Publications by authors named "Miquel Martín"

21 Publications

  • Page 1 of 1

EST64454: a Highly Soluble σ Receptor Antagonist Clinical Candidate for Pain Management.

J Med Chem 2020 12 25;63(23):14979-14988. Epub 2020 Nov 25.

ESTEVE Pharmaceuticals, Torre Esteve, Passeig de la Zona Franca, 109, 08038 Barcelona, Spain.

The synthesis and pharmacological activity of a new series of pyrazoles that led to the identification of 1-(4-(2-((1-(3,4-difluorophenyl)-1-pyrazol-3-yl)methoxy)ethyl)piperazin-1-yl)ethanone (, EST64454) as a σ receptor (σR) antagonist clinical candidate for the treatment of pain are reported. The compound is easily obtained through a five-step synthesis suitable for the production scale and shows an outstanding aqueous solubility, which together with its high permeability in Caco-2 cells will allow its classification as a BCS class I compound. It also shows high metabolic stability in all species, linked to an adequate pharmacokinetic profile in rodents, and antinociceptive properties in the capsaicin and partial sciatic nerve ligation models in mice.
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http://dx.doi.org/10.1021/acs.jmedchem.0c01575DOI Listing
December 2020

Functional and molecular heterogeneity of D2R neurons along dorsal ventral axis in the striatum.

Nat Commun 2020 04 23;11(1):1957. Epub 2020 Apr 23.

IGF, CNRS, INSERM, Université Montpellier, Montpellier, France.

Action control is a key brain function determining the survival of animals in their environment. In mammals, neurons expressing dopamine D2 receptors (D2R) in the dorsal striatum (DS) and the nucleus accumbens (Acb) jointly but differentially contribute to the fine regulation of movement. However, their region-specific molecular features are presently unknown. By combining RNAseq of striatal D2R neurons and histological analyses, we identified hundreds of novel region-specific molecular markers, which may serve as tools to target selective subpopulations. As a proof of concept, we characterized the molecular identity of a subcircuit defined by WFS1 neurons and evaluated multiple behavioral tasks after its temporally-controlled deletion of D2R. Consequently, conditional D2R knockout mice displayed a significant reduction in digging behavior and an exacerbated hyperlocomotor response to amphetamine. Thus, targeted molecular analyses reveal an unforeseen heterogeneity in D2R-expressing striatal neuronal populations, underlying specific D2R's functional features in the control of specific motor behaviors.
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http://dx.doi.org/10.1038/s41467-020-15716-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7181842PMC
April 2020

Ciprofloxacin as a cause of acute renal failure.

Enferm Infecc Microbiol Clin 2020 10 22;38(8):402-403. Epub 2020 Feb 22.

Servei de Medicina Interna, Hospital de Mataró, CSDM, Mataró, Barcelona, España.

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http://dx.doi.org/10.1016/j.eimc.2020.01.010DOI Listing
October 2020

Cafeteria diet induces neuroplastic modifications in the nucleus accumbens mediated by microglia activation.

Addict Biol 2018 03 5;23(2):735-749. Epub 2017 Sep 5.

Laboratory of Neuropharmacology (DCEXS), Parc de Recerca Biomèdica de Barcelona/Universitat Pompeu Fabra (PRBB/UPF), Spain.

High-palatable and caloric foods are widely overconsumed due to hedonic mechanisms that prevail over caloric necessities leading to overeating and overweight. The nucleus accumbens (NAc) is a key brain area modulating the reinforcing effects of palatable foods and is crucially involved in the development of eating disorders. We describe that prolonged exposure to high-caloric chocolate cafeteria diet leads to overeating and overweight in mice. NAc functionality was altered in these mice, presenting structural plasticity modifications in medium spiny neurons, increased expression of neuroinflammatory factors and activated microglia, and abnormal responses after amphetamine-induced hyperlocomotion. Chronic inactivation of microglia normalized these neurobiological and behavioural alterations exclusively in mice exposed to cafeteria diet. Our data suggest that prolonged exposure to cafeteria diet produces neuroplastic and functional changes in the NAc that can modify feeding behaviour. Microglia activation and neuroinflammation play an important role in the development of these neurobiological alterations.
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http://dx.doi.org/10.1111/adb.12541DOI Listing
March 2018

Morphine-induced locomotor sensitization produces structural plasticity in the mesocorticolimbic system dependent on CB1-R activity.

Addict Biol 2016 11 15;21(6):1113-1126. Epub 2015 Jul 15.

Laboratory of Neuropharmacology, Parc de Recerca Biomèdica de Barcelona/Universitat Pompeu Fabra, Spain.

Changes in structural plasticity produced by the chronic exposure to drugs of abuse, such as alterations in dendritic spine densities, participate in the development of maladaptive learning processes leading to drug addiction. Understanding the neurobiological mechanisms involved in these aberrant changes is crucial to clarify the neurobiological substrate of addiction. Drug-induced locomotor sensitization has been widely accepted as a useful animal model to study these mechanisms related to drug addiction. We have evaluated the changes in structural plasticity in the mesocorticolimbic system involved in morphine-induced locomotor sensitization. The role of the cannabinoid receptor type 1 (CB1-R) in these neuroplastic alterations has also been studied using CB1-R-deficient (CB1-R KO) mice. Structural plasticity changes promoted by morphine are a highly dynamic phenomenon that evolves during the entire time course of the behavioral sensitization in wild-type (WT) animals. The different phases of the sensitization process were related to specific changes in connectivity between neurons revealed by modifications in dendritic spines in specific areas of the mesocorticolimbic system. Moreover, the lack of morphine-induced locomotor sensitization in CB1-R KO mice was accompanied by abnormal alterations in structural plasticity in the same mesocorticolimbic areas. These specific structural plasticity changes mediated by CB1-R activity seem necessary for the normal progression of morphine-induced locomotor sensitization and could play a critical role in the addictive process.
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http://dx.doi.org/10.1111/adb.12281DOI Listing
November 2016

Epigenetics, behavior and early nicotine.

Nat Neurosci 2016 06;19(7):863-4

Laboratory of Neuropharmacology, Parc de Recerca Biomèdica de Barcelona, Universitat Pompeu Fabra (PRBB/UPF), Barcelona, Spain.

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http://dx.doi.org/10.1038/nn.4330DOI Listing
June 2016

Operant behavior to obtain palatable food modifies neuronal plasticity in the brain reward circuit.

Eur Neuropsychopharmacol 2013 Feb 20;23(2):146-59. Epub 2012 May 20.

Laboratori de Neurofarmacologia, Univeristat Pompeu Fabra, PRBB, Barcelona, Spain.

Palatability enhances food intake by hedonic mechanisms that prevail over caloric necessities. Different studies have demonstrated the role of endogenous cannabinoids in the mesocorticolimbic system in controlling food hedonic value and consumption. We hypothesize that the endogenous cannabinoid system could also be involved in the development of food-induced behavioral alterations, such as food-seeking and binge-eating, by a mechanism that requires neuroplastic changes in the brain reward pathway. For this purpose, we evaluated the role of the CB1 cannabinoid receptor (CB1-R) in the behavioral and neuroplastic changes induced by operant training for standard, highly caloric or highly palatable isocaloric food using different genetics, viral and pharmacological approaches. Neuroplasticity was evaluated by measuring changes in dendritic spine density in neurons previously labeled with the dye DiI. Only operant training to obtain highly palatable isocaloric food induced neuroplastic changes in neurons of the nucleus accumbens shell and prefrontal cortex that were associated to changes in food-seeking behavior. These behavioral and neuroplastic modifications induced by highly palatable isocaloric food were dependent on the activity of the CB1-R. Neuroplastic changes induced by highly palatable isocaloric food are similar to those produced by some drugs of abuse and may be crucial in the alteration of food-seeking behavior leading to overweight and obesity.
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http://dx.doi.org/10.1016/j.euroneuro.2012.04.004DOI Listing
February 2013

Operant behavior to obtain palatable food modifies ERK activity in the brain reward circuit.

Eur Neuropsychopharmacol 2013 Mar 12;23(3):240-52. Epub 2012 May 12.

Laboratori de Neurofarmacologia, Univeristat Pompeu Fabra, PRBB, Barcelona, Spain.

Food palatability produces behavioral modifications that resemble those induced by drugs of abuse. Palatability-induced behavioral changes require both, the activation of the endogenous cannabinoid system, and changes in structural plasticity in neurons of the brain reward pathway. The ERK intracellular pathway is activated by CB1 receptors (CB1-R) and plays a crucial role in neuroplasticity. We investigated the activation of the ERK signaling cascade in the mesocorticolimbic system induced by operant training to obtain highly palatable isocaloric food and the involvement of the CB1-R in these responses. Using immunofluorescence techniques, we analyzed changes in ERK intracellular pathway activation in the mesocorticolimbic system of wild-type and CB1 knockout mice (CB1-/-) trained on an operant paradigm to obtain standard, highly caloric or highly palatable isocaloric food. Operant training for highly palatable isocaloric food, but not for standard or highly caloric food, produced a robust activation of the ERK signaling cascade in the same brain areas where this training modified structural plasticity. These changes induced by the operant training were absent in CB1-/-. We can conclude that the activation of the ERK pathway is associated to the neuroplasticity induced by operant training for highly palatable isocaloric food and might be involved in CB1-R mediated alterations in behavior and structural plasticity.
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http://dx.doi.org/10.1016/j.euroneuro.2012.04.009DOI Listing
March 2013

Effects of the cell type-specific ablation of the cAMP-responsive transcription factor in noradrenergic neurons on locus coeruleus firing and withdrawal behavior after chronic exposure to morphine.

J Neurochem 2010 Nov 19;115(3):563-73. Epub 2010 Aug 19.

Department of Molecular Biology of the Cell I, German Cancer Research Center, Heidelberg, Germany.

Repeated exposure to opiates leads to cellular and molecular changes and behavioral alterations reflecting a state of dependence. In noradrenergic neurons, cyclic AMP (cAMP)-dependent pathways are activated during opiate withdrawal, but their contribution to the activity of locus coeruleus noradrenergic neurons and behavioral manifestations remains controversial. Here, we test whether the cAMP-dependent transcription factors cAMP responsive element binding protein (CREB) and cAMP-responsive element modulator (CREM) in noradrenergic neurons control the cellular markers and the physical signs of morphine withdrawal in mice. Using the Cre/loxP system we ablated the Creb1 gene in noradrenergic neurons. To avoid adaptive effects because of compensatory up-regulation of CREM, we crossed the conditional Creb1 mutant mice with a Crem-/- line. We found that the enhanced expression of tyrosine hydroxylase normally observed during withdrawal was attenuated in CREB/CREM mutants. Moreover, the withdrawal-associated cellular hyperactivity and c-fos expression was blunted. In contrast, naloxone-precipitated withdrawal signs, such as jumping, paw tremor, tremor and mastication were preserved. We conclude by a specific genetic approach that the withdrawal-associated hyperexcitability of noradrenergic neurons depends on CREB/CREM activity in these neurons, but does not mediate several behavioral signs of morphine withdrawal.
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http://dx.doi.org/10.1111/j.1471-4159.2010.06709.xDOI Listing
November 2010

Central and peripheral consequences of the chronic blockade of CB1 cannabinoid receptor with rimonabant or taranabant.

J Neurochem 2010 Mar 17;112(5):1338-13351. Epub 2009 Dec 17.

Laboratori de Neurofarmacologia, Departament de Ciencies Experimentals i de la Salut, Universitat Pompeu Fabra, PRBB, Barcelona, Spain.

The endocannabinoid system plays a crucial role in the pathophysiology of obesity. However, the clinical use of cannabinoid antagonists has been recently stopped because of its central side-effects. The aim of this study was to compare the effects of a chronic treatment with the CB(1) cannabinoid antagonist rimonabant or the CB(1) inverse agonist taranabant in diet-induced obese female rats to clarify the biological consequences of CB(1) blockade at central and peripheral levels. As expected, chronic treatment with rimonabant and taranabant reduced body weight and fat content. Interestingly, a decrease in the number of CB(1) receptors and its functional activity was observed in all the brain areas investigated after chronic taranabant treatment in both lean and obese rats. In contrast, chronic treatment with rimonabant did not modify the density of CB(1) cannabinoid receptor binding, and decreased its functional activity to a lower degree than taranabant. Six weeks after rimonabant and taranabant withdrawal, CB(1) receptor density and activity recovered to basal levels. These results reveal differential adaptive changes in CB(1) cannabinoid receptors after chronic treatment with rimonabant and taranabant that could be related to the central side-effects reported with the use of these cannabinoid antagonists.
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http://dx.doi.org/10.1111/j.1471-4159.2009.06549.xDOI Listing
March 2010

Interferon-gamma is a critical modulator of CB(2) cannabinoid receptor signaling during neuropathic pain.

J Neurosci 2008 Nov;28(46):12136-45

Institute of Molecular Psychiatry and Department of Psychiatry, University of Bonn, 53105 Bonn, Germany.

Nerve injuries often lead to neuropathic pain syndrome. The mechanisms contributing to this syndrome involve local inflammatory responses, activation of glia cells, and changes in the plasticity of neuronal nociceptive pathways. Cannabinoid CB(2) receptors contribute to the local containment of neuropathic pain by modulating glial activation in response to nerve injury. Thus, neuropathic pain spreads in mice lacking CB(2) receptors beyond the site of nerve injury. To further investigate the mechanisms leading to the enhanced manifestation of neuropathic pain, we have established expression profiles of spinal cord tissues from wild-type and CB(2)-deficient mice after nerve injury. An enhanced interferon-gamma (IFN-gamma) response was revealed in the absence of CB(2) signaling. Immunofluorescence stainings demonstrated an IFN-gamma production by astrocytes and neurons ispilateral to the nerve injury in wild-type animals. In contrast, CB(2)-deficient mice showed neuronal and astrocytic IFN-gamma immunoreactivity also in the contralateral region, thus matching the pattern of nociceptive hypersensitivity in these animals. Experiments in BV-2 microglia cells revealed that transcriptional changes induced by IFN-gamma in two key elements for neuropathic pain development, iNOS (inducible nitric oxide synthase) and CCR2, are modulated by CB(2) receptor signaling. The most direct support for a functional involvement of IFN-gamma as a mediator of CB(2) signaling was obtained with a double knock-out mouse strain deficient in CB(2) receptors and IFN-gamma. These animals no longer show the enhanced manifestations of neuropathic pain observed in CB(2) knock-outs. These data clearly demonstrate that the CB(2) receptor-mediated control of neuropathic pain is IFN-gamma dependent.
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http://dx.doi.org/10.1523/JNEUROSCI.3402-08.2008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3844840PMC
November 2008

Crucial role of CB(2) cannabinoid receptor in the regulation of central immune responses during neuropathic pain.

J Neurosci 2008 Nov;28(46):12125-35

Institute of Molecular Psychiatry, University of Bonn, 53105 Bonn, Germany.

Neuropathic pain is a clinical manifestation of nerve injury difficult to treat even with potent analgesic compounds. Here, we used different lines of genetically modified mice to clarify the role played by CB(2) cannabinoid receptors in the regulation of the central immune responses leading to the development of neuropathic pain. CB(2) knock-out mice and wild-type littermates were exposed to sciatic nerve injury, and both genotypes developed a similar hyperalgesia and allodynia in the ipsilateral paw. Most strikingly, knock-outs also developed a contralateral mirror image pain, associated with an enhanced microglial and astrocytic expression in the contralateral spinal horn. In agreement, hyperalgesia, allodynia, and microglial and astrocytic activation induced by sciatic nerve injury were attenuated in transgenic mice overexpressing CB(2) receptors. These results demonstrate the crucial role of CB(2) cannabinoid receptor in modulating glial activation in response to nerve injury. The enhanced manifestations of neuropathic pain were replicated in irradiated wild-type mice reconstituted with bone marrow cells from CB(2) knock-outs, thus demonstrating the implication of the CB(2) receptor expressed in hematopoietic cells in the development of neuropathic pain at the spinal cord.
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http://dx.doi.org/10.1523/JNEUROSCI.3400-08.2008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3844839PMC
November 2008

Cocaine but not natural reward self-administration nor passive cocaine infusion produces persistent LTP in the VTA.

Neuron 2008 Jul;59(2):288-97

Ernest Gallo Clinic and Research Center, Department of Neurology, University of California, San Francisco, Emeryville, CA 94608, USA.

Persistent drug-seeking behavior is hypothesized to co-opt the brain's natural reward-motivational system. Although ventral tegmental area (VTA) dopamine (DA) neurons represent a crucial component of this system, the synaptic adaptations underlying natural rewards and drug-related motivation have not been fully elucidated. Here, we show that self-administration of cocaine, but not passive cocaine infusions, produced a persistent potentiation of VTA excitatory synapses, which was still present after 3 months abstinence. Further, enhanced synaptic function in VTA was evident even after 3 weeks of extinction training. Food or sucrose self-administration induced only a transient potentiation of VTA glutamatergic signaling. Our data show that synaptic function in VTA DA neurons is readily but reversibly enhanced by natural reward-seeking behavior, while voluntary cocaine self-administration induced a persistent synaptic enhancement that is resistant to behavioral extinction. Such persistent synaptic potentiation in VTA DA neurons may represent a fundamental cellular phenomenon driving pathological drug-seeking behavior.
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http://dx.doi.org/10.1016/j.neuron.2008.05.024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2593405PMC
July 2008

CB1 knockout mice display impaired functionality of 5-HT1A and 5-HT2A/C receptors.

J Neurochem 2007 Dec 18;103(5):2111-20. Epub 2007 Oct 18.

Department of Physiology and Pharmacology, University of Cantabria, Cantabria, Spain.

Interaction between brain endocannabinoid (EC) and serotonin (5-HT) systems was investigated by examining 5-HT-dependent behavioral and biochemical responses in CB(1) receptor knockout mice. CB(1) knockout animals exhibited a significant reduction in the induction of head twitches and paw tremor by the 5-HT(2A/C) receptor selective agonist (+/-) DOI, as well as a reduced hypothermic response following administration of the 5-HT(1A) receptor agonist (+/-)-8-OH-DPAT. Additionally, exposure to the tail suspension test induced enhanced despair responses in CB(1) knockout mice. However, the tricyclic antidepressant imipramine and the 5-HT selective reuptake inhibitor fluoxetine induced similar decreases in the time of immobility in the tail suspension test in CB(1) receptor knockout and wild-type mice. No differences were found between both genotypes with regard to 5-HT(2A) receptor and 5-HT(1A) receptors levels, measured by autoradiography in different brain areas. However, a significant decrease in the ability of both, the 5-HT(1A) receptor agonist (+/-)-8-OH-DPAT and the 5-HT(2A/C) receptor agonist (-)DOI, to stimulate [(35)S]GTPgammaS binding was detected in the hippocampal CA(1) area and fronto-parietal cortex of CB(1) receptor knockout mice, respectively. This study provides evidence that CB(1) receptors are involved in the regulation of serotonergic responses mediated by 5-HT(2A/C) and 5-HT(1A) receptors, and suggests that a reduced coupling of 5-HT(1A) and 5-HT(2A) receptors to G proteins might be involved in these effects.
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http://dx.doi.org/10.1111/j.1471-4159.2007.04961.xDOI Listing
December 2007

Withdrawal from intermittent ethanol exposure increases probability of burst firing in VTA neurons in vitro.

J Neurophysiol 2007 Oct 15;98(4):2297-310. Epub 2007 Aug 15.

Ernest Gallo Clinic and Research Center, University of California San Francisco, Department of Neurology, Emeryville, CA 94608, USA.

Changing the activity of ventral tegmental area (VTA) dopamine neurons from pacemaker to burst firing is hypothesized to increase the salience of stimuli, such as an unexpected reward, and likely contributes to withdrawal-associated drug-seeking behavior. Accordingly, pharmacological, behavioral, and electrophysiological data suggest an important role of the VTA in mediating alcohol-dependent behaviors. However, the effects of repeated ethanol exposure on VTA dopamine neuron ion channel function are poorly understood. Here, we repeatedly exposed rats to ethanol (2 g/kg ethanol, ip, twice per day for 5 days), then examined the firing patterns of VTA dopamine neurons in vitro after 7 days withdrawal. Compared with saline-treated animals, the function of the small conductance calcium-dependent potassium channel (SK) was reduced in ethanol-treated animals. Consistent with a role for SK in regulation of burst firing, NMDA applied during firing facilitated the transition to bursting in ethanol-treated but not saline-treated animals; NMDA consistently induced bursting only in saline-treated animals when SK was inhibited. Also, enhanced bursting in ethanol-treated animals was not a result of differences in NMDA-induced depolarization. Further, I(h) was also reduced in ethanol-treated animals, which delayed recovery from hyperpolarization, but did not account for the increased NMDA-induced bursting in ethanol-treated animals. Finally, repeated ethanol exposure and withdrawal also enhanced the acute locomotor-activating effect of cocaine (15 mg/kg, ip). Thus withdrawal after repeated ethanol exposure produced several alterations in the physiological properties of VTA dopamine neurons, which could ultimately increase the ability of VTA neurons to produce burst firing and thus might contribute to addiction-related behaviors.
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http://dx.doi.org/10.1152/jn.00824.2007DOI Listing
October 2007

Effects of constitutive deletion of opioid receptors on the basal densities of Fas and Fas-associated protein with death domain (FADD) in the mouse brain: a delta-opioid tone inhibits FADD.

Eur Neuropsychopharmacol 2007 Apr 9;17(5):366-74. Epub 2006 Oct 9.

Laboratori de Neurofarmacologia, Institut Universitari d'Investigació en Ciències de la Salut (IUNICS), Universitat de les Illes Balears, E-07122 Palma de Mallorca, Spain.

The acute effects of opiate drugs and opiate addiction have been associated with modulation of Fas/FADD (Fas-Associated protein with Death Domain) signaling complex in the rat brain. This study investigated the possible existence of endogenous opioid tones regulating the basal activities of Fas receptor forms and FADD in the brain, using gene-targeted mice lacking mu-, delta- or kappa-opioid peptide receptors (KO mice). In mu-KO mice, but not in delta- or kappa-KO mice, the basal immunodensity of native Fas (35 kDa monomeric form) was decreased in the cerebral cortex (33%) when compared with WT littermates. In delta-KO mice, but not in mu- or kappa-KO mice, the basal content of 120 kDa Fas aggregates (complexes of monomers relevant in Fas signaling) was markedly increased in the cortex (93%). In contrast, no differences between genotypes were observed in the basal expression of glycosylated Fas (51/48/45 kDa forms). Notably, the basal content of FADD (the adaptor protein that couples Fas to caspases and transmits the death signal) was increased in the cerebral cortex of delta-KO mice (48%), but not in mu- or kappa-KO mice. In addition, the basal content of phosphorylated FADD at Ser191 (the relevant species of FADD implicated in nonapoptotic signals) was also upregulated in the cortices of delta-opioid receptor KO mice (6.5-11.0-fold). The results suggest that mu-receptors tonically stimulate (through endogenous opioid peptides) the activation of native Fas, whereas delta-receptors tonically inhibit the expression of Fas aggregates and that of FADD and phosphorylated FADD (Ser191) in the mouse brain. These data are in line with the acute opposite modulation of Fas and FADD induced by mu- and delta-opiate agonists, and strongly support the notion of an anti-apoptotic delta-opioid tone that restrains Fas signaling.
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http://dx.doi.org/10.1016/j.euroneuro.2006.08.008DOI Listing
April 2007

Cocaine self-administration selectively abolishes LTD in the core of the nucleus accumbens.

Nat Neurosci 2006 Jul 28;9(7):868-9. Epub 2006 May 28.

Ernest Gallo Clinic and Research Center, 5858 Horton Street, Suite 200, Emeryville, California 94608, USA.

The core and shell of the nucleus accumbens have critical, differential roles in drug-dependent behaviors. Here we show that operant cocaine self-administration inhibits long-term depression (LTD) in both structures after 1 d of abstinence. However, after 21 d of abstinence, LTD was abolished exclusively in the nucleus accumbens core of cocaine self-administering rats, suggesting that voluntary cocaine self-administration induced long-lasting neuroadaptations in the core that could underlie drug-seeking behavior and relapse.
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http://dx.doi.org/10.1038/nn1713DOI Listing
July 2006

Development and expression of neuropathic pain in CB1 knockout mice.

Neuropharmacology 2006 Jan 19;50(1):111-22. Epub 2005 Sep 19.

Laboratori de Neurofarmacologia, Facultat de Ciències de la Salut i de la Vida, Ciències Experimentals i de la Salut, Universitat Pompeu Fabra, Barcelona, Spain.

Neuropathic pain is a clinical manifestation characterized by the presence of spontaneous pain, allodynia and hyperalgesia. Here, we have evaluated the involvement of CB1 cannabinoid receptors in the development and expression of neuropathic pain. For this purpose, partial ligation of the sciatic nerve was performed in CB1 cannabinoid receptor knockout mice and their wild-type littermates. The development of mechanical and thermal allodynia, and thermal hyperalgesia was evaluated by using the von Frey filaments, cold-plate and plantar tests, respectively. Pre-surgical tactile and thermal withdrawal thresholds were similar in both genotypes. In wild-type mice, sciatic nerve injury led to a neuropathic pain syndrome characterized by a marked and long-lasting reduction of the paw withdrawal thresholds to mechanical and thermal stimuli. These manifestations developed similarly in mice lacking CB1 cannabinoid receptors. We have also investigated the consequences of gabapentin administration in these animals. Gabapentin (50 mg/kg/day, i.p.) induced a similar suppression of mechanical and thermal allodynia in both wild-type and CB1 knockout mice. Mild differences between genotypes were observed concerning the effect of gabapentin in the expression of thermal hyperalgesia. Taken together, our results indicate that CB1 cannabinoid receptors are not critically implicated in the development of neuropathic pain nor in the anti-allodynic and anti-hyperalgesic effects of gabapentin in this model.
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http://dx.doi.org/10.1016/j.neuropharm.2005.07.022DOI Listing
January 2006

Acute antinociceptive responses in single and combinatorial opioid receptor knockout mice: distinct mu, delta and kappa tones.

Eur J Neurosci 2003 Feb;17(4):701-8

Laboratori de Neurofarmacologia, Facultat de Ciéncies de la Salut i de la Vida, Universitat Pompeu Fabra, C/Dr Aiguader 80, 08003 Barcelona, Spain.

We have examined responses of mice lacking mu, delta and kappa opioid receptor (MOR, DOR and KOR, respectively) genes, as well as combinatorial mutants, in several pain models. This is the first truly comparative study of all three opioid receptor-deficient mice, with genotypes and gender analysis using mice on the hybrid 50% 129/SV : 50% C57BL/6 genetic background. In the tail-immersion test, only KOR-/- females showed decreased withdrawal latencies. This modification was also found in MOR/KOR and MOR/DOR/KOR, but not MOR/DOR mutants. The hotplate test revealed increased nociceptive sensitivity for MOR-/-, a phenotype which was also observed in double mutants involving the MOR deletion, and in the triple mutants. The tail-pressure test showed increased response for both MOR-/- and DOR-/- mutants, a modification which was enhanced in the triple-mutant mice. In the formalin test, MOR-/- and DOR-/- mice showed increased responses in the early and late phases, respectively, while the triple mutant tended to show enhanced nociception in both phases. Finally, the enhanced response of KOR-/- mice in the writhing test, which we have demonstrated previously, was confirmed in double MOR/KOR- and triple-mutant mice. Together, the data support the existence of an antinociceptive opioid tone. Each receptor presents a distinct pattern of activities, with mu receptors influencing responses to mechanical, chemical and thermal nociception at a supraspinal level, kappa receptors involved in spinally mediated thermal nociception and chemical visceral pain, and delta receptors modulating mechanical nociception and inflammatory pain. Phenotypes of mutant mice were subtle, suggesting a low endogenous opioid tone in the regulation of physiological pain.
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http://dx.doi.org/10.1046/j.1460-9568.2003.02482.xDOI Listing
February 2003

Morphine withdrawal is modified in pituitary adenylate cyclase-activating polypeptide type I-receptor-deficient mice.

Brain Res Mol Brain Res 2003 Jan;110(1):109-18

Laboratory of Neuropharmacology, Faculty of Medicine, University Pompeu Fabra, c/ Doctor Aiguader 80, 08003 Barcelona, Spain.

The pituitary adenylate cyclase-activating polypeptide type I-receptor (PAC1) is a G-protein-coupled receptor that is widely expressed in neurons of the central and peripheral nervous system. The strong expression of PAC1 in the second sensory neuron as well as in brainstem regions such as the locus coeruleus prompted us to elucidate the potential in vivo role of PAC1-mediated signalling in pain perception and opioid addiction using a PAC1-deficient mouse line. We observed a selective involvement of PAC1 in the mediation of visceral pain. While there was no impairment in acute somatic pain perception, PAC1-mutants exhibited a dramatically decreased response in the abdominal writhing test. These data in concert with data from the literature implicate PAC1 in the mediation of visceral and chronic pain. In addition, we observed that PAC1 did not influence the motivational aspects of opioid addictive properties, since morphine-induced rewarding effects and sensitization to locomotor responses were completely maintained in PAC1-deficient mice. However, there was a dramatic increase in physical withdrawal signs after naloxone-precipitated morphine withdrawal in PAC1 mutants. At the cellular level, electrophysiological examinations in locus coeruleus neurons from morphine-dependent wild-type and PAC1-deficient mice did not reveal any differences in firing rates. These data therefore suggested that most likely disruption of PAC1-mediated signalling in afferents towards the locus coeruleus but not within the intrinsic locus coeruleus system led to the enhancement of somatic withdrawal signs.
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http://dx.doi.org/10.1016/s0169-328x(02)00646-0DOI Listing
January 2003

Involvement of CB1 cannabinoid receptors in emotional behaviour.

Psychopharmacology (Berl) 2002 Feb 20;159(4):379-87. Epub 2001 Nov 20.

Laboratori de Neurofarmacologia, Facultat de Ciències de la Salut i de la Vida, Universitat Pompeu Fabra, C/ Doctor Aiguader 80, 08003 Barcelona, Spain.

Rationale: Endogenous and exogenous cannabinoids acting through the CB1 cannabinoid receptors are implicated in the control of a variety of behavioural and neuroendocrine functions, including emotional responses, and learning and memory processes. Recently, knockout mice deficient in the CB1 cannabinoid receptor have been generated, and these animals result in an excellent tool to evaluate the neurophysiology of the endogenous cannabinoid system.

Objectives: To establish the role of the CB1 cannabinoid receptor in several emotional-related behavioural responses, including aggressiveness, anxiety, depression and learning models, using CB1 knockout mice.

Methods: We evaluated the spontaneous responses of CB1 knockout mice and wild-type controls under different behavioural paradigms, including the light/dark box, the chronic unpredictable mild stress, the resident-intruder test and the active avoidance paradigm.

Results: Our findings showed that CB1 knockout mice presented an increase in the aggressive response measured in the resident-intruder test and an anxiogenic-like response in the light/dark box. Furthermore, a higher sensitivity to exhibit depressive-like responses in the chronic unpredictable mild stress procedure was observed in CB1 knockout mice, suggesting an increased susceptibility to develop an anhedonic state in these animals. Finally, CB1 knockout mice showed a significant increase in the conditioned responses produced in the active avoidance model, suggesting an improvement of learning and memory processes.

Conclusions: Taken together these findings demonstrate that endogenous cannabinoids through the activation of CB1 receptors are implicated in the control of emotional behaviour and participate in the physiological processes of learning and memory.
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http://dx.doi.org/10.1007/s00213-001-0946-5DOI Listing
February 2002