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J Flórez

Publications and source records attributed to J Flórez.

At least 37 records · Page 2Linked to original sources
PubMed1997

Cholinergic, serotonergic and catecholaminergic neurons are not affected in Ts65Dn mice.

Ts65DN mice were developed as a model of Down syndrome (DS); they are trisomic for the distal segment of chromosome 16 (MMU16), which contains genes syntenic with some of the genes located on the critical region of human chromosome 21 (HSA21). Since behavioral and neurochemical disturbances have been observed in this animal model, it seemed interesting to perform an immunohistochemical characterization of the main cholinergic, catecholaminergic and serotonergic nuclei. However, when the brains of Ts65Dn mice were compared with those of control littermates, no differences were found either in the morphology of the neurons of the three systems or in the number of immunoreactive cells. The results indicate that these systems are not affected by the triplication of some of the genes present on chromosome 16.

Animals↗
PubMed1997

Alterations of central noradrenergic transmission in Ts65Dn mouse, a model for Down syndrome.

Mice with segmental trisomy 16 (Ts65Dn) which have triplication of a region of mouse chromosome 16 homologous to the Down syndrome critical region in human chromosome 21, are used as a model for Down syndrome. Functioning of the central beta-noradrenergic transmission was studied in Ts65Dn mice. Binding analysis in cerebral cortex revealed no change in the number of beta-adrenoceptors and a slight reduction of affinity. The beta-adrenoceptor transduction was assessed by analyzing cAMP formation in the cerebral cortex, hippocampus and cerebellar cortex under basal conditions and after stimulation with isoprenaline and forskolin. Basal production of cAMP was significantly reduced in hippocampus and cerebellar cortex of Ts65Dn mice compared to control, but not in cerebellum. After phosphodiesterase inhibition, net increments in cAMP accumulation were similar in both groups of mice. Stimulation of cAMP production by isoprenaline (10 microM) and forskolin (10 microM) was much higher in hippocampus than in cerebral cortex of either group. In both areas, but not in cerebellum, the stimulatory responses were consistently and significantly smaller in Ts65Dn than in control mice. Concentration-response curves for isoprenaline and forskolin were generated in the cerebral cortex. Emax responses were lower in trisomic than in control mice; however, in Ts65Dn mice the slope of the response curve to isoprenaline was markedly depressed whereas that to forskolin was similar to control. It is concluded that Ts65Dn mice show severe deficiencies in the synaptic transmission of the central beta-noradrenergic system, which are selective for specific brain areas.

1-Methyl-3-isobutylxanthine↗
PubMed1996

Impaired cyclic AMP production in the hippocampus of a Down syndrome murine model.

Behavioral and learning disturbances have been found in mice with partial trisomy 16, a new model for Down syndrome. Basal production of cyclic AMP in the hippocampus of trisomic mice was shown to be impaired. In addition, the responses of adenylyl cyclase to the stimulation of beta-adrenoceptors with isoprenaline and of the catalytic subunit with forskolin were both severely depressed.

1-Methyl-3-isobutylxanthine↗
PubMed1995

A behavioral assessment of Ts65Dn mice: a putative Down syndrome model.

Mice which are trisomic for only the human chromosome (Chr) 21-homologous segment of mouse Chr 16 (segmental trisomy), including a portion of the Down syndrome region of human Chr 21, have recently been developed. Since these segmentally trisomic mice, designated Ts(17(16))65Dn, survive to adulthood, they may represent a mouse model for the study of Down syndrome. A partial characterization of their behavioral phenotype was undertaken by evaluating the sensorimotor reflexes, exploration, locomotor activity, emotionality and spatial learning in 16 male Ts65Dn mice (TS) and 16 control (CO) littermates. No sensorimotor deficits appeared in TS compared to CO mice. By contrast, head-dipping behaviour in the hold board was increased in TS mice with respect to the CO group, showing a higher repetition rate of previously explored holes. Crossings in the open field and total arm entries in the plus maze were higher in TS than in the CO group during the dark phase of the light-dark (LD) cycle under red light, but not during the light phase of the LD cycle under white light. Entries into the open arms of the plus maze were increased overall in TS mice when compared to CO mice, but no differences were found in time spent in the open arms. TS mice showed impaired place learning in the Morris water maze, whereas they were able to reach the same performance as CO animals in cued learning. Thus, absence of sensorimotor deficits, increased exploration, hyperactivity under certain experimental conditions and a moderate impairment of spatial learning were the principal characteristics observed in TS mice compared to their CO littermates.

Animals↗
PubMed1995

Regulation of dihydropyridine-sensitive Ca++ channels during opioid tolerance and supersensitivity in rats.

The changes in cerebral dihydropyridine (DHP)-sensitive Ca++ channels (L-type) associated with tolerance and supersensitivity to the antinociceptive effect of the mu-opioid receptor agonist sufentanil were analyzed in rats. The tail-flick test was used to assess the nociceptive threshold. DHP binding and autoradiographic assays were performed with [3H]nimodipine and [3H]PN 200-110 [isopropyl 4-(2,1,3-benzoxadizol-4-yl)- 1,4-dihydro-2,6-dimethyl-5-methoxycarbonylpyridine-3-carboxylate], respectively. Chronic s.c. infusion of sufentanil (2 micrograms/hr) for 7 days induced tolerance (tolerance index, 5.6) in association with up-regulation of DHP binding sites in cerebral cortex membranes (+36%), as well as in brain sections. Animals were rendered hypersensitive to the antinociceptive effect of sufentanil by chronic and simultaneous infusion of sufentanil (2 micrograms/hr) and nimodipine (1 microgram/hr) for 7 days (potentiation index, 40 vs. tolerant). Under these conditions, a greater increase in the number of DHP binding sites was observed in cortex membranes (+71%), and more evidently in brain sections. In these animals, withdrawal of nimodipine for 48 hr returned the dose-response curve of sufentanil to the tolerant values, whereas Ca++ channels remained increased. The role of an increased influx through L-type channels in opioid tolerance is reinforced. Our results also suggest that, although changes in neuronal Ca++ fluxes are not the only underlying mechanism, the increase and the sustained blockade of Ca++ channels with nimodipine is essential for the expression of opioid supersensitivity.

Analgesics, Opioid↗
PubMed1995

Mu-opioid receptor regulation during opioid tolerance and supersensitivity in rat central nervous system.

We have analyzed by radiometric procedures in rat central nervous system the changes in the properties of mu-opioid receptors associated with tolerance and supersensitivity to the opioid agonist sufentanil. This study has used [3H]-[D-Ala2,MePhe4,Gly- (ol)5(2)]-enkephalin, a highly selective ligand, to label mu-opioid receptors in both membranes and tissue sections. The induction of opioid tolerance by chronic infusion for 7 days of high doses of sufentanil, a high efficacy agonist, produced mu-opioid receptor down-regulation, with a significant decrease in their density in both cortical (-67%) and spinal cord membranes (-55%) and no changes in the affinity constant. Autoradiographic studies showed an overall decrease of[3H]-Ala2,MePhe4,Gly-(ol)5(2)]-enkephalin binding in the somatosensory cortex (around -30%). When the dihydropyridine-Ca++ channel antagonist nimodipine was administered alone for 7 days, no significant changes in the density or affinity constant of mu-opioid receptors were observed. However, the chronic and simultaneous administration of nimodipine and sufentanil (7 days), induced a pronounced modification on the density of mu-opioid receptors of the rat central nervous system and blocked the down-regulation observed in sufentanil-treated (tolerant) rats. These neurochemical findings may account for the functional interaction we have observed previously in the analgesic studies between nimodipine and sufentanil. Our data strongly suggest a functional role of L-type Ca++ channels in the mediation of opioid tolerance and super-sensitivity.

Analgesics, Opioid↗
PubMed1994

Enhancement of opiate analgesia by nimodipine in cancer patients chronically treated with morphine: a preliminary report.

The ability of nimodipine, a calcium-channel blocker, to enhance morphine analgesia and/or modify the development of tolerance was studied in patients with cancer pain who had needed successive increments of morphine for periods ranging from 21 to 780 days. Assessment of daily morphine consumption was the primary effect parameter. Nimodipine succeeded in reducing the daily dose of morphine in 16 of 23 patients (oral, n = 13; intrathecal, n = 3), and failed to modify it in 2 patients. Total oral daily dose was reduced by nimodipine (120 mg/day) from 282.6 +/- 47.7 mg to 158.7 +/- 26.2 mg (n = 15, P < 0.001). Intrathecal morphine was also reduced by 1-5 mg/day. Nimodipine was withdrawn in 5 patients during the first week of treatment due to intolerance (n = 3) or aggravation of the disease (n = 2). These preliminary results support experimental findings showing that pharmacological interference with Ca(2+)-related events may modify chronic opioid effects, including the expression of tolerance.

Administration, Oral↗
PubMed1993

The Ca2+ channel agonist Bay K 8644 induces central respiratory depression in cats, an effect blocked by naloxone.

We analyzed the respiratory effects induced by the Ca2+ channel agonist Bay K 8644 and its enantiomers, Bay R 5417 and Bay R 4407, applied to the ventral medullary surface of cats. Bay K 8644 (10 to 100 micrograms) and Bay R 5417 (50 to 200 micrograms) elicited a dose-dependent respiratory depression. Naloxone (0.1 mg/kg), but not D-naloxone, reversed these effects, indicating that an endogenous opioid mechanism was involved. Bay R 4407 (100 micrograms) was ineffective. The respiratory depressant effects induced by Bay K 8644 and its (-) enantiomer were a consequence of their agonist properties on the L-type Ca2+ channel, since (1) the activity of Bay K 8644 was stereospecific, and (2) nimodipine prevented the effect. We suggest that potent activation of Ca2+ channels or other mechanisms by high doses of Ca2+ agonists elicits the release of endogenous opioid peptides in medullary respiration-related structures.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed1993

Potentiation of acute opioid-induced respiratory depression and reversal of tolerance by the calcium antagonist nimodipine in awake rats.

The interaction between sufentanil, a mu-opioid agonist, and the Ca2+ antagonist nimodipine on respiration and on the development of opioid tolerance in awake rats has been analyzed. Our previous work demonstrated that chronic treatment with nimodipine together with sufentanil increases the analgesic potency of the opioid 50 fold. Therefore, we have investigated whether the opioid-induced respiratory depression is potentiated in parallel with the analgesia. Ventilation was measured by the whole body plethysmographic method. In naive rats, sufentanil (10-80 micrograms/kg) consistently induced a dose-dependent respiratory depression. Pretreatment with nimodipine (200 micrograms/kg) potentiated this effect but to a lesser extent than it potentiated analgesia. After chronic administration of the opioid (2 micrograms/h, 7 days) tolerance was manifested as a reduction in both the area under the time course curve and in the maximum effect. Nimodipine (1 microgram/h) administered concurrently with sufentanil for 7 days counteracted the tolerance to respiratory depression but no additional potentiation was observed. These results demonstrate that the interaction between nimodipine and sufentanil is not limited to antinociception but also extends to respiratory depression. However, compared with analgesia, the clinical relevance of a potential increase in opioid-induced respiratory depression by nimodipine may be negligible.

Animals↗
PubMed1992

Vitamin D status in children with Down's syndrome.

The serum levels of the active Vitamin D metabolites 25-hydroxyvitamin D[25(OH)D], 1,25-dihydroxyvitamin D[1,25(OH)2D] and 24,25 dihydroxyvitamin D [24,25(OH)2D], were studied in 21 children with Down's syndrome (DS) in Cantabria, a northern region of Spain, located at 44 degrees N latitude. Serum calcium, magnesium, phosphate, alkaline phosphatase, parathormone and osteocalcine were also determined. In the DS group, the average values of the three Vitamin D metabolites were comparable to those of an age-matched group both in winter and summer times. No child with DS showed values below the normal range, either in Vitamin D metabolites, or in the other parameters of calcium metabolism. The normal increment of 25(OH)D and 24,25(OH)2 values from March to October was not observed in five children. This anomaly was corrected in three, after adequate rules of sun exposure during summer time were followed. In the other two, the 25(OH)D levels were high throughout the study. This investigation shows that children with DS do not require Vitamin D prescription when appropriate periods of sunlight exposure are provided.

24,25-Dihydroxyvitamin D 3↗
PubMed1991

High-affinity choline uptake carrier in Alzheimer's disease: implications for the cholinergic hypothesis of dementia.

We examined the density and the state of affinity of [3H]hemicholinium-3 ([3H]HC-3) binding sites, a marker of the presynaptic high-affinity choline uptake (HACU) carrier, in 4 representative regions of 13 postmortem Alzheimer's disease (AD) brains, as well as in 12 matched control brains. Significant reductions in the densities of [3H]HC-3 binding sites were found both in frontal cortex (-44.7%) and hippocampus (-36.5%) of AD brains in comparison to controls. On the other hand the densities of [3H]HC-3 binding sites in AD brains in caudate-putamen and cerebellar cortex showed no significant differences when compared to controls. No significant change in the state of affinity of these sites could be observed in the saturation assays carried out in hippocampus and frontal cortex. Our findings concur with the reported data by using other presynaptic cholinergic markers in AD and confirm that some degree of cholinergic degeneration, highly specific for the basal forebrain neurons, occurs in AD. However, these results, obtained in a group of AD brains belonging to severely demented patients, do not show a dramatic loss of the HACU in many AD brains. Although this fact could be due to the existence of a compensatory mechanism, our results probably suggest that dementia in AD cannot be explained only by the loss of neocortical cholinergic presynaptic terminals arising from the basal forebrain and also may clarify as to why the acetylcholine precursors or the muscarinic agonists are not effective in AD dementia.

Aged↗
PubMed1991

Ca2+ channel modulation by dihydropyridines modifies sufentanil-induced respiratory depression in cats.

We analyzed the interaction between sufentanil, a selective mu agonist, and two dihydropyridines, the Ca2+ antagonist, nimodipine, and the Ca2+ agonist, Bay K 8644, on the respiratory actions induced in the brainstem of cats. Drugs were applied topically to the ventral medullary surface. Sufentanil (0.26-26 nmol) consistently induced an immediate and dose-dependent reduction in tidal volume. Respiratory frequency was only depressed by the higher doses of the opiate. Pretreatment with nimodipine (0.19 and 0.38 mumol) potentiated the respiratory depression induced by sufentanil (0.26 nmol). The potentiation included both frequency and tidal volume. On the other hand, under the influence of Bay K 8644 (0.28 nmol), the respiratory effect of the opiate (7.8 nmol) was partially antagonized. Our results indicate that modulation of the L-type Ca2+ channels by dihydropyridines modifies sufentanil-induced respiratory depression at the controlling medullary mechanisms of breathing.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed1990

Tolerance to the respiratory actions of opiates: withdrawal tolerance and asymmetrical cross-tolerance.

Cross-tolerance to the respiratory depression induced by i.c.v. [D-Ala2,D-Leu5]enkephalin (DADLE) and by s.c., i.c.v. and i.v. morphine was studied in anesthetized rats that had been rendered tolerant to s.c. sufentanil (4 micrograms/h per 7 days). Tolerance induced by i.c.v. sufentanil was also compared during withdrawal and its absence. Tolerance was evaluated by estimation of the changes in both the maximum attained reduction of respiratory frequency (Emax) and the area under the time-course curve for the effects (AUC). In contrast to the failure to develop tolerance, as estimated with the Emax, after i.c.v. sufentanil in the absence of abstinence (tolerance index: 1.1), rats displayed significant degrees of cross-tolerance to i.c.v. morphine (3.6), i.c.v. DADLE (4.3) and s.c. morphine (6.6). No tolerance, however, was obtained to i.v. morphine. Tolerance to i.c.v. sufentanil in non-abstinent rats was not present when the Emax was considered but was when AUC was considered. During withdrawal animals showed tolerance as estimated with both the Emax and AUC. These results complement previous findings and show that the appearance of dissimilar degrees of cross-tolerance to different agonists depends not only on their intrinsic activities but also on their pharmacokinetic properties. These observations, along with the critical influence of withdrawal upon the manifestation of tolerance, support the need to distinguish between the development of the tolerance state and the degree of tolerance that can be expressed under specific conditions.

Animals↗
PubMed1990

Autoradiographic studies of neurotransmitter receptors in the brain of newborn infants with Down syndrome.

The autoradiographic pattern of cholinergic muscarinic receptors in the brain of two newborn infants with Down syndrome (DS) (stillbirths, 31 and 39 gestational weeks), were compared with that of age-matched control fetuses. Densities and distribution patterns of muscarinic receptors in the forebrain were similar in both groups. However, a marked receptor reduction was found in the midbrain (superior colliculus, substantia nigra) of DS brains compared to control brains. The results indicate the existence of deficient prenatal development of cholinergic transmission in DS that may be responsible for the occurrence of specific difficulties in early postnatal life.

Autoradiography↗
PubMed1990

Calcium channel modulation by dihydropyridines modifies sufentanil-induced antinociception in acute and tolerant conditions.

The study was aimed at elucidating the possible participation of L-type Ca2+ channel in the acute analgesic effect of an opiate and the development of tolerance to this action. Sufentanil, a selective mu agonist, and two dihydropyridines, the Ca2+ antagonist nimodipine and the Ca2+ agonist Bay K 8644, were selected. The tailflick test was used to assess the nociceptive threshold. In naive rats, nimodipine (200 micrograms/kg) potentiated the analgesic effect of sufentanil reducing the ED50 from 0.26 to 0.08 microgram/kg. Similar results were observed with its (-)-enantiomer Bay N 5248, while the (+) enantiomer Bay N 5247 was ineffective. Tolerance to the opiate was induced by chronic subcutaneous administration of sufentanil with minipumps (2 micrograms/h, 7 days). In these conditions the dose-response curve to sufentanil was displaced to the right and the ED50 was increased to 1.49 micrograms/kg. In tolerant rats, nimodipine preserved its potentiating ability and prevented the displacement to the right of the sufentanil dose response-curve (ED50 = 0.48 microgram/kg). When nimodipine was pumped (1 microgram/h, 7 days) concurrently with sufentanil, the development of tolerance to the opioid was not disturbed. However, the expression of tolerance was abolished and even the effect of acutely administered sufentanil was markedly potentiated (ED50 = 0.03 microgram/kg). Similar experiments were performed with Bay K 8644. In naive rats, Bay K 8644 at a low dose (20 micrograms/kg) that behaves as a calcium agonist, antagonized the analgesic effect of sufentanil (ED50 = 0.58 microgram/kg), whereas at a high dose (200 micrograms/kg) it potentiated this action (ED50 = 0.15 microgram/kg).(ABSTRACT TRUNCATED AT 250 WORDS)

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗