Altered Cerebellar Response to Somatosensory Stimuli in the Cntnap2 Mouse Model of Autism.

Atypical sensory processing is currently included within the diagnostic criteria of autism. The cerebellum is known to integrate sensory inputs of different modalities through its connectivity to the cerebral cortex. Interestingly, cerebellar malformations are among the most replicated features found in postmortem brain of individuals with autism. We studied sensory processing in the cerebellum in a mouse model of autism, knock-out (KO) for the Cntnap2 gene. Cntnap2 is widely expressed in Purkinje cells (PCs) and has been recently reported to regulate their morphology. Further, individuals with CNTNAP2 mutations display cerebellar malformations and CNTNAP2 antibodies are associated with a mild form of cerebellar ataxia. Previous studies in the Cntnap2 mouse model show an altered cerebellar sensory learning. However, a physiological analysis of cerebellar function has not been performed yet. We studied sensory evoked potentials in cerebellar Crus I/II region on electrical stimulation of the whisker pad in alert mice and found striking differences between wild-type and Cntnap2 KO mice. In addition, single-cell recordings identified alterations in both sensory-evoked and spontaneous firing patterns of PCs. These changes were accompanied by altered intrinsic properties and morphologic features of these neurons. Together, these results indicate that the Cntnap2 mouse model could provide novel insight into the pathophysiological mechanisms of autism core sensory deficits.

Synthesis, Pharmacological, and Biological Evaluation of 2-Furoyl-Based MIF-1 Peptidomimetics and the Development of a General-Purpose Model for Allosteric Modulators (ALLOPTML).

This work describes the synthesis and pharmacological evaluation of 2-furoyl-based Melanostatin (MIF-1) peptidomimetics as dopamine D2 modulating agents. Eight novel peptidomimetics were tested for their ability to enhance the maximal effect of tritiated N-propylapomorphine ([3H]-NPA) at D2 receptors (D2R). In this series, 2-furoyl-l-leucylglycinamide (6a) produced a statistically significant increase in the maximal [3H]-NPA response at 10 pM (11 ± 1%), comparable to the effect of MIF-1 (18 ± 9%) at the same concentration. This result supports previous evidence that the replacement of proline residue by heteroaromatic scaffolds are tolerated at the allosteric binding site of MIF-1. Biological assays performed for peptidomimetic 6a using cortex neurons from 19-day-old Wistar-Kyoto rat embryos suggest that 6a displays no neurotoxicity up to 100 µM. Overall, the pharmacological and toxicological profile and the structural simplicity of 6a makes this peptidomimetic a potential lead compound for further development and optimization, paving the way for the development of novel modulating agents of D2R suitable for the treatment of CNS-related diseases. Additionally, the pharmacological and biological data herein reported, along with >20 000 outcomes of preclinical assays, was used to seek a general model to predict the allosteric modulatory potential of molecular candidates for a myriad of target receptors, organisms, cell lines, and biological activity parameters based on perturbation theory (PT) ideas and machine learning (ML) techniques, abbreviated as ALLOPTML. By doing so, ALLOPTML shows high specificity Sp = 89.2/89.4%, sensitivity Sn = 71.3/72.2%, and accuracy Ac = 86.1%/86.4% in training/validation series, respectively. To the best of our knowledge, ALLOPTML is the first general-purpose chemoinformatic tool using a PTML-based model for the multioutput and multicondition prediction of allosteric compounds, which is expected to save both time and resources during the early drug discovery of allosteric modulators.

Síndrome opsoclonus mioclonus. Experiencia en los últimos 12 años en un hospital terciario / Opsoclonus-myoclonus syndrome: Experience in a tertiary hospital in the last 12 years

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Neurobiological Mechanisms of Autism Spectrum Disorder and Epilepsy, Insights from Animal Models.

Autism Spectrum Disorder (ASD) and epilepsy are two neurodevelopmental disorders that have a high comorbidity rate, suggesting that a common neurodevelopmental mechanism exists. However, to date there is no conclusive way to predict whether a child will develop either syndrome or both and to what degree associated phenotypes will be affected. Failure to consistently identify predictive patterns of ASD and/or epilepsy diagnosis stems from the fact that they are etiologically heterogeneous conditions and research into their neuropathological mechanisms becomes challenging. Whole genome/exome sequencing has advanced our understanding of the genetic causes of ASD and epilepsy to an extent that currently about half of all ASD as well as epilepsy cases are known to have a genetic basis. In fact, a picture is emerging of both conditions as a collection of distinct genetically defined disorders, although the role of environmental factors has also been established. A plethora of animal models, most of them based on identified human genetic mutations and a few on known environmental causes, have been developed. Animal models provide a major experimental avenue for studying the underlying cellular and molecular mechanisms of human disorders. They also provide invaluable preclinical tools that can be used to test therapeutic approaches. In this review, we first summarize the methods for validating mouse models of ASD and epilepsy. Second, we present the current models validated for the comorbidity and finally, we recapitulate the common pathomechanisms identified in these models with special emphasis on synaptic plasticity.

Aspectos clínicos y neuropsicológicos del síndrome de hipoventilación central congénita / Clinical and neuropsychological characteristics in congenital central hypoventilation syndrome

Introducción. El síndrome de hipoventilación central congénita (SHCC) es una enfermedad rara producida por mutaciones en el gen PHOX2B. Los pacientes muestran una reducida respuesta a la hipercapnia e hipoxia acompañada de alteraciones difusas del sistema nervioso autónomo y ocasionalmente alteraciones en neuroimagen. No se ha descrito un perfil neuropsicológico específico en los niños y adolescentes con SHCC. Casos clínicos. Se presentan tres casos (de edades comprendidas entre 4 y 19 años) con diferente perfil de afectación cognitiva y funcional. Se comparan los perfiles de los tres casos con los hallazgos descritos en la bibliografía sobre neuropsicología en el SHCC. Conclusiones. El perfil de afectación funcional en el SHCC es variable: en el caso 1 se describe un grave retraso global en el desarrollo con rasgos autistas y acusadas implicaciones funcionales. En el caso 2, la atrofia bilateral del hipocampo se asocia a déficit en cognición social y alteraciones en funciones ejecutivas con moderada repercusión funcional. El caso 3 muestra dificultades en algunas funciones ejecutivas cognitivas (planificación y fluidez no verbal), pero sin repercusión funcional. La evaluación neuropsicológica puede ayudar en el manejo clínico de estos pacientes determinando y orientando la necesidad de tratamientos rehabilitadores

Introduction. Congenital central hypoventilation syndrome (CCHS) syndrome is a rare disease caused by mutations in the PHOX2B gene. Patients show a reduced response to hypercapnia and hypoxia accompanied by diffuse disturbances of the autonomic nervous system and occasionaly also disturbances in neuroimaging. A specific neuropsychological profile has not been described in children and adolescents with CCHS. Case reports. We describe three cases (aged between 4 and 19 years) with different profiles of affectation in cognitive and functionality. These profiles are compared with the features described in the literature about neuropsychology in CCHS. Conclusions. The profile of functional impairment in the CCHS is variable: in case 1, a severe global developmental delay with autistic features and marked functional involvement is described. In case 2, bilateral atrophy of the hippocampus is associated with involvement in social cognition and in executive functions with moderate functional repercussion. Case 3 shows difficulties in some cognitive executive functions (planning and non-verbal fluency), but without functional repercussion. Neuropsychological assessment can help in the clinical management of these patients by determining and guiding the need for rehabilitation treatments

Neuropsychological profile and social cognition in congenital central hypoventilation syndrome (CCHS): Correlation with neuroimaging in a clinical case.

INTRODUCTION: Congenital central hypoventilation syndrome (CCHS) is a rare genetic disorder due to paired-like homeobox gene (PHOX2B) mutations. CCHS patients suffer from dysregulation of the autonomic nervous system characterized by the absence of or extremely reduced response to hypercapnia and hypoxia, with neuropsychological deficits. The aim of this exploratory study is to describe the longitudinal neuropsychological profile and its correlations with magnetic resonance imaging (MRI) of a child with CCHS with a PHOX2B mutation. METHOD: A comprehensive neuropsychological evaluation was conducted serially at age 7 years 4 months and 10 years 3 months, including assessment of intellectual functioning (IQ), motor functioning, perception, attention, executive functions, language, memory, social cognition, academic skills, and psychopathology. Reliable change index (RCI) scores were used to assess changes between assessments. We collected spin lattice relaxation time (T1)-weighted, fluid-attenuated inversion recovery (FLAIR), and spin spin lattice relaxation time (T2)-weighted images from the child at age 10 years 3 months using a 1.5-tesla MRI scanner. RESULTS: IQ, processing speed index (PSI), social cognition (theory of mind and facial emotion recognition), selective attention, naming, academic skills (reading/comprehension), and manual speed with right hand declined in the second evaluation relative to the initial evaluation, while visuoconstructional praxis, receptive vocabulary, working memory, and arithmetic skill improved. The patient showed a remarkable global deterioration in executive functions (planning, task flexibility, behavioral regulation, and metacognition) as revealed by parental report and clinical evaluation. MRI revealed gliosis from the head to tail of the hippocampus and thinning of parahippocampal gyri. CONCLUSIONS: In a clinical case of CCHS, serial evaluation revealed deterioration of executive functions and social cognition over a 3-year interval. These changes corresponded to hippocampal damage as revealed in MRI, which may have affected social cognition through its role in the default mode network. Serial neuropsychological assessment is clinically useful in managing the needs of these patients.

[Reversible neuropsychological deterioration associated to zonisamide in a paediatric patient with tuberous sclerosis]. / Deterioro neuropsicologico reversible asociado a zonisamida en un paciente pediatrico con esclerosis tuberosa.

AIM: To document reversible cognitive deterioration associated to high doses of zonisamide, using the Reliable Change Index to control practice effects derived from repetitive neuropsychological assessments. CASE REPORT: A 11 year-old boy with tuberous sclerosis complex and left frontal refractory epilepsy, evaluated within a paediatric epilepsy surgery program. The epileptogenic zone was found to be related with a tuber situated on the left inferior frontal gyrus. The effects of high doses of zonisamide simulate a disturbance of eloquent cortex within the epileptogenic zone and the impact of uncontrolled seizures on cognitive functioning over the language-dominant hemisphere. Drug withdrawal significantly improved total intelligence index, verbal comprehension intellectual index and specific language-sustained cognitive abilities, beyond practice effects. CONCLUSIONS: The differentiation between cognitive effects of drugs and functional deficits resulting from eloquent cortex involvement within the epileptogenic zone can be of crucial importance in the decision-making process for epilepsy surgery.

TITLE: Deterioro neuropsicologico reversible asociado a zonisamida en un paciente pediatrico con esclerosis tuberosa.Objetivo. Documentar el deterioro cognitivo reversible asociado a altas dosis de zonisamida, utilizando indices de cambio fiable para controlar los efectos de practica derivados de evaluaciones neuropsicologicas repetidas. Caso clinico. Niño de 11 años con complejo esclerosis tuberosa y epilepsia refractaria del lobulo frontal izquierdo, evaluado en el contexto de un programa de cirugia de la epilepsia pediatrica. La zona epileptogena se relaciono con un tuber epileptogeno localizado en el giro frontal inferior del hemisferio izquierdo. Los efectos de altas dosis de zonisamida mimetizaron una afectacion de la corteza elocuente en la zona epileptogena y un impacto de las crisis no controladas en el funcionamiento cognitivo asociado al hemisferio dominante para el lenguaje. La retirada del farmaco mejoro significativamente, mas alla de los efectos de practica, el cociente intelectual total, el indice intelectual de comprension verbal y habilidades cognitivas especificas sustentadas en el lenguaje. Conclusiones. La diferenciacion entre los efectos cognitivos de los farmacos y la existencia de un deficit funcional por afectacion de la corteza elocuente en el area epileptogena puede ser crucial para la toma de decisiones en cirugia de la epilepsia.

Deterioro neuropsicológico reversible asociado a zonisamida en un paciente pediátrico con esclerosis tuberosa / Reversible neuropsychological deterioration associated to zonisamide in a paediatric patient with tuberous sclerosis

Objetivo. Documentar el deterioro cognitivo reversible asociado a altas dosis de zonisamida, utilizando índices de cambio fiable para controlar los efectos de práctica derivados de evaluaciones neuropsicológicas repetidas. Caso clínico. Niño de 11 años con complejo esclerosis tuberosa y epilepsia refractaria del lóbulo frontal izquierdo, evaluado en el contexto de un programa de cirugía de la epilepsia pediátrica. La zona epileptógena se relacionó con un túber epileptógeno localizado en el giro frontal inferior del hemisferio izquierdo. Los efectos de altas dosis de zonisamida mimetizaron una afectación de la corteza elocuente en la zona epileptógena y un impacto de las crisis no controladas en el funcionamiento cognitivo asociado al hemisferio dominante para el lenguaje. La retirada del fármaco mejoró significativamente, más allá de los efectos de práctica, el cociente intelectual total, el índice intelectual de comprensión verbal y habilidades cognitivas específicas sustentadas en el lenguaje. Conclusiones. La diferenciación entre los efectos cognitivos de los fármacos y la existencia de un déficit funcional por afectación de la corteza elocuente en el área epileptógena puede ser crucial para la toma de decisiones en cirugía de la epilepsia (AU)

Aim. To document reversible cognitive deterioration associated to high doses of zonisamide, using the Reliable Change Index to control practice effects derived from repetitive neuropsychological assessments. Case report. A 11 year-old boy with tuberous sclerosis complex and left frontal refractory epilepsy, evaluated within a paediatric epilepsy surgery program. The epileptogenic zone was found to be related with a tuber situated on the left inferior frontal gyrus. The effects of high doses of zonisamide simulate a disturbance of eloquent cortex within the epileptogenic zone and the impact of uncontrolled seizures on cognitive functioning over the language-dominant hemisphere. Drug withdrawal significantly improved total intelligence index, verbal comprehension intellectual index and specific languagesustained cognitive abilities, beyond practice effects. Conclusions. The differentiation between cognitive effects of drugs and functional deficits resulting from eloquent cortex involvement within the epileptogenic zone can be of crucial importance in the ecision-making process for epilepsy surgery (AU)

Coassembly and coupling of SK2 channels and mGlu5 receptors.

Group I metabotropic glutamate (mGlu) receptors regulate hippocampal CA1 pyramidal neuron excitability via Ca(2+) wave-dependent activation of small-conductance Ca(2+)-activated K(+) (SK) channels. Here, we show that mGlu5 receptors and SK2 channels coassemble in heterologous coexpression systems and in rat brain. Further, in cotransfected cells or rat primary hippocampal neurons, mGlu5 receptor stimulation activated apamin-sensitive SK2-mediated K(+) currents. In addition, coexpression of mGlu5 receptors and SK2 channels promoted plasma membrane targeting of both proteins and correlated with increased mGlu5 receptor function that was unexpectedly blocked by apamin. These results demonstrate a reciprocal functional interaction between mGlu5 receptors and SK2 channels that reflects their molecular coassembly.

Involvement of neuronal nitric oxide synthase in desensitisation of µ-opioid receptors in the rat locus coeruleus.

Nitric oxide (NO) has been recently shown to enhance µ-opioid receptor (MOR) desensitisation in locus coeruleus (LC) neurons. The aim of this study was to evaluate by single-unit extracellular recordings in rat brain slices whether the neuronal NO synthase is involved in MOR desensitisation in LC neurons. As expected, a high concentration of the opioid agonist Met(5)-enkephalin (ME; 10 µM, 10 min) strongly desensitised the inhibition induced by a test application of ME (0.8 µM, 1 min), whereas lower ME concentrations (1 and 3 µM) only weakly desensitised it. The neuronal NO synthase inhibitors 7-nitroindazole (10-100 µM), S-methyl-L-thiocitrulline (0.01-10 µM) and N(ω)-propyl-L-arginine (1-10 µM) attenuated ME (10 µM)-induced opioid desensitisation, although the endothelial NO synthase inhibitor N(5)-(1-iminoethyl)-L-ornithine (3-30 µM) failed to change it. The NO donor sodium nitroprusside (1 mM), but not its inactive analog potassium ferricyanide (1 mM), enhanced the ME (3 µM)-induced desensitisation and prevented the effect of S-methyl-L-thiocitrulline (10 µM). Sodium nitroprusside (1 mM) failed to change the desensitisation of α2-adrenoceptors by noradrenaline (100 µM, 10 min). These results suggest the contribution of NO and a neuronal type of NO synthase in homologous MOR desensitisation in rat LC neurons.

Granulaciones aracnoideas como causa de perforación del tegmen timpani / Arachnoid granulations as cause of tegmen tympani defects

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Impact of mindfulness training on attentional control and anger regulation processes for psychotherapists in training.

OBJECTIVES: Little empirical literature focuses on psychotherapists' cultivation of internal states of mind necessary for controlling attention and responding empathically to the client. We explore the effects of mindfulness training on emotional and attentional measures in Spanish resident intern psychiatrists and clinical psychologists. METHOD: One hundred and three residents were assigned to an experimental group (n = 60) that completed an 8-week mindfulness training versus a wait-list control group (n = 43). We evaluated emotional variables (sadness, anxiety, and anger, using standard instruments), state of mindfulness (using the Mindfulness Awareness Attention Scale), and attentional control variables using objective measures such as a continuous performance task and the Stroop task before and after mindfulness training. RESULTS: Our study provides data that suggest that mindfulness training significantly improves measures of trait anger and attentional control. CONCLUSIONS: Further research is needed to replicate these findings, explore the effects of mindfulness training on other aspects of emotional regulation and cognition, and evaluate the impact of these effects within clinical situations.

Ethanol reversal of cellular tolerance to morphine in rat locus coeruleus neurons.

Consumption of ethanol is a considerable risk factor for death in heroin overdose. We sought to determine whether a mildly intoxicating concentration of ethanol could alter morphine tolerance at the cellular level. In rat locus coeruleus (LC) neurons, tolerance to morphine was reversed by acute exposure of the brain slice to ethanol (20 mM). Tolerance to the opioid peptide [d-Ala(2),N-MePhe(4),Gly-ol]-enkephalin was not reversed by ethanol. Previous studies in LC neurons have revealed a role for protein kinase C (PKC)α in µ-opioid receptor (MOPr) desensitization by morphine and in the induction and maintenance of morphine tolerance, but we have been unable to demonstrate that 20 mM ethanol produces significant inhibition of PKCα. The ability of ethanol to reverse cellular tolerance to morphine in LC neurons was absent in the presence of the phosphatase inhibitor okadaic acid, indicating that dephosphorylation is involved. In human embryonic kidney 293 cells expressing the MOPr, ethanol reduced the level of MOPr phosphorylation induced by morphine. Ethanol reversal of tolerance did not appear to result from a direct effect on MOPr since acute exposure to ethanol (20 mM) did not modify the affinity of binding of morphine to the MOPr or the efficacy of morphine for G-protein activation as measured by guanosine 5'-O-(3-[(35)S]thio)triphosphate binding. Similarly, ethanol did not affect MOPr trafficking. We conclude that acute exposure to ethanol enhances the effects of morphine by reversing the processes underlying morphine cellular tolerance.

[Primary stabbing headache: clinical characteristics and response to treatment in a series of 67 patients]. / Cefalea primaria punzante: caracteristicas clínicas y respuesta al tratamiento en una serie de 67 pacientes.

INTRODUCTION: Primary stabbing headache (PSH) is defined by the presence of short stabbing pains in the first branch of the trigeminal nerve. According to population-based studies, it is very prevalent, but most cases present stabbing pains with low frequencies and intensities that do not lead the patient to seek medical attention. AIMS: We report on 67 cases of PSH attended in the headache service of a tertiary hospital. In the study, the demographic and clinical characteristics are studied, treatment response is reviewed and the features of PSH are compared in terms of whether it was the only headache or was accompanied by others. PATIENTS AND METHODS: The study involved 67 patients (51 females and 16 males) diagnosed with PSH between January 2008 and January 2012, of a total number of 1668 (4%) patients attended in the above-mentioned service. RESULTS: Age at onset: 34.5 ± 16.7 years. Forty-nine cases (73.1%) were associated to another headache, above all migraine. Stabbing pains were often bilateral; 38 (56.7%) patients suffered more than one a day and 11 (16.4%) had more than 10 per day. They lasted less than five seconds in 48 patients (71.6%) and more than 10 seconds in 11 of them (16.4%), with an intensity of 6.8 ± 1.5. The age of onset of PSH was higher if it was the only type of headache than if it was accompanied by others. Twenty-six (38.8%) patients required preventive treatment for the associated headache and 16 (23.8%) took indomethacin, with a similar response in the two groups (73 versus 75%). CONCLUSIONS; PSH is not infrequent in headache clinics, but its phenotype differs from that reported in population-based studies. The characteristics of PSH vary depending on whether it is the only headache or is associated with others. Preventive treatment is often required and patients respond well to it.

Cefalea primaria punzante: características clínicas y respuesta al tratamiento en una serie de 67 pacientes / Primary stabbing headache: clinical characteristics and response to treatment in a series of 67 patients

Introducción. La cefalea primaria punzante (CPP) se define por la presencia de punzadas breves localizadas en la primera rama del nervio trigémino. Según estudios de base poblacional, es muy prevalente, pero la mayoría de casos presenta punzadas de baja frecuencia e intensidad que no requieren consulta médica. Objetivos. Presentar 67 casos de CPP de la consulta de cefaleas de un hospital terciario, analizar las características demográficasy clínicas, revisar la respuesta al tratamiento y comparar las características de la CPP según sea cefalea única o se acompañe de otras. Pacientes y métodos. Muestra de 67 pacientes (51 mujeres y 16 varones) diagnosticados de CPP entre enero de 2008 y enero de 2012, de un total de 1.668 (4%) atendidos en dicha consulta. Resultados. Edad al inicio: 34,5 ± 16,7 años. Cuarenta y nueve casos (73,1%) asociaban otra cefalea, sobre todo migraña. Las punzadas eran frecuentemente bilaterales; 38 pacientes (56,7%) sufrían más de una al día y 11 (16,4%) más de 10 al día. Su duración era menor de cinco segundos en 48 (71,6%) pacientes y mayor de 10 segundos en 11 (16,4%), con una intensidad de 6,8 ± 1,5. La edad de inicio de la CPP era mayor si era cefalea única que si acompañaba a otras. Veintiséis (38,8%) pacientes requirieron un preventivo para la cefalea asociada y 16 (23,8%) indometacina con respuesta similar en los dos grupos (73 frente a 75%). Conclusiones. La CPP no es infrecuente en una consulta de cefaleas, pero su fenotipo difiere del descrito en estudios de base poblacional. Las características de la CPP son diferentes en función de si es cefalea única o asocia otras. Se requiere tratamiento preventivo con frecuencia y la respuesta es buena (AU)

Introduction. Primary stabbing headache (PSH) is defined by the presence of short stabbing pains in the first branch of the trigeminal nerve. According to population-based studies, it is very prevalent, but most cases present stabbing pains with low frequencies and intensities that do not lead the patient to seek medical attention. Aims. We report on 67 cases of PSH attended in the headache service of a tertiary hospital. In the study, the demographic and clinical characteristics are studied, treatment response is reviewed and the features of PSH are compared in terms of whether it was the only headache or was accompanied by others. Patients and methods. The study involved 67 patients (51 females and 16 males) diagnosed with PSH between January 2008 and January 2012, of a total number of 1668 (4%) patients attended in the above-mentioned service. Results. Age at onset: 34.5 ± 16.7 years. Forty-nine cases (73.1%) were associated to another headache, above all migraine. Stabbing pains were often bilateral; 38 (56.7%) patients suffered more than one a day and 11 (16.4%) had more than 10 per day. They lasted less than five seconds in 48 patients (71.6%) and more than 10 seconds in 11 of them (16.4%), with an intensity of 6.8 ± 1.5. The age of onset of PSH was higher if it was the only type of headache than if it was accompanied by others. Twenty-six (38.8%) patients required preventive treatment for the associated headache and 16 (23.8%) took indomethacin, with a similar response in the two groups (73 versus 75%). Conclusions. PSH is not infrequent in headache clinics, but its phenotype differs from that reported in population-based studies. The characteristics of PSH vary depending on whether it is the only headache or is associated with others. Preventive treatment is often required and patients respond well to it (AU)

µ-Opioid receptor desensitization: homologous or heterologous?

There is considerable controversy over whether µ-opioid receptor (MOPr) desensitization is homologous or heterologous and over the mechanisms underlying such desensitization. In different cell types MOPr desensitization has been reported to involve receptor phosphorylation by various kinases, including G-protein-coupled receptor kinases (GRKs), second messenger and other kinases as well as perturbation of the MOPr effector pathway by GRK sequestration of G protein ßγ subunits or ion channel modulation. Here we report that in brainstem locus coeruleus (LC) neurons prepared from relatively mature rats (5-8 weeks old) rapid MOPr desensitization induced by the high-efficacy opioid peptides methionine enkephalin and DAMGO was homologous and not heterologous to α(2)-adrenoceptors and somatostatin SST(2) receptors. Given that these receptors all couple through G proteins to the same set of G-protein inwardly rectifying (GIRK) channels it is unlikely therefore that in mature neurons MOPr desensitization involves G protein ßγ subunit sequestration or ion channel modulation. In contrast, in slices from immature animals (less than postnatal day 20), MOPr desensitization was observed to be heterologous and could be downstream of the receptor. Heterologous MOPr desensitization was not dependent on protein kinase C or c-Jun N-terminal kinase activity, but the change from heterologous to homologous desensitization with age was correlated with a decrease in the expression levels of GRK2 in the LC and other brain regions. The observation that the mechanisms underlying MOPr desensitization change with neuronal development is important when extrapolating to the mature brain results obtained from experiments on expression systems, cell lines and immature neuronal preparations.