Biomedical subjects

R Maldonado

Publications and source records attributed to R Maldonado.

At least 19 recordsLinked to original sources

PubMed2000

Analgesic doses of the enkephalin degrading enzyme inhibitor RB 120 do not have discriminative stimulus properties.

The systemically active mixed inhibitor of enkephalin metabolism, N-((S)-2-benzyl-3[(S) 2-amino-4-methylthio)butyldithio-]-1-oxopropyl)-L-alanine benzylester (RB 120), alone or in combination with 4-¿[2-[[3-(1H-indol-3-yl))-2-methyl-1-oxo-2-[[(tricyclo[3.3.1.1. ]dec-2-yloxy) carbonyl]amino¿propyl]amino]-1-phenylethyl]amino¿-4-oxo-[R-(R*, R*)]-butanoate N-methyl-D-glucamine (CI 988; CCK(1) receptor antagonist) was investigated for discriminative and morphine generalisation effects using an operant drug discrimination paradigm in rats. Animals dosed with RB 120 (10 mg/kg) failed to develop a discriminative response. Combined CI 988 (0.3 mg/kg) and RB 120 (10 mg/kg) also failed to elicit a discriminative response. Morphine-trained animals (3.0 mg/kg) did not generalise to RB 120 (10 and 20 mg/kg). Similarly, subsequent retraining of the same animals with 1.5 mg/kg of morphine did not elicit generalisation to RB 120 (10 or 20 mg/kg). Combined RB 120 (10 or 20 mg/kg) and CI 988 (0.3 or 3.0 mg/kg) treatment produced no notable drug lever selection in rats able to discriminate morphine (1.5 mg/kg) from saline. These results suggest that RB 120 may have low abuse potential at analgesic doses.

Alanine↗

PubMed2000

[Hysteria epidemics, epidemic conversion disorder or epidemic somatotrophic disorders?: a new case of a fact for the 21st century].

OBJECTIVES: To describe a new outbreak of "mass hysteria" or "epidemic conversion disorder" occurring in Barcelona in 1997. Based on this outbreak's features differentiating it from other similar outbreaks described in the literature or treated by the same team, to propose a change in the theoretical framework for these group somatomorphic phenomena. DESIGN: A study describing clinical epidemiological research and the interventions performed. SETTING: Urban health centre. Epidemiological research and data analysis performed by the Municipal Health Institute (MHI) of Barcelona. INTERVENTIONS AND MEASUREMENTS: The following were performed: a) Diagnostic screening of population. b) The usual epidemiological surveys of the MHI. c) Semi-structured interviews with the quarter's care professionals. d) Two group sessions with the quarter's health professionals. MHI experts analysed statistically the data provided by measurements b) and c). RESULTS: 276 people (42% of the population of the quarter) were studied. The attack rate was 10%. Data analysis noted that communication of the fantasy of the outbreak of scabies facilitated self-diagnosis and even diagnosis by health professionals. CONCLUSIONS: Given the frequency and the social and health implications of this kind of somatomorphic disorder, both in the developed countries and those "on the road to development", clinical researchers and epidemiologists should not wait to pose the possibility of hysteria until after the "organic" aetiology of an epidemic outbreak has been completely discounted. The second series of conclusions points towards the incorrectness of defining all these outbreaks as mass hysterical disorders. In reality, we should be thinking, more openly and in a more scientifically modern way, of epidemic somatomorphic disorders of various kinds. The outbreak described in the current study could be referred to as the hypochondriform variety of outbreak, whereas those described elsewhere by the same team could be understood as the conversion variety.

Adolescent↗

PubMed2000

A behavioural model to reveal place preference to delta 9-tetrahydrocannabinol in mice.

RATIONALE: The rewarding properties of delta 9-tetrahydrocannabinol (THC) are difficult to demonstrate in rodents using standard procedures. OBJECTIVE: To evaluate the motivational responses of THC in the place conditioning paradigm in mice after minimizing the dysphoric effects of the first drug exposure and/or the consequences of its pharmacokinetic properties. METHODS: Mice were conditioned to THC (1 or 5 mg/kg) using an unbiased procedure with an elevated number of pairings and long conditioning time. RESULTS: A place aversion was observed with 5 mg/kg THC using a standard protocol. Similar results were obtained when the CB-1 receptor antagonist SR 141716A (1 mg/kg) was administered immediately after each THC conditioning period. However, mice receiving a priming THC injection and conditioned 24 h later showed a place preference with 1 mg/kg THC and no effect with 5 mg/kg THC. CONCLUSION: THC produces a clear place preference in mice by using a long period of conditioning and avoiding the possible dysphoric consequences of the first drug exposure.

Animals↗

PubMed2000

Mice deficient for delta- and mu-opioid receptors exhibit opposing alterations of emotional responses.

The role of the opioid system in controlling pain, reward and addiction is well established, but its role in regulating other emotional responses is poorly documented in pharmacology. The mu-, delta- and kappa- opioid receptors (encoded by Oprm, Oprd1 and Oprk1, respectively) mediate the biological activity of opioids. We have generated Oprd1-deficient mice and compared the behavioural responses of mice lacking Oprd1, Oprm (ref. 6) and Oprk1 (ref. 7) in several models of anxiety and depression. Our data show no detectable phenotype in Oprk1-/- mutants, suggesting that kappa-receptors do not have a role in this aspect of opioid function; opposing phenotypes in Oprm-/- and Oprd1-/- mutants which contrasts with the classical notion of similar activities of mu- and delta-receptors; and consistent anxiogenic- and depressive-like responses in Oprd1-/- mice, indicating that delta-receptor activity contributes to improvement of mood states. We conclude that the Oprd1-encoded receptor, which has been proposed to be a promising target for the clinical management of pain, should also be considered in the treatment of drug addiction and other mood-related disorders.

Animals↗

PubMed2000

Increased rewarding properties of morphine in dopamine-transporter knockout mice.

The activation of dopamine (DA) neurotransmission plays a crucial role in the behavioural responses to drugs of abuse. In particular, increased extracellular levels of DA within the mesolimbic pathway have been implicated in the rewarding and locomotor stimulatory properties of morphine. We investigated the behavioural responses to morphine in mice with a genetic disruption of the DA transporter (DAT), resulting in a constitutively high level of extrasynaptic DA. In the conditioned place preference test, DAT-/- mice exhibited a stronger rewarding response to morphine (5 mg/kg, s.c.) compared with control littermates. However, the same dose of morphine failed to increase locomotor activity in DAT-/- mice, whilst enhancing locomotion in DAT+/- and DAT+/+ animals. Morphine-induced analgesia was unaffected in mutant mice, but the behavioural expression of naloxone-induced withdrawal signs was blunted. In vivo voltammetry in the shell of the nucleus accumbens revealed that morphine was able to stimulate DA neurons in DAT-/- mice, resulting in the accumulation of higher extracellular DA levels compared with control animals. Morphine also induced a higher rate of c-fos transcription in the shell of the nucleus accumbens in mutant mice. We conclude that morphine-induced rewarding responses are firmly established in DAT mutant mice despite a DA transmission that is already tonically activated, and independently of any effect on locomotion. These particular behavioural responses to morphine may be associated with the action of the drug on DA release and c-fos expression in the shell of the nucleus accumbens of DAT-/- mice.

Analgesia↗

PubMed2000

Cannabinoid withdrawal is dependent upon PKA activation in the cerebellum.

Region-specific up-regulation of the cyclic AMP pathway is considered an important molecular mechanism in the origin of the somatic manifestations of the withdrawal syndrome to known drugs of abuse. Nevertheless, the existence of a withdrawal syndrome after prolonged cannabinoid administration has long been a controversial issue. Recent studies, in different species, have shown that withdrawal to prolonged cannabinoid exposure precipitated by the cannabinoid antagonist SR141716A is characterized by physical signs underlying impairment of motor coordination. Interestingly, cannabinoid withdrawal is accompanied by an increase of adenylyl cyclase activity in the cerebellum. Here, we investigate the functional role of the cyclic AMP pathway in the cerebellum in the establishment of cannabinoid withdrawal. We show that after SR141716A precipitation of cannabinoid withdrawal, basal and calcium-calmodulin-stimulated adenylyl cyclase activities as well as active PKA in the cerebellum increase in a transient manner with a temporal profile which matches that of the somatic expression of abstinence. Selectively blocking the up-regulation of the cyclic AMP pathway in the cerebellum, by microinfusing the cyclic AMP blocker Rp-8Br-cAMPS in this region, markedly reduced both PKA activation and the somatic expression of cannabinoid withdrawal. Our results (i) directly link the behavioural manifestations of cannabinoid withdrawal with the up-regulation of the cyclic AMP pathway in the cerebellum, pointing towards common molecular adaptive mechanisms for dependence and withdrawal to most drugs of abuse; (ii) suggest a particular role for the cerebellum as a major neurobiological substrate for cannabinoid withdrawal.

8-Bromo Cyclic Adenosine Monophosphate↗

PubMed1999

Altered emotional and locomotor responses in mice deficient in the transcription factor CREM.

Various transcription factors act as nuclear effectors of the cAMP-dependent signaling pathway. These are the products of three genes in the mouse, CREB, CRE modulator (CREM), and ATF-1. CREM proteins are thought to play important roles within the hypothalamic-pituitary axis and in the control of rhythmic functions in the pineal gland. We have generated CREM-mutant mice and investigated their response in a variety of behavioral tests. CREM-null mice show a drastic increase in locomotion. In contrast to normal mice, the CREM-deficient mice show equal locomotor activity during the circadian cycle. The anatomy of the hypothalamic suprachiasmatic nuclei, the center of the endogenous pacemaker, is normal in mutant mice. Remarkably, CREM mutant mice also elicit a different emotional state, revealed by a lower anxiety in two different behavioral models, but they preserve the conditioned reactiveness to stress. These results demonstrate the high degree of functional specificity of each cAMP-responsive transcription factor in behavioral control.

Animals↗

PubMed1999

Mu-opioid receptor specific antagonist cyprodime: characterization by in vitro radioligand and [35S]GTPgammaS binding assays.

The use of compounds with high selectivity for each opioid receptor (mu, delta and kappa) is crucial for understanding the mechanisms of opioid actions. Until recently non-peptide mu-opioid receptor selective antagonists were not available. However, N-cyclopropylmethyl-4,14-dimethoxy-morphinan-6-one (cyprodime) has shown a very high selectivity for mu-opioid receptor in in vivo bioassays. This compound also exhibited a higher affinity for mu-opioid receptor than for delta- and kappa-opioid receptors in binding assays in brain membranes, although the degree of selectivity was lower than in in vitro bioassays. Cyprodime has recently been radiolabelled with tritium resulting in high specific radioactivity (36.1 Ci/mmol). We found in in vitro binding experiments that this radioligand bound with high affinity (K(d) 3. 8+/-0.18 nM) to membranes of rat brain affording a B(max) of 87. 1+/-4.83 fmol/mg. Competition studies using mu, delta and kappa tritiated specific ligands confirmed the selective labelling of cyprodime to a mu-opioid receptor population. The mu-opioid receptor selective agonist [D-Ala(2),N-MePhe(4),Gly(5)-ol]enkephalin (DAMGO) was readily displaced by cyprodime (K(i) values in the low nanomolar range) while the competition for delta- ([D-Pen(2), D-Pen(5)]enkephalin (DPDPE)) and kappa- (5alpha,7alpha, 8beta-(-)-N-methyl-N-[7-(1-pyrrolidinyl)-1-oxaspiro(4, 5)dec-8-yl]-benzene-acetamide (U69,593)) opioid receptor selective compounds was several orders of magnitude less. We also found that cyprodime inhibits morphine-stimulated [35S]GTPgammaS binding. The EC(50) value of morphine increased about 500-fold in the presence of 10 microM cyprodime. These findings clearly indicate that cyprodime is a useful selective antagonist for mu-opioid receptor characterization.

Animals↗

PubMed1999

Use of selective antagonists and antisense oligonucleotides to evaluate the mechanisms of BUBU antinociception.

Evidence suggests that the antinociceptive effects of selective delta-opioid receptor agonists may involve an activation of the mu-receptor in some experimental conditions. The aim of this study was to clarify the receptors involved in the antinociceptive responses of the selective and systemically active delta-opioid receptor agonist Tyr-D-Ser-(O-tert-butyl)-Gly-Phe-Leu-Thr-(O-tert-butyl) (BUBU). The antinociception induced by systemic (i.v.) or central (i.c.v.) administration of BUBU was measured in the hot plate (jumping and paw lick latencies) and tail immersion tests in mice. In both tests, the responses were more intense when BUBU was administered by central route. The pre-treatment with the mu-opioid receptor antagonist cyprodime blocked the effects induced by central BUBU in the hot plate and tail immersion tests. The delta-opioid receptor antagonist naltrindole had no effect on BUBU-induced antinociception in the hot plate but decreased BUBU responses in the tail immersion test. Further evidence for this dual receptor action of BUBU was demonstrated by using antisense oligodeoxynucleotides. Thus, a reduction in central BUBU-induced antinociception was observed in the tail immersion test after the administration of antisense probes that selectively blocked the expression of mu- or delta-opioid receptors. These findings clearly indicate using a dual pharmacological and molecular approach that BUBU mediates its antinociceptive effects via activation of both mu- and delta-opioid receptors.

Analgesics↗

PubMed1999

[Haemophilus influenzae type b invasive disease and meningococcal disease: incidence and characteristics in Barcelona, 1994-1995. Work Group IMS-IUSPC for Surveillance and Control of Meningitis].

BACKGROUND: The purpose of the study is to estimate the incidence of Haemophilus influenzae type b invasive disease (HibID) and meningococcal disease (MD) in Barcelona (Catalonia, Spain) for the years 1994-1995. MATERIAL AND METHODS: Data were obtained from the nominal registry of the surveillance system for reportable transmissible diseases of the Barcelona City Health Department, combining the reporting system with active surveillance, including microbiological reports and the review of hospital discharge registries to ensure completeness. RESULTS: During this two-years period there were 17 cases of HibID (12 meningitis), and for 12 cases there was a laboratory confirmation. The annual incidence rate can be estimated at 15.4 cases of HibID for 100,000 children below 5 years of age, and 4.5 cases for 100,000 children below 15 years. The annual incidence rates for Hib meningitis were 3.2 for 100,000 below 15 years. There were 60 cases of MD, and for 33 there was a laboratory confirmation, with a majority of serogroup B. The annual incidence rate of MD can be estimated at 32.6 cases for 100,000 below 5 years and 16 cases for 100,000 below 15 years. The incidence rate of meningococcal meningitis is at least 5.9 cases for 100,000 below 15 years of age. CONCLUSIONS: These results confirm the relatively low incidence of Hib meningitis in Barcelona, Spain, while the Hib vaccine was not in systematic use, much lower than the incidence of MD. The incidence rates are similar to all other population-based studies in Spain, except for the Basque Country study.

Adolescent↗

PubMed1998

Cerebral glucose metabolism during opioid withdrawal following methylnaloxonium injection into the locus coeruleus.

Previous studies have demonstrated a widespread stimulation of regional cerebral metabolic rate(s) for glucose (rCMRglc) in morphine-dependent rats subjected to opioid withdrawal precipitated by systemic injection of naloxone. Nonetheless, many of the behavioral signs of opioid withdrawal are produced by intracerebral injections of an opioid antagonist, methylnaloxonium (MN), into the locus coeruleus (LC). The purpose of the present work was to determine the extent to which cerebral metabolic alterations in opioid withdrawal could be initiated by a local action in LC. Intracerebral injections of MN into LC increased rCMRglc in morphine-dependent rats, and the anatomical distribution of this effect was similar to that produced by systemic injections of naloxone. The present data support the view that LC is a major substrate of opioid withdrawal in the brain, and they suggest that LC plays an important role in changing rCMRglc during opioid withdrawal induced by systemic naloxone administration.

Amygdala↗

PubMed1998

Activity of the delta-opioid receptor is partially reduced, whereas activity of the kappa-receptor is maintained in mice lacking the mu-receptor.

Previous pharmacological studies have indicated the possible existence of functional interactions between mu-, delta- and kappa-opioid receptors in the CNS. We have investigated this issue using a genetic approach. Here we describe in vitro and in vivo functional activity of delta- and kappa-opioid receptors in mice lacking the mu-opioid receptor (MOR). Measurements of agonist-induced [35S]GTPgammaS binding and adenylyl cyclase inhibition showed that functional coupling of delta- and kappa-receptors to G-proteins is preserved in the brain of mutant mice. In the mouse vas deferens bioassay, deltorphin II and cyclic[D-penicillamine2, D-penicillamine5] enkephalin exhibited similar potency to inhibit smooth muscle contraction in both wild-type and MOR -/- mice. delta-Analgesia induced by deltorphin II was slightly diminished in mutant mice, when the tail flick test was used. Deltorphin II strongly reduced the respiratory frequency in wild-type mice but not in MOR -/- mice. Analgesic and respiratory responses produced by the selective kappa-agonist U-50,488H were unchanged in MOR-deficient mice. In conclusion, the preservation of delta- and kappa-receptor signaling properties in mice lacking mu-receptors provides no evidence for opioid receptor cross-talk at the cellular level. Intact antinociceptive and respiratory responses to the kappa-agonist further suggest that the kappa-receptor mainly acts independently from the mu-receptor in vivo. Reduced delta-analgesia and the absence of delta-respiratory depression in MOR-deficient mice together indicate that functional interactions may take place between mu-receptors and central delta-receptors in specific neuronal pathways.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗

PubMed1998

Antinociception produced by the peptidase inhibitor, RB 101, in rats with adrenal medullary transplant into the spinal cord.

This study was undertaken to investigate the effects induced by the systemic administration of RB 101 [N-[(R,S)-2-benzyl-3[(S)(2-amino-4-methylthio)butyl dithio]-1-oxoprpyl]-L-phenylalanine benzyl ester], a mixed inhibitor of the enkephalin catabolism able to cross the blood-brain barrier, in antinociception produced by adrenal medullary tissue transplanted in the rat spinal subarachnoid space. For this purpose, the antinociceptive responses induced by intravenous (i.v.) administration of RB 101 were evaluated in the tail-flick in rats transplanted 28 and 56 days before the test. Systemic administration of RB 101 induced antinociceptive effects in sham-operated rats, as previously reported. RB 101 also enhanced significantly the antinociception produced by the autotransplant 28 and 56 days after surgery. The antinociceptive responses of RB 101 in both sham-operated and autotransplanted rats were blocked by naloxone, but were not modified by the noradrenergic antagonist, phentolamine, suggesting a selective involvement of opioid mechanisms. The present results indicate that the inhibitors of enkephalin catabolism enhance the antinociception induced by adrenal medullary transplants.

Adrenal Medulla↗

PubMed1998

Involvement of delta-opioid receptors in the effects induced by endogenous enkephalins on learned helplessness model.

Pharmacological, neurochemical and behavioural findings support a possible role of endogenous opioids in clinical depression. There is evidence from animal studies that delta-opioid receptors are involved in several behavioural responses to opioids, including motivational activities. In the present study, the mixed enkephalin catabolism inhibitor, RB 101 (N(R,S)-2-benzyl-3[(S)-(2-amino-4-methylthiobutyldithio]-1-oxoprop yl)-L-phenylalanine benzyl ester) (1.25, 2.5 and 5 mg/kg), induced a dose-dependent antidepressant-like effect in a learned helplessness model. Thus, RB 101 reversed escape deficits in rats previously subjected to inescapable shocks, suggesting the involvement of endogenous enkephalins in depression. Similar effects were observed after administration of the selective delta-opioid receptor agonist, BUBU (Tyr-D.Ser-(O-tert-butyl)-Gly-Phe-Leu-Thr(O-Tet-butyl-OH) (1 and 2 mg/kg). Moreover, RB 101 effects were antagonized by administration of naltrindole (NTI) (0.1 mg/kg), which points to a preferential involvement of delta-opioid receptors in this enkephalin-controlled behaviour. As RB 101 has been reported to be almost devoid of opiate-related side-effects, it could represent a promising alternative in the treatment of depressive patients who are unresponsive to, or intolerant of, classical antidepressants.

Analgesics↗

PubMed1998

Disruption of the kappa-opioid receptor gene in mice enhances sensitivity to chemical visceral pain, impairs pharmacological actions of the selective kappa-agonist U-50,488H and attenuates morphine withdrawal.

***micro***-, delta- and kappa-opioid receptors are widely expressed in the central nervous system where they mediate the strong analgesic and mood-altering actions of opioids, and modulate numerous endogenous functions. To investigate the contribution of the kappa-opioid receptor (KOR) to opioid function in vivo, we have generated KOR-deficient mice by gene targeting. We show that absence of KOR does not modify expression of the other components of the opioid system, and behavioural tests indicate that spontaneous activity is not altered in mutant mice. The analysis of responses to various nociceptive stimuli suggests that the KOR gene product is implicated in the perception of visceral chemical pain. We further demonstrate that KOR is critical to mediate the hypolocomotor, analgesic and aversive actions of the prototypic kappa-agonist U-50, 488H. Finally, our results indicate that this receptor does not contribute to morphine analgesia and reward, but participates in the expression of morphine abstinence. Together, our data demonstrate that the KOR-encoded receptor plays a modulatory role in specific aspects of opioid function.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗

PubMed1998

Genetic analysis of drug addiction: the role of cAMP response element binding protein.

Many drugs of abuse, administered repeatedly over time, cause physical dependence which is expressed by a withdrawal syndrome when the drug is removed from the system. These processes can be thought of as adaptations of the neuronal system to an altered pharmacological state. The molecular mechanisms underlying these adaptations are still not known. A considerable amount of evidence is accumulating which implicates alterations in several components of the cAMP signal transduction cascade in these drug-induced processes. The transcription factor cAMP response element binding protein (CREB) in particular has been shown both in vitro and in vivo to be altered in response to several drugs of abuse, including opiates. This review discusses in detail this transcription factor and demonstrates its importance in the signal transduction cascades involving abused substances.

Animals↗

PubMed1998

Behavioural and biochemical evidence for signs of abstinence in mice chronically treated with delta-9-tetrahydrocannabinol.

Tolerance and dependence induced by chronic delta-9-tetrahydrocannabinol (THC) administration were investigated in mice. The effects on body weight, analgesia and hypothermia were measured during 6 days of treatment (10 or 20 mg kg(-1) THC twice daily). A rapid tolerance to the acute effects was observed from the second THC administration. The selective CB-1 receptor antagonist SR 141716A (10 mg kg(-1)) was administered at the end of the treatment, and somatic and vegetative manifestations of abstinence were evaluated. SR 141716A administration precipitated several somatic signs that included wet dog shakes, frontpaw tremor, ataxia, hunched posture, tremor, ptosis, piloerection, decreased locomotor activity and mastication, which can be interpreted as being part of a withdrawal syndrome. Brains were removed immediately after the behavioural measures and assayed for adenylyl cyclase activity. An increase in basal, forskolin and calcium/calmodulin stimulated adenylyl cyclase activities was specifically observed in the cerebellum of these mice. The motivational effects of THC administration and withdrawal were evaluated by using the place conditioning paradigm. No conditioned change in preference to withdrawal associated environment was observed. In contrast, a conditioned place aversion was produced by the repeated pairing of THC (20 mg kg(-1)), without observing place preference at any of the doses used. This study constitutes a clear behavioural and biochemical model of physical THC withdrawal with no motivational aversive consequences. This model permits an easy quantification of THC abstinence in mice and can be useful for the elucidation of the molecular mechanisms involved in cannabinoid dependence.

Analysis of Variance↗

PubMed1998

Field trial of a vaccine against New World cutaneous leishmaniasis in an at-risk child population: safety, immunogenicity, and efficacy during the first 12 months of follow-up.

The safety, immunogenicity, and efficacy of a vaccine against cutaneous leishmaniasis in rural Ecuadorian children was assessed in a randomized, controlled, double-blinded study. Vaccine group subjects received 2 intradermal doses of a whole, killed promastigote vaccine cocktail plus bacille Calmette-Guérin (BCG) adjuvant. Control subjects got 2 doses of BCG only. The subjects who received both vaccination doses, 438 in the vaccine group (79.3%) and 406 in the control group (83.4%), were followed for 12 months. No serious adverse side effects were identified in either group. Significantly more vaccine group subjects than controls converted to a positive Montenegro skin test (85.1% vs. 20.1%; chi2 = 279; P < .001). The incidence of cutaneous leishmaniasis was significantly reduced in the vaccine compared with the control group (2.1% vs. 7.6%; chi2 = 8.95; P < .003). The protective efficacy of the vaccine was 72.9% (95% confidence interval = 36.1%-88.5%).

Child↗