis.

PURPOSE: To determine the location of conjunctival epithelial stem cells. METHODS: Wistar rats received daily injection of 5-bromo-2-deoxyuridine (BrdU) at a dose of 5 mg/100 g for 2 weeks followed by a 1-month BrdU-free period before death. After the rats were sacrificed, the orbital contents and eyelids were exenterated en bloc, fixed in buffer formalin, and embedded in paraffin. To compare the proliferative capacity of ocular epithelial cells, 1.0% phorbol myristate (TPA) in petrolatum was topically applied once daily to both eyes of Wistar rats for 12 days. After 6, 12, 18, and 24 hours and 2, 4, 6, 8, 10, and 12 days of TPA treatment, rats were administered BrdU intraperitoneally 7 hours before they were sacrificed. The ocular epithelium was fixed and processed for immunochemistry, and the labeling index (LI) of every epithelial zone was determined. RESULTS: Slow-cycling cells, detected as label-retaining cells (LRCs), were found in bulbar, fornical, and palpebral epithelia and mucocutaneous junctions, as well as in limbal epithelia. The greatest numbers of LRCs were identified in palpebral epithelium. Under normal situations, in conjunctiva the LI was lowest in palpebral epithelium (2.1 +/- 0.5) compared with bulbar (2.2 +/- 0.5), fornical (2.3 +/- 0.4) epithelia and mucocutaneous junction (3.4 +/- 0.9), respectively. In cornea, the LI was lowest in limbal epithelium (1.8 +/- 0.7) compared with central corneal epithelium (3.5 +/- 0.6). Twenty-four hours after TPA treatment, an 8.2-fold increase in the palpebral epithelial basal cell labeling index was noted compared with 4.7-fold, 5.7-fold, and 3.8-fold increases in bulbar, fornical, and mucocutaneous junction epithelial basal cell labeling indices, and a sevenfold increase in the limbal basal cell labeling indices compared with a 2.1-fold increase in the corneal basal cell labeling index, respectively. Limbal and palpebral epithelia maintained a significantly greater proliferative response (5.5-to 6.3-fold increase, respectively) during chronic stimulation than corneal, bulbar, fornical epithelia, and mucocutaneous junction (0.6- to 2.3-fold increase, respectively). CONCLUSIONS: In Wistar rat conjunctiva, slow-cycling cells are primarily located in palpebral epithelium, which has greater proliferative capacity than other conjunctival epithelia. This finding means that, in the Wistar rat, the conjunctival epithelial stem cells are mainly located in palpebral epithelium. These data open new perspectives in ocular epithelial development and are relevant in conjunctival wound repair.

Animals↗
PubMed2002

Differential gene expression in gamma-irradiated BALB/3T3 fibroblasts under the influence of 3-aminobenzamide, an inhibitior of parp enzyme.

3-Aminobenzamide (3AB) is an inhibitor of poly (ADP-ribose) polymerase (PARP), an enzyme implicated in the maintenance of genomic integrity, which is activated in response to radiation-induced DNA strand breaks. cDNA macroarray membranes containing 1536 clones were used to characterize the gene expression profiles displayed by mouse BALB/3T3 fibroblasts (A31 cell line) in response to ionizing irradiation alone or in combination with 3AB. A31 cells in exponential growth were pre-treated with 3AB 4mM 1h before gamma-irradiation (4Gy), remaining in culture during 6h until harvesting time. A31 cells treated with 3AB alone presented a down-regulation in genes involved in protein processing and cell cycle control, while an up-regulation of genes involved in apoptosis and related to DNA/RNA synthesis and repair was verified. A31 cells irradiated with 4Gy displayed 41 genes differentially expressed, being detected a down-regulation of genes involved in protein processing and apoptosis, and genes controlling the cell cycle. Concomitantly, another set of genes for protein processing and related to DNA/RNA synthesis and repair were found to be up-regulated. A positive or negative interaction effect between 3AB and radiation was verified for 29 known genes. While the combined treatment induced a synergistic effect on the expression of LCK proto-oncogene and several genes related to protein synthesis/processing, a negative interaction effect was found for the expression of genes related to cytoskeleton and extracellular matrix assembly (SATB1 and Anexin III), cell cycle control (tyrosine kinase), and genes participating in DNA/RNA synthesis and repair (RNA helicase, FLAP endonuclease-1, DNA-3 glycosylase methyladenine, splicing factor SC35 and Soh1). The present data open the possibility to investigate the direct participation of specific genes, or gene products acting in concert in the mechanism underlying the cell response to radiation-induced DNA damage under the influence of PARP inhibitor.

3T3 Cells↗
PubMed2000

Nerve growth factor and retinoic acid inhibit proliferation and invasion in thyroid tumor cells.

NGF has anti-proliferative and anti-invasive effects in neuroendocrine tumors. In the present work we examined the effects of NGF and retinoic acid on cell proliferation and invasion in thyroid carcinoma cells. We found that NGF and retinoic acid do not affect cell proliferation on their own but in combination they produce a strong inhibition. We also found that retinoic acid regulates the matrix metalloproteinase 2 activity and invasion. In contrast, NGF inhibited invasion and reverted the effect of retinoic acid. This effect of NGF is likely mediated by an increase in adhesion to laminin and collagen IV and the inhibition of cell migration. NGF also induced the expression of the p75 NGF receptor. In conclusion, NGF and retinoic acid in combination inhibit proliferation and invasion of thyroid papillary carcinoma cells. These data open the possibility of a potential combined therapy for thyroid papillary carcinomas.

Antineoplastic Agents↗
PubMed2003

On the role of menopause for sleep-endocrine alterations associated with major depression.

Aging and menopause are associated with alterations of the sleep EEG, while age-related changes of the hypothalamo-pituitary-adrenal (HPA) axis remain controversial. Major depression is also associated with typical sleep-endocrine changes, including enhanced activity of the HPA axis, while an influence of age and gender on these alterations is less clear. To test the hypothesis that after menopause sleep-endocrine alterations associated with major depression are accentuated, we examined the sleep EEG and nocturnal hormone secretion (ACTH, cortisol, GH, estradiol, LH, FSH, and leptin) in 16 drug-free female patients, mostly with the first episode of a major depressive disorder (seven pre- and nine postmenopausal subjects) and 19 female controls (10 subjects in the early follicular phase and nine postmenopausal subjects). Nocturnal cortisol secretion was increased in postmenopausal patients with depression, while a decrease was noted in postmenopausal controls. Sleep alterations typically associated with depression, namely a reduction in sleep continuity and slow wave sleep (SWS) and an increase in REM density, were prominent in post- but not in premenopausal patients. An inverse correlation was noted between the decline in SWS and sleep continuity and FSH secretion in patients with depression, suggesting a role of menopause for these sleep-endocrine alterations typically associated with major depression. In contrast, in premenopausal patients we noted primarily a shift in SWS and delta-EEG activity from the first to the second non-REM period, which was not related to age or hormone secretion. Though the relatively small number of subjects per group precludes a definitive conclusion, our data open up the possibility that the sleep-endocrine changes typically associated with major depression are most prominent in postmenopausal patients. Whether the predominant alteration of the distribution of SWS and delta EEG activity in younger patients with a first episode of major depression has a predictive value for the future course of the disease remains to be investigated.

Adrenocorticotropic Hormone↗
PubMed2001

Cerebral networks in sensorimotor disturbances.

Increasing evidence suggests that the human brain employs multiple, interconnected brain areas for information processing and control of behavior, including the performance of laboratory tasks. Brain diseases are expected to affect these networks directly by interference and indirectly as a consequence of deficit compensation. Covariance analyses applied to functional brain imaging data open the opportunity to study neural networks and their disease-related changes in the human brain. Here, we review our analytic approach based on principal component analysis (PCA) to address such questions. We will discuss its methodological foundations and applications in patients with sensorimotor disorders. We will show that PCA in combination with, both, hypothesis-driven testing and correlation statistics provides a powerful tool for elucidating disease-related abnormalities and postlesional reorganization of neural networks in the human brain.

Adult↗
PubMed1998

Profiling of the eye aqueous humor in exfoliation syndrome by high-performance liquid chromatographic analysis of hyaluronan and galactosaminoglycans.

The concentrations of hyaluronan and galactosaminoglycans -- i.e., chondroitin sulfate and dermatan sulfate -- were measured in the aqueous humor of the eye from patients with exfoliation syndrome and from healthy persons. The glycosaminoglycans/proteoglycans were almost completely precipitated (>97%) with ethanol in the presence of dextran as carrier and, following enzymic digestion, hyaluronan and galactosaminoglycans, were quantitatively converted to delta4,5-disaccharides. Non-degraded heparan sulfate and proteins/glycoproteins were removed by ultrafiltration using a Centricon 3 membrane. Separation and determination of hyaluronan- and galactosaminoglycan-derived delta-disaccharides were performed by ion-suppression HPLC. For an accurate analysis in triplicate, as little as 50 microl of aqueous humor is required. Application of this method to the analysis of samples from six patients with exfoliation syndrome and three healthy persons showed that hyaluronan levels in patients (6.65-16.15 microg ml(-1)) were significantly higher (3-8 times) than in healthy persons (2.0-2.24 microg ml(-1)). There was no significant alteration in the galactosaminoglycan concentration. The obtained data open a new area in the deeper understanding of the exfoliation syndrome pathophysiology and in establishing a highly sensitivity and accurate HPLC method for its diagnosis and patient's follow-up.

Aqueous Humor↗
PubMed1995

The Benchmarking Effort for Networking Children's Hospitals (BENCHmark).

BACKGROUND: In 1992, 12 large children's hospitals established the Benchmarking Effort for Networking Children's Hospitals (BENCHmark). The goal was for the BENCHmark effort to supplement the hospitals' continuous quality improvement (CQI) programs and to speed adoption of best practices from peer institutions. For three years, the hospitals have been comparing data on cost, quality, and speed indicators. Also, "best practice" groups have met to share information on how processes can be improved. RESULTS: The BENCHmark hospitals have experienced significant process improvement in areas such as emergency department waiting time and admitting process time. EXAMPLE: The BENCHmark hospitals selected admitting as one of the first best practice groups to meet. Interdisciplinary staff from all BENCHmark hospitals met three times over the course of a year to define their indicator and share information on best practices. St Louis Children's Hospital, as a result, instituted a pre-arrival team and cross-trained staff, with the result being a reduction of admitting processing time from 58 minutes to 19 minutes. Same-day surgery patients now bypass the admitting department and go directly to the surgical floor. Patient and surgeon satisfaction has increased greatly. CONCLUSIONS: Hospitals that are planning to benchmark are encouraged to reach consensus on project goals and to focus on indicators that provide a clear business advantage. Physician involvement is key to improving performance and physicians will only be engaged if the hospitals against whom they are benchmarked are considered peers. Being willing to share initial data openly seems to be a key factor in determining successful integration of the BENCHmark process into hospital CQI efforts. The BENCHmark project has been so successful that a second group of 12 comparable pediatric institutions, known as the Network II, has been established.

Efficiency, Organizational↗
PubMed2002

Proton and electron pathways in the bacterial nitric oxide reductase.

Electron- and proton-transfer reactions in bacterial nitric oxide reductase (NOR) have been investigated by optical spectroscopy and electrometry. In liposomes, NOR does not show any generation of an electric potential during steady-state turnover. This electroneutrality implies that protons are taken up from the same side of the membrane as electrons during catalysis. Intramolecular electron redistribution after photolysis of the partially reduced CO-bound enzyme shows that the electron transfer in NOR has the same pathway as in the heme-copper oxidases. The electron is transferred from the acceptor site, heme c, via a low-spin heme b to the binuclear active site (heme b3/FeB). The electron-transfer rate between hemes c and b is (3 +/- 2) x 10(4) s(-1). The rate of electron transfer between hemes b and b3 is too fast to be resolved (>10(6) s(-1)). Only electron transfer between heme c and heme b is coupled to the generation of an electric potential. This implies that the topology of redox centers in NOR is comparable to that in the heme-copper cytochrome oxidases. The optical and electrometric measurements allow identification of the intermediate states formed during turnover of the fully reduced enzyme, as well as the associated proton and electron movement linked to the NO reduction. The first phase (k = 5 x 10(5) s(-1)) is electrically silent, and characterized by the disappearance of absorbance at 433 nm and the appearance of a broad peak at 410 nm. We assign this phase to the formation of a ferrous NO adduct of heme b3. NO binding is followed by a charge separation phase (k = 2.2 x 10(5) s(-1)). We suggest that the formation of this intermediate that is not linked to significant optical changes involves movement of charged side chains near the active site. The next step creates a negative potential with a rate constant of approximately 3 x 10(4) s(-1) and a weak optical signature. This is followed by an electrically silent phase with a rate constant of 5 x 10(3) s(-1) leading to the last intermediate of the first turnover (a rate constant of approximately 10(3) s(-1)). The fully reduced enzyme has four electrons, enough for two complete catalytic cycles. However, the protons for the second turnover must be taken from the bulk, resulting in the generation of a positive potential in two steps. The optical measurements also verify two phases in the oxidation of low-spin hemes. Based on these results, we present mechanistic models of NO reduction by NOR. The results can be explained with a trans mechanism rather than a cis model involving FeB. Additionally, the data open up the possibility that NOR employs a P450-type mechanism in which only heme b3 functions as the NO binding site during turnover.

Bacterial Proteins↗
PubMed2004

Oral bioavailability of a new class of micro-opioid receptor agonists containing 3,6-bis[Dmt-NH(CH(2))(n)]-2(1H)-pyrazinone with central-mediated analgesia.

The inability of opioid peptides to be transported through epithelial membranes in the gastrointestinal tract and pass the blood-brain barrier limits their effectiveness for oral application in an antinociceptive treatment regime. To overcome this limitation, we enhanced the hydrophobicity while maintaining the aqueous solubility properties in a class of opioid-mimetic substances by inclusion of two identical N-termini consisting of Dmt (2',6'-dimethyl-l-tyrosine) coupled to a pyrazinone ring platform by means of alkyl chains to yield the class of 3,6-bis[Dmt-NH-(CH(2))(n)]-2(1H)-pyrazinones. These compounds displayed high micro-opioid receptor affinity (K(i)micro = 0.042-0.115 nM) and selectivity (K(i)delta/K(i)micro = 204-307) and functional micro-opioid receptor agonism (guinea-pig ileum, IC(50) = 1.3-1.9 nM) with little or undetectable bioactivity toward delta-opioid receptors (mouse vas deferens) and produced analgesia in mice in a naloxone reversible manner when administered centrally (intracerebroventricular, i.c.v.) or systemically (subcutaneously and orally). Furthermore, the most potent compound, 3,6-bis(3'-Dmt-aminopropyl)-5-methyl-2(1H)-pyrazinone (7'), lacked functional delta-opioid receptor bioactivity and was 50-63-fold and 18-21-fold more active than morphine by icv administration as measured analgesia using tail-flick (spinal involvement) and hot-plate (supraspinal effect) tests, respectively; the compound ranged from 16 to 63% as potent upon systemic injection. These analgesic effects are many times greater than unmodified opioid peptides. The data open new possibilities for the rational design of potential opioid-mimetic drugs that pass through the epithelium of the gastrointestinal tract and the blood-brain barrier to target brain receptors.

Administration, Oral↗