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A Baamonde

Publications and source records attributed to A Baamonde.

At least 37 records · Page 2Linked to original sources
PubMed1992

Antidepressant-type effects of endogenous enkephalins protected by systemic RB 101 are mediated by opioid delta and dopamine D1 receptor stimulation.

The role of endogenous enkephalins in behavioural control in mice was investigated by i.v. injection of RB 101 (N-[(R,S)-2-benzyl-3[(S)(2-amino-4- methylthio)butyl dithio]-1-oxopropyl]-L-phenylalanine benzyl ester). RB 101 is a recently reported systemically active mixed inhibitor prodrug of the two enzymes which metabolize the enkephalins neutral endopeptidase 24.11 and aminopeptidase N. RB 101 (2.5-10 mg/kg) induced a dose-dependent long-lasting hyperlocomotion and attenuated the conditioned suppression of motility in mice placed in an environment where they had received footshocks 24 h before. In addition, RB 101 decreased the duration of immobility in the forced swim test. All these actions of RB 101 were antagonized by the selective delta antagonist, naltrindole, supporting the preferential involvement of delta opioid receptors in these enkephalin-controlled behavioural responses. The effects induced by RB 101 were also suppressed by prior administration of the selective dopamine D1 antagonist, SCH 23390, but not by the D2 antagonist, sulpiride. Attenuation of the conditioned suppression of motility was associated with increased striatal dihydroxyphenylacetic acid (DOPAC)/dopamine (DA) and homovanillic acid (HVA)/DA ratios, both effects being antagonized by naltrindole. This latter compound is also efficient to inhibit the effect of imipramine in the mouse forced swim test. Taken together, these results support the occurrence of tonic and phasic controls of mood-related behaviour by endogenous enkephalins through delta and D1 receptor stimulation and suggest a possible future use of these mixed inhibitors as new antidepressants.

Animals↗
PubMed1992

In vivo occupation of mouse brain opioid receptors by endogenous enkephalins: blockade of enkephalin degrading enzymes by RB 101 inhibits [3H]diprenorphine binding.

With the aim of possibly studying the local activity of brain enkephalinergic pathways by autoradiography and positron emission tomography, preliminary competition experiments of [3H]diprenorphine binding in mouse brain were carried out after i.v. administration of the first systemically-active mixed inhibitor of enkephalin degrading enzymes RB 101 (N(R,S)-2-benzyl-3[(S)-(2-amino-4-methylthiobutyldithio]-1-oxoprop yl]- L-phenylalanine benzyl ester). Although devoid of affinity for the opioid binding sites, RB 101 inhibited the [3H]diprenorphine binding to the opioid receptors in a dose-dependent manner. This effect, very likely due to an RB 101-induced increase in extracellular levels of enkephalins, reached a plateau at a dose of 10 mg/kg, where almost 30% displacement was observed. Intravenous administration of either 5 or 20 mg/kg of RB 101 in mice submitted to warm-swim stress led to an additional [3H]diprenorphine displacement, which reached 45% compared to unstressed controls. This ceiling effect could account for the reported minimal morphine-like side effects induced by mixed inhibitors. A large increase in endogenous enkephalin levels induced by RB 101, associated or not with stress, was also indirectly demonstrated by the analgesic responses elicited by i.v. injection of the mixed inhibitor. This effect was blocked by naloxone but not by the delta antagonist naltrindole (NTI), supporting a preferential implication of mu receptors in supraspinal analgesia. Taken together, these results suggest that RB 101 could be used to determine the precise in vivo localization of enkephalinergic pathways recruited by various stimuli.

Analgesics↗
PubMed1991

Brain passage of BUBU, a highly selective and potent agonist for delta opioid receptors: in vivo binding and mu versus delta receptors occupancy.

The peptidase-resistance and bioavailability of BUBU [H-Tyr-D.Ser(OtBu)-Gly-Phe-Leu-Thr(OtBu)-OH], a highly selective and potent agonist of the delta opioid receptor, have been investigated in vitro and in vivo. In vitro at 37 degrees C, the peptide was fully resistant to degradation by rat serum and strongly resistant to degradation by rat brain membranes. In vivo 0.065% of the dose of [3H]BUBU injected intravenously to the mouse was present 15 min later in the brain. The percentage determined for [3H]DAGO [H-Tyr-D.Ala-Gly-(NMe)Phe-Gly-ol], a selective ligand for mu sites, was 0.038%. Specific binding to mouse brain membranes, determined after intracerebroventricular injection of [3H]BUBU, was saturable and a high affinity (KDapp = 25 pmol) was evaluated for the delta-agonist. Competition experiments showed that BUBU is a selective ligand for delta receptors in vivo. Comparison of the analgesic potency (hot plate test) of ICV or IV administered increasing doses of BUBU and DAGO with their in vivo binding properties supports the preferential involvement of mu receptors in supraspinal analgesia. BUBU also induced an increase in spontaneous locomotion after IV administration at a dose lower than that which produced analgesia. The quantitative results obtained in the present study demonstrate that BUBU and DAGO could be used to characterize the pharmacological responses induced by selective stimulation of delta and mu receptors after systemic administration.

Analgesics↗
PubMed1991

Systemic administration of (Tyr-D-Ser(O-tert-butyl)-Gly-Phe-Leu-Thr(O-tert-butyl), a highly selective delta opioid agonist, induces mu receptor-mediated analgesia in mice.

The mu opioid receptors are unquestionably implicated both in supraspinal and spinal analgesia, but there is some controversy about the role of delta receptors in the control of pain at the supraspinal level. This could be due, at least in part, to the local or i.c.v. administration of the opioid agonists. It was therefore interesting to reassess the overall contribution of mu and delta opioid receptors in modulating nociceptive thermal stimuli in the hot plate-test in mice after i.v. injections of DAMGO (Tyr-D-Ala-Gly-(NMe)Phe-Gly-ol) and BUBU (Tyr-D-Ser(O-tert-butyl)-Gly-Phe-Leu-Thr(O-tert-butyl), two highly selective mu and delta receptor agonists, respectively, whose passage into the brain has been demonstrated recently. Both agonists induced dose-dependent, short-lasting (less than 30 min), antinociceptive responses that peaked 5 min after the administration of DAMGO and 10 min after the administration of BUBU. At these times, DAMGO [ED50: 1.26 mumols (0.65 mg)/kg] was 34 times more potent than BUBU [ED50: 42.5 mumols (34 mg)/kg] in the jump response and 13 times more potent in the paw lick. Apparent pA2 values of naloxone (0.004-0.1 mg/kg s.c.) antagonism for DAMGO and BUBU did not differ significantly, 6.95 +/- 0.054 and 7.28 +/- 0.030 for paw lick tests and 7.11 +/- 0.045 and 7.25 +/- 0.027 for jump tests, respectively. The slopes of the pA2 plots were close to the theoretical -1 value for competitive antagonism.(ABSTRACT TRUNCATED AT 250 WORDS)

Analgesia↗
PubMed1991

Effects of some inhibitors of arachidonic acid metabolism in rat uterus in vitro.

The effect of four eicosanoid synthesis inhibitors (ESIs): mepacrine (6 x 10(-6) to 10(-4) M), nordihydroguaiaretic acid (NDHGA, 10(-6) to 10(-5) M), indomethacin (2 x 10(-6) and 2 x 10(-5) M) and imidazole (10(-5) and 10(-4) M), were studied on contractions induced by cumulative doses (4 and 20 mU/ml) of oxytocin (OT) on the uterus of rats both in natural estrus and ovariectomized. ESIs were also assayed on contractions induced by carbachol (10(-4) M) and KCl (60 mM) in rat uterus under natural estrus, and OT (10 mU/ml)-induced contractions in rat uterus incubated in calcium-free EDTA treated medium. Mepacrine, NDHGA and indomethacin, but not imidazol, inhibited in a dose-dependent way contractions induced by OT in the uterus. The effect was higher in ovariectomized than in natural estrus rats. Mepacrine and NDHGA, but not indomethacin or imidazole, inhibited contractions induced by carbachol and relaxed tonic contractions to KCl (60 mM). Mepacrine, NDHG and indomethacin also inhibited tonic contractions by OT in calcium-free EDTA treated medium. Our results suggest that mepacrine, NDHGA and indomethacin, independently of inhibition of eicosanoids synthesis, reduce the entry of extracellular calcium and/or the release of intracellular calcium.

Animals↗
PubMed1990

Effects of inhibitors of eicosanoid synthesis in the uterus of ovariectomized rats and rats in natural oestrus: relation with calcium.

1. The effects of 4 inhibitors of eicosanoid synthesis (ESIs)--mepacrine (MEP, 10(-5) - 3 x 10(-4) M), nordihydroguaiaretic acid (NDHGA, 10(-6) - 2 x 10(-5) M), indomethacin (IND, 2 x 10(-6) M and 2 x 10(-5) M) and imidazole (IMI, 10(-5) M and 10(-4) M)--on the motility induced by oxytocin (OT, 0.5 and 4 mU/ml) in uterus of rats in natural oestrus and of ovariectomized rats have been studied. 2. MEP, NDHGA and IND, but not IMI, inhibited the motility induced by both concentrations of OT in natural oestrus. Ovariectomy enhanced the effects of all ESIs, except the one of MEP. 3. MEP and NDHGA, but not IND or IMI, inhibited the contractions induced by methacholine (10(-5) M) and prostaglandin F2a (10(-6) M) and relaxed in a dose-dependent way the tonic component of the contractile response to KCl 60 mM (DI50: 6.14 +/- 0.38 and 1.38 +/- 0.29 x 10(-5) M, respectively). 4. CaCl2 (0.1-10 mM) reverted the relaxation of KCl contractions produced by MEP but not by NDHGA.

Animals↗
PubMed1990

Novel approaches in the development of new analgesics.

A recently developed series of highly selective and systemically active delta-agonists such as Tyr-X-Gly-Phe-Leu-Thr(OtBu), with X = D.Ser (OtBu) in BUBU and X = D.Cys(StBu) in BUBUC, and complete inhibitors of enkephalin metabolism (Kelatorphan, RB 38 A, PC 12) have enabled the major role played by mu-opioid receptors in supraspinal analgesia to be demonstrated. This is in agreement with the results of in vivo mu-receptor occupancy measured by taking into account the cross-reactivity of the delta-ligands for mu-sites. In contrast, mu and delta binding sites seem to act independently to control pain at the spinal level. Strong analgesic effects, especially in arthritic rats, can also be obtained by complete protection of tonically or phasically released endogenous enkephalins with mixed inhibitors such as RB38A. Chronic icv administration of the mu agonist DAGO, led to a severe naloxone precipitated withdrawal syndrome whilst a weak dependence was seen with the delta agonist, DSTBULET or with RB 38 A. Moreover, mixed inhibitors did not induce any significant respiratory depression. All these data emphasize the interest in developing delta-agonists and mixed inhibitors with appropriate bioavailability for clinical evaluation.

Amino Acid Sequence↗
PubMed1990

Effects induced by chronic treatment with selective D1 or D2 antagonists on open-field behavior and colonic temperature.

We have studied the behavioral responses in open-field and the changes in body temperature induced after chronic treatment with a selective D1 antagonist, SCH 23390, a selective D2+ antagonist, sulpiride, or a non specific but preferential D2 antagonist, haloperidol. After chronic treatment with SCH 23390 or sulpiride, rats were challenged with SKF 38393, selective D1 agonist, or LY 171555, selective D2 agonist, in order to study the responses of D1 and D2 stimulation. After chronic SCH 23390, an increase of the locomotion and of the number of rears were observed whereas, no changes were induced by chronic sulpiride or haloperidol. Acute treatment with sulpiride blocked the hyperlocomotion induced by chronic SCH 23390. In naive rats acute administration of SKF 38393 or LY 171555 did not produce any change in locomotion or rearing. In rats treated chronically with SCH 23390 this acute administration of LY 171555 induced an increase of the number of squares and of the number of rears. In these animals, acute administration of SKF 38393 also augmented the number of squares crossed. In contrast, chronic sulpiride did not modify behavioral responses obtained after acute SKF 38393 or LY 171555. Colonic temperature was not changed after acute SKF 38393 while acute LY 171555 induced a hypothermia. Chronic sulpiride did not modify the responses of SKF 38393 or LY 171555, but an increase in body temperature was observed after acute SKF 38393 in animals chronically treated with SCH 23390. The present results support a different behavioral expression of D1 and D2 supersensitivity in rats. Furthermore, chronic treatment with a D1 antagonist induced facilitatory effects on D2 behavioral responses; however, these D1-D2 interactions were not observed in body temperature responses.

Animals↗
PubMed1987

Tuberous sclerosis and pregnancy; report of a case with renal and pulmonary involvement.

Tuberous sclerosis is a very infrequent hereditary disease, usually defined by the triad of epilepsy, mental retardation and adenoma sebaceum, although alterations in other organs can exist. Tuberous sclerosis in its association with pregnancy has seldom been described in the literature. One such case is reported here; that of a 24-yr-old woman whose pulmonary involvement constitutes its differentiating characteristic. We make special mention of the improvement of the respiratory function, without any modification of the renal function, in contrast with other previously published cases. She gave birth spontaneously by vaginal via. Finally, we underline the importance of prenatal diagnosis and genetic advice for these patients.

Adult↗
PubMed1987

Congenital hypofibrinogenemia and pregnancy, obstetric and hematological management.

A 27-year-old pregnant woman with severe congenital hypofibrinogenemia was studied from the 18th to the 40th week of pregnancy, after which she had a normal delivery. The results of the quantitative and qualitative fibrinogen studies done on the patient made it possible to rule out associated dysfibrinogenemia. No variations in the concentration and function of fibrinogen were observed during gestation. The only treatment given was a transfusion of fresh plasma prior to delivery. The importance of fibrinogen in maintaining normal placental insertion and the obstetric management of predelivery and delivery are discussed.

Adult↗
PubMedDate not supplied

Prenatal diagnosis of idiopathic neonatal hemochromatosis with MRI.

Intrauterine diagnosis of perinatal hemochromatosis is difficult. Noninvasive detection of hepatic iron deposition is crucial. We report the first case diagnosed intrauterine with magnetic resonance imaging (MRI). By visual analysis, if the fetal liver is less intense than maternal or fetal fat signal for T2* gradient echo image, hemochromatosis should be suggested.

Female↗
PubMedDate not supplied

Synthesis, biochemical and pharmacological properties of BUBUC, a highly selective and systemically active agonist for in vivo studies of delta-opioid receptors.

Based on the results of conformational studies of linear and cyclic delta-opioid peptides such as BUBU [Tyr-D-Ser(OtBu)-Gly-Phe-Leu-Thr(OtBu)] and DPLPE c[Tyr-D-Pen-Gly-Phe-Pen], a new enkephalin-related peptide, Tyr-D-Cys(StBu)-Gly-Phe-Leu-Thr(OtBu) (BUBUC) was synthesized and tested for its opioid activity and selectivity at both the peripheral and central levels. Amongst all the synthetic compounds described so far, BUBUC appears to be the most highly delta-selective probe [KI (mu) = to 2980 nM, KI (delta): 2.9 nM, KI (mu)/KI (delta) approximately 1000]. This selectivity was confirmed by the results of pharmacological studies, including measurements of supraspinal analgesia and behavioral changes in mice. In the later test, BUBUC was shown to increase the rearing activity after IV administration at very low concentrations (0.1 mg/kg) and this effect was reversed by the delta-selective antagonist naltrindole. No antinociceptive response was observed at a 10-fold higher concentration. Thanks to its enzymatic stability and its hydrophobicity. BUBUC is the first systemically active, highly selective delta agonist and should therefore be useful to characterize the physiological role of delta-opioid receptors.

Amino Acid Sequence↗