Acute myelopathy in adulthood as a delayed consequence of radiation therapy during early infancy.
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Acute Disease↗
Biomedical subjects
J Romero
Publications and source records attributed to J Romero.
Extrapyramidal and neuroendocrine effects of AM404, an inhibitor of the carrier-mediated transport of anandamide.
A selective inhibitor of the carrier-mediated transport of endogenous cannabinoids, N-(4-hydroxyphenyl)-arachidonylethanolamide (AM404), has been recently synthesized and proposed as a useful tool for studying the physiological effects of endogenous cannabinoids and as a potential therapeutic agent in a variety of diseases. In the present study, we have examined the effects of this compound in two important brain processes in which a role for anandamide and other endogenous cannabinoids has been claimed: neuroendocrine regulation and extrapyramidal motor activity. A single and well-characterized dose of AM404, which presumably resulted in a significant elevation of the levels of endogenous cannabinoids, produced a marked decrease in plasma prolactin (PRL) levels, with no changes in luteinizing hormone (LH) levels. This decrease in PRL levels was accompanied by an increase in the activity of tyrosine hydroxylase (TH) in the medial basal hypothalamus. Both decreased PRL secretion and increased hypothalamic TH activity have been reported to occur after the administration of anandamide. Administration of AM404 also produced a marked motor inhibition in the open-field test, as also reported for anandamide, with a decrease in ambulatory and exploratory activities and an increase in the time spent in inactivity. This was accompanied by a decrease in the activity of TH in the substantia nigra, an effect also previously observed for anandamide.
3,4-Dihydroxyphenylacetic Acid↗
Role of endocannabinoids in brain development.
In addition to those functions that have been extensively addressed in this special issue, such as nociception, motor activity, neuroendocrine regulation, immune function and others, the endogenous cannabinoid system seems to play also a role in neural development. This view is based on a three-fold evidence. A first evidence emerges from neurotoxicological studies that showed that synthetic and plant-derived cannabinoids, when administered to pregnant rats, produced a variety of changes in the maturation of several neurotransmitters and their associated-behaviors in their pups, changes that were evident at different stages of brain development. A second evidence comes from studies that demonstrated the early appearance of elements of the endogenous cannabinoid system (receptors and ligands) during the brain development. The atypical location of these elements during fetal and early postnatal periods favours the notion that this system may play a role in specific molecular events related to neural development. Finally, a third evidence derives from studies using cultures of fetal glial or neuronal cells. Cannabinoid receptors are present in some of these cultured cells and their activation produced a set of cellular effects consistent with a role of this system in the process of neural development. All this likely supports that endocannabinoids, early synthesized in nervous cells, play a role in events related to development, by acting through the activation of second messenger-coupled cannabinoid receptors.
Animals↗
Pharmacological and biochemical interactions between opioids and cannabinoids.
Opioids and cannabinoids are among the most widely consumed drugs of abuse in humans. A number of studies have shown that both types of drugs share several pharmacological properties, including hypothermia, sedation, hypotension, inhibition of both intestinal motility and locomotor activity and, in particular, antinociception. Moreover, phenomena of cross-tolerance or mutual potentiation of some of these pharmacological effects have been reported. In recent years, these phenomena have supported the possible existence of functional links in the mechanisms of action of both types of drugs. The present review addresses the recent advances in the study of pharmacological interactions between opioids and cannabinoids, focusing on two aspects: antinociception and drug addiction. The potential biochemical mechanisms involved in these pharmacological interactions are also discussed together with possible therapeutic implications of opioid-cannabinoid interactions.
Cannabinoids↗
Cannabinoid receptor and WIN-55,212-2-stimulated [35S]GTPgammaS binding and cannabinoid receptor mRNA levels in several brain structures of adult male rats chronically exposed to R-methanandamide.
We and others have recently demonstrated that the pharmacological tolerance observed after prolonged exposure to plant and synthetic cannabinoids in adult individuals seems to have a pharmacodynamic basis, based on the observed down-regulation of cannabinoid receptors in the brain of cannabinoid-tolerant rats. However, we were unable to elicit a similar receptor down-regulation after a chronic exposure to anandamide, the first discovered endogenous cannabinoid, possibly because of its rapid metabolic breakdown in arachidonic acid and ethanolamine. The present study was designed to progress in these previous studies, by using R-methanandamide, a more stable analog, instead anandamide. In addition, we examined not only cannabinoid receptor binding, but also WIN-55,212-2-stimulated [35S]-GTPgammaS binding, by autoradiography, and cannabinoid receptor mRNA levels, by in situ hybridization. Results were as follows. The daily administration of R-methanandamide for a period of five days produced decreases in cannabinoid receptor binding in the lateral caudate-putamen, cerebellum, entopeduncular nucleus and substantia nigra. The remaining areas, the medial caudate-putamen, globus pallidus, cerebral cortex (layers I and VI), hippocampus (dentate gyrus and Ammon's horn) and several limbic structures (nucleus accumbens, septum nuclei and basolateral amygdaloid nucleus), exhibited no changes in cannabinoid receptor binding. Similarly, the levels of cannabinoid receptor mRNA expression decreased in the lateral and medial caudate-putamen and in the CA1 and CA2 subfields of the Ammon's horn in the hippocampus after the chronic exposure to R-methanandamide, whereas the remaining areas showed no changes. WIN-55,212-2-stimulated [35S]-GTPgammaS binding did not change in the lateral caudate-putamen, cerebral cortex (layer I), septum nuclei and hippocampal structures (dentate gyrus and Ammon's horn) of animals chronically exposed to R-methanandamide, whereas a certain trend to decrease could be observed in the substantia nigra and deep layer (VI) of the cerebral cortex in these animals. In summary, as reported for other cannabinoid receptor agonists, the prolonged exposure of rats to R-methanandamide, a more stable analog of anandamide, was able to produce cannabinoid receptor-related changes in contrast with the absence of changes observed early with the metabolically labile anandamide. The observed changes exhibited an evident regional pattern with areas, such as basal ganglia, cerebellum and hippocampus, responding to chronic R-methanandamide treatment while regions, such as the cerebral cortex and limbic nuclei, not responding.
Animals↗
[Expression of inducible nitric oxide synthase in the carotid of rats after endothelial skinning: the effects of platelets and treatment with abciximab].
BACKGROUND: Functional evidence suggests that endothelial denudation stimulates inducible nitric oxide synthase (iNOS) activity in the vascular wall. In vitro studies done in our laboratory have shown that iNOS expression in smooth muscle cells is reduced by endothelial cells. The object of this study was to analyze the iNOS protein expression in the arterial wall after in vivo deendothelialization, and the role of platelet activation abciximab in the expression of this protein. MATERIALS AND METHODS: Endothelial denudation was performed in the left carotid artery of Wistar rats. The right carotid artery was used as control. RESULTS: iNOS protein was only weakly expressed at 6, 24 and 48 hours after endothelial denudation. Since platelet adhesion and aggregation occur early after endothelial damage, we have analyzed the role of activated platelets in iNOS protein expression during the first two days after angioplasty. Early after in vivo endothelial injury, thrombocytopenic rats showed a marked iNOS protein expression. Similar results were obtained by blocking the platelet glycoprotein IIb/IIIa in rats treated with abciximab (Reopro). CONCLUSIONS: iNOS protein is weakly expressed in the arterial wall after endothelial denudation. Platelets play a crucial role preventing iNOS protein expression early after endothelial damage through a mechanism that depends on GP IIb/IIIa, an effect that can be avoided with glycoprotein IIb/IIIa, blockers, such as abciximab.
Abciximab↗
The erythrocyte effects of haemoglobin O(ARAB).
To test the hypothesis that HbOARAB induces an increase in red cell mean corpuscular haemoglobin concentration (MCHC), we studied members of four Tunisian families who were either homo- or heterozygous for HbOARAB or were double heterozygotes for HbS and HbOARAB. The alpha-gene status was also tested. The findings included: (1) Distinctive variation in red cell density (MCHC) as determined by separation of red cells on isopycnic gradients: (a) All red cells from patients homozygous for HbOARAB were denser than normal red cells, as is observed for homozygous HbC patients. (b) In patients heterozygous for HbOARAB, red cell density was strongly influenced by the presence of alpha-thalassaemia. The coexistence of -alpha/alphaalpha resulted in an average red cell density slightly greater than normal (AA) red cells. Patients heterozygous for HbOARAB with a normal complement of four alpha genes had denser red cells similar to sickle cell disease with some cells of normal density but with most cells very dense. (c) Finally, the double heterozygotes for HbS and HbOARAB had significant haemolytic anaemia and red cells denser than normal with some as dense as the densest cells found in sickle cell anaemia. (2) Reticulocytes in patients homozygous for HbOARAB were found in the densest density fraction of whole blood. (3) Cation transport in patients homozygous for HbOARAB was abnormal, with K:Cl cotransport activity similar to that of HbS-Oman and only somewhat lower than in sickle cell anaemia red cells. The activity of the Gardos channel was indistinguishable from that found in HbS, HbC and HbS-Oman cells. We conclude that the erythrocytic pathogenesis of HbOARAB involves the dehydration of red cells due, at least in part, to the K:Cl cotransport system. The similarity of the charge and consequences of the presence of both HbC and HbOARAB, which are the products of mutations at opposite ends of the beta-chain, raises the possibility that this pathology is the result of a charge-dependent interaction of these haemoglobins with the red cell membrane and/or its cytoskeleton and that this abnormality is present early in red cell development.
Adolescent↗
Structural alterations of lignins in transgenic poplars with depressed cinnamyl alcohol dehydrogenase or caffeic acid O-methyltransferase activity have an opposite impact on the efficiency of industrial kraft pulping
We evaluated lignin profiles and pulping performances of 2-year-old transgenic poplar (Populus tremula x Populus alba) lines severely altered in the expression of caffeic acid/5-hydroxyferulic acid O-methyltransferase (COMT) or cinnamyl alcohol dehydrogenase (CAD). Transgenic poplars with CAD or COMT antisense constructs showed growth similar to control trees. CAD down-regulated poplars displayed a red coloration mainly in the outer xylem. A 90% lower COMT activity did not change lignin content but dramatically increased the frequency of guaiacyl units and resistant biphenyl linkages in lignin. This alteration severely lowered the efficiency of kraft pulping. The Klason lignin level of CAD-transformed poplars was slightly lower than that of the control. Whereas CAD down-regulation did not change the frequency of labile ether bonds or guaiacyl units in lignin, it increased the proportion of syringaldehyde and diarylpropane structures and, more importantly with regard to kraft pulping, of free phenolic groups in lignin. In the most depressed line, ASCAD21, a substantially higher content in free phenolic units facilitated lignin solubilization and fragmentation during kraft pulping. These results point the way to genetic modification of lignin structure to improve wood quality for the pulp industry.
Journal Article↗
Identification of endocannabinoids and cannabinoid CB(1) receptor mRNA in the pituitary gland.
Most data on effects of natural and synthetic cannabinoids on anterior pituitary hormone secretion point out to a primary impact on the hypothalamus. There is also some evidence, however, of possible direct actions of these compounds on the anterior pituitary, although the presence of cannabinoid receptors in the pituitary has not been documented as yet. In the present study, we evaluated the presence of cannabinoid CB(1) receptor-mRNA transcripts in the pituitary gland by in situ hybridization. We observed CB(1) receptor-mRNA transcripts in the anterior pituitary and to a lesser extent in the intermediate lobe whereas they were absent in the neural lobe. We then examined whether CB(1) receptor-mRNA levels in both pituitary lobes responded to chronic activation by a specific agonist, as did receptors located in adjacent hypothalamic nuclei and in other brain regions. Daily administration of CP-55,940 for 18 days produced a small, but statistically significant paradoxical increase in CB(1) receptor-mRNA levels in the anterior pituitary, with no changes in the intermediate lobe, in contrast to reduced CB(1) receptor-mRNA levels observed in the ventromedial hypothalamic nucleus (VMN), and to decreased CB(1) receptor binding in the VMN and the arcuate nucleus. The time-course of up-regulation of CB(1) receptor-mRNA transcripts in the anterior lobe was biphasic; daily administration of Delta(9)-tetrahydrocannabinol produced an early and marked decrease in CB(1) receptor-mRNA levels after 1 and 3 days, followed by normalization after 7 days and by a small increase after 14 days. We also checked whether endogenous cannabinoid ligands are present in the anterior pituitary and the hypothalamus. Although anandamide itself was detected only in trace amounts, concentrations of its precursor N-arachidonoyl-phosphatidyl-ethanolamine and of 2-arachidonoyl-glycerol were found in both tissues, suggesting that endocannabinoids may be synthetized in the anterior pituitary. In summary, CB(1) receptors and corresponding ligands seem to be expressed in cells of the anterior and intermediate lobes of the pituitary, but the response of CB(1) receptor-mRNA transcripts in the anterior lobe to chronic agonist activation is different than the desensitization observed in hypothalamic nuclei.
Animals↗
In vivo radiosensitizing effect of the adenovirus E1A gene in murine and human malignant tumors.
The adenovirus E1A gene is a potent inducer of chemosensitivity and radiosensitivity through p53-dependent and independent mechanisms. We have studied the sensitivity of murine (MSC11A5, a sarcomatoid epidermoid carcinoma) and human (HeLa, human cervix carcinoma) E1A-expressing tumors, in vivo, after treatment with cisplatin or gamma-irradiation. In athymic mice, half-body irradiation was performed in an AECL Cobalt unit, at an SSD of 80 cm. Daily fractions of 300 cGy over 3 days, up to a total dose of 9 Gy. Cisplatin was injected intraperitoneally at a dose of 9 mg per kg of body weight. After gamma-irradiation or intraperitoneal injection of cisplatin, about 30% of the E1A-expressing tumors regressed completely or were associated with a marked decrease in tumorigenicity over the following weeks. We conclude that malignant tumors, when expressing adenovirus E1A, are very sensitive to treatment with DNA-damaging agents, in vivo, regardless of the p53 status of the tumors.
Adenovirus E1A Proteins↗
[Bacteremia by Staphylococcus aureus: analysis of 311 episodes].
BACKGROUND: The aim of this study was to set up the differences between nosocomial and community acquired S. aureus bacteremia, to identify the features of the patients at high risk of endocarditis and to define the characteristics of the patients with methicillin resistant S. aureus (MRSA). METHODS: We prospectively studied 311 cases of S. aureus bacteremia detected at our hospital during a four-year period. RESULTS: Nosocomial acquisition of bacteremia was found in 63% of the cases, 45% of which were caused by MRSA. Nosocomial bacteria generally presented in older patients with more severe underlying conditions and a higher prevalence of invasive procedures than patients with the community-acquired disease. Likewise, the primary focus of infection was identifiable in most of the nosocomial episodes and mortality was also higher. Endocarditis presented in 19% of the bacteremia episodes and almost 90% of patients with endocarditis were intravenous drug users (IDU). The risk of endocarditis in this group was 64% whereas it was only 3% in non-IDU patients. Overall mortality was 33% and mortality directly due to the bacteremia was 22%. CONCLUSIONS: IDU patients were at high risk of endocarditis but most had a favourable outcome. Bacteremia was community-acquired in these patients and they rarely presented MRSA bacteremia. Patients with previous valvular diseases were at high risk of endocarditis and had a high mortality. Non-IDU patients with community-acquired bacteremia were at a low risk of endocarditis, regardless of whether a primary focus of infection had been identified or not. Mortality was lower in this group than in patients with nosocomial bacteremia and there were no cases of MRSA bacteremia. Mortality was higher in patients treated with vancomycin than in patients treated with other antibiotics active against S. aureus.
Adult↗
[Bacteremia by Clostridium perfringens: complication of the manual extraction of a fecaloma].
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Bacteremia↗
[Bacteremias in a university hospital: study of etiologic agents and their sensitivity patterns].
OBJECTIVE: To determine the bacterial etiology of bacteremic episodes recorded at our hospital during 1995 and their antimicrobial susceptibility patterns. METHODS: The microbiological records of all bacteremic episodes detected at our hospital from January to December 1995 were analysed. The susceptibility patterns of the 334 gram-positive aerobic isolates to 11 antimicrobials and of 236 gram-negative aerobic isolates to 16 antimicrobial agents were determined. The reference agar dilution method was used for these determinations. RESULTS: The incidence of bacteremia was 19.3/1,000 admissions. Gram-positive aerobic bacteria accounted for 56.6% of monomicrobial bacteremias; the microorganisms recovered most frequently were coagulase-negative staphylococci (22.4%), Escherichia coli (16.5%) and Staphylococcus aureus (14.2%); 75 polymicrobial episodes were recorded. Over half of bacteremic episodes occurred at medical services. Hematologic diseases and solid tumours were the most common underlying diseases. No resistance to glycopeptides was observed among the staphylococci studied. The incidence of resistance to vancomycin in enterococci was small (1.5%). The aminoglycosides tested and some beta lactams showed good activity against the gram-negative bacilli studied. CONCLUSIONS: To carry out an epidemiologic surveillance of bacteremic episodes occurring at every hospital it is necessary to provide information on trends observed in the etiology of such infections, possible outbreaks, antimicrobial resistance, and uncommon pathogens.
Adolescent↗
Bone and cartilage tissue engineering.
Tissue engineering of musculoskeletal tissues, particularly bone and cartilage, is a rapidly advancing field. In bone, technology has centered on bone graft substitute materials and the development of biodegradable scaffolds. Recently, tissue engineering strategies have included cell and gene therapy. The availability of growth factors and the expanding knowledge base concerning the genetics and regulation of bone formation have generated new materials for tissue-engineering applications. This information base also has benefited cartilage tissue engineering. The problems are more complex, however, and the solutions appear more elusive. Advances in scaffold design and cell culture have improved the prognosis for success.
Animals↗
Effects of cannabinoids on prolactin and gonadotrophin secretion: involvement of changes in hypothalamic gamma-aminobutyric acid (GABA) inputs.
CB1 cannabinoid receptors are located in hypothalamic nuclei and their activation alters several hypothalamic neurotransmitters resulting in, among other things, decreased prolactin (PRL) and luteinizing hormone (LH) secretion from the anterior pituitary gland. In the present study, we addressed two related objectives to further explore this complex regulation. First, we examined whether changes in gamma-aminobutyric acid (GABA) and/or dopamine (DA) inputs in the medial basal hypothalamus might occur in parallel to the effects resulting from the activation of CB1 receptors on PRL and gonadotrophin secretion in male rats. Thus, the acute administration of (-)-delta9-tetrahydrocannnabinol (delta9-THC) produced, as expected, a marked decrease in plasma PRL and LH levels, with no changes in follicle-stimulating hormone (FSH) levels. This was paralleled by an increase in the contents of GABA, but not of DA, in the medial basal hypothalamus and, to a lesser extent, in the anterior pituitary gland. The co-administration of delta9-THC and SR141716, a specific antagonist for CB1 receptors, attenuated both PRL and LH decrease and GABA increase, thus asserting the involvement of the activation of CB1 receptors in these effects. As a second objective, we tested whether the prolonged activation of these receptors might induce tolerance with regard to the decrease in PRL and LH release, and whether this potential tolerance might be related to changes in CB1-receptor binding and/or mRNA expression. The chronic administration of R-methanandamide (AM356), a more stable analog of anandamide, the putative endogenous cannabinoid ligand, produced a marked decrease in plasma PRL and LH levels, with no changes in FSH. The decreases were of similar magnitude to those caused by a single injection of this cannabimimetic ligand, thus suggesting the absence of tolerance. In parallel, the analysis of CB1-receptor binding and mRNA expression in several hypothalamic structures proved that the acute or chronic administration of AM356 did not affect either the binding or the synthesis of these receptors. In summary, the activation of CB1 receptors in hypothalamic nuclei produced the expected decrease in PRL and LH secretion, an effect which might be related to an increase in GABAergic activity in the hypothalamus-anterior pituitary axis. The prolonged activation of these receptors for five days did not elicit tolerance in terms of an attenuation in the magnitude of the decrease in PRL and LH, and, accordingly, did not alter CB1-receptor binding and mRNA levels in the hypothalamic nuclei examined.
Animals↗
Changes in cannabinoid receptor binding and mRNA levels in several brain regions of aged rats.
We have recently found that cannabinoid receptor binding and gene expression markedly decreased in extrapyramidal structures of aged rats. The present study was designed to analyze the possible existence of similar aging-induced changes in cannabinoid receptor binding and gene expression in brain regions other than extrapyramidal areas, but that also contain a significant population of cannabinoid receptors, such as the cerebellum, hippocampal structures, limbic and hypothalamic nuclei, the cerebral cortex and others. To this end, we analyzed cannabinoid receptor binding, using autoradiography, and cannabinoid receptor mRNA levels, using in situ hybridization, in slide-mounted brain sections obtained from young (3 month old) and aged (> 2 year old) rats. Results were as follows. In the cerebellum, aged rats exhibited a marked decrease in cannabinoid receptor binding in the molecular layer (-33.3%), although accompanied by no changes in mRNA levels in the granular layer. In the cerebral cortex, a small, although statistically significant, decrease in binding was found in the deep layer (VI) (-18.3%) of aged rats, whereas no changes were found in the superficial layer (I). As in the case of the cerebellum, mRNA levels did not change in the cerebral cortex layers (II-III and V-VI). The different regions of the Ammon's horn of the hippocampus exhibited similar cannabinoid receptor binding levels in aged and young rats. Interestingly, mRNA levels decreased in aged rats to a small, but statistically significant, extent (CA1: -26.1%; CA2: -21.6%; CA3: -14.4%). This was also seen in another hippocampal structure, the dentate gyrus (-14.6%), although in this region binding levels increased in aged rats (+28.4%). Two hypothalamic structures, the arcuate nucleus and the ventromedial hypothalamic nucleus, exhibited decreased cannabinoid receptor binding in aged rats (-31.1% and -30.3%, respectively), but this was not seen in the medial preoptic area. This was accompanied by no changes in mRNA levels in the ventromedial hypothalamic nucleus. In the limbic structures, aged rats exhibited similar binding levels to young rats. This was seen in the nucleus accumbens, septum nuclei and basolateral amygdaloid nucleus. However, mRNA levels slightly decreased in the basolateral amygdaloid nucleus (-13.4%), whereas they were not altered in the septum nuclei. Finally, other brain structures, such as the central gray substance and the brainstem, exhibited similar binding levels in aged and young rats. However, it is important to note that mRNA levels increased significantly (+211.2%) in the brainstem of aged rats, an area where the levels of binding and mRNA were very low in young rats. This marked increase may be related to an increase in the presence of glial elements in this region, as revealed by the increase in the immunoreactivity for glial fibrillary acidic protein observed in the brainstem of aged rats as compared to young animals. In summary, senescence was associated with changes in cannabinoid receptors in the cerebellum, the cerebral cortex, limbic and hypothalamic structures, the hippocampus and other brain regions. However, the changes observed (i) were not as marked and relevant as those early reported in extrapyramidal areas, and (ii) exhibited regional differences that might be attributed to the different roles played by these receptors in each region. Of particular relevance by their magnitude were the aging-induced decrease in binding found in the cerebellum and the hypothalamus, and the increase in mRNA levels observed in the brainstem. The latter might be related to an increase in the presence of glial cells which might contain cannabinoid receptor mRNA.
Aging↗
Autoradiographic analysis of cannabinoid receptor binding and cannabinoid agonist-stimulated [35S]GTP gamma S binding in morphine-dependent mice.
The present study was designed to test the possible existence of changes in brain cannabinoid receptors in morphine-dependent mice. To this end, we compared cannabinoid receptor binding and WIN 55,212-2-stimulated [35S]guanylyl-5'-O-(gamma-thio)-triphosphate ([35S]GTP gamma S) binding in several brain regions of mice chronically exposed to morphine or saline. The existence of opiate dependence in morphine-injected mice was assessed by analyzing the well-known jumping behavior induced by the blockade of opioid receptors with naloxone, whereas these animals were unresponsive to the blockade of cannabinoid receptors with SR141716. The different structures analyzed exhibited similar cannabinoid receptor binding levels in morphine-dependent and control mice, with the only exception of the globus pallidus, which exhibited a very small, but statistically significant, increase. In addition, the activation of cannabinoid receptors with WIN 55,212-2 increased [35S]GTP gamma S binding in most of the structures examined. The increase was of similar magnitude in morphine-dependent and control mice, except in the substantia nigra, where morphine-dependent mice exhibited lesser [35S]GTP gamma S binding levels in basal conditions, although a significantly higher WIN 55,212-2-stimulated binding. Other structures, such as the central gray substance, where there was a poor agonist-induced stimulation in control mice, exhibited, however, higher levels of WIN 55,212-2-stimulated [35S]GTP gamma S binding in morphine-dependent mice, whereas these animals tended to exhibit a higher [35S]GTP gamma S binding levels in basal conditions, although a lesser and not statistically significant WIN 55,22-2-stimulated binding, in the deep layers of the cerebral cortex. Thus, the data support the potential existence of a specific effect of morphine in the coupling of cannabinoid receptors to GTP-binding proteins, rather than on receptor binding, although this was observed only in the substantia nigra and central gray substance.
Analgesics↗
Chronic administration of cannabinoids regulates proenkephalin mRNA levels in selected regions of the rat brain.
This study was designed to examine the interactions between the cannabinoid and enkephalinergic systems in the rat brain. To this aim, we have examined the effects of subchronic (5 days) administration (10 mg.kg-1.day-1; i.p.) of delta 9 -tetrahydrocannabinol (THC) or R-methanandamide (AM356) and chronic (18 days) administration with the synthetic cannabinoid receptor agonist CP-55,940 (1 mg.kg-1.day-1; i.p) on proenkephalin (PENK) mRNA levels in several brain regions of the rat. Twenty micrometer brain sections from striatum, nucleus accumbens, paraventricular nucleus, ventromedial nucleus, periaqueductal grey matter and mammillary nucleus were hybridized with an oligonucleotide probe complementary to PENK using in situ hybridization technique. Subchronic administration of THC or AM356 increased PENK mRNA levels in the ventromedial nucleus of the hypothalamus, (82%) and (39%), in the periaqueductal grey matter, (97%) and (49%), and mammillary nucleus, (43%) and (9%), respectively. In contrast, both drugs were without effect in the striatum and nucleus accumbens. On the other hand, chronic administration of CP-55,940 increased PENK mRNA levels in the striatum (44%), nucleus accumbens (25%), paraventricular (31%) and ventromedial nuclei of the hypothalamus (41%). These results revealed that chronic cannabinoid administration increases opioid gene expression in the rat central nervous system and suggest an interaction between the cannabinoid and enkephalinergic systems that may be part of a molecular integrative response to behavioral and neurochemical alterations that occur in cannabinoid drug abuse.
Animals↗