Ablation of the tail of the ventral tegmental area compensates symptoms in an experimental model of Parkinson's disease

Parkinson's disease is a neurodegenerative disorder partly caused by the loss of the dopamine neurons of the nigrostriatal pathway. It is accompanied by motor as well as non-motor symptoms, including pain and depression. The tail of the ventral tegmental area (tVTA) or rostromedial tegmental nucleus (RMTg) is a GABAergic mesopontine structure that acts as a major inhibitory brake for the substantia nigra pars compacta (SNc) dopamine cells, thus controlling their neuronal activity and related motor functions. The present study tested the influence of suppressing this tVTA brake on motor and non-motor symptoms in a rat model of Parkinson's disease. Using behavioral approaches, we showed that male Sprague-Dawley rats with bilateral and partial 6-hydroxydopamine SNc lesion displayed motor impairments in the rotarod test, impairments that were no more present following a co-lesion of the tVTA. Using a larger set of behavioral tests, we then showed that such SNc lesion also led to non-motor symptoms, including lower body weight, lower mechanical nociceptive thresholds in the forceps test and lower thermal nociceptive thresholds in the incremented hot-plate test, and a decreased sucrose preference in a 2-bottle choice paradigm. The excitotoxic co-lesion of the tVTA led to compensation of body weight, mechanical nociceptive thresholds and anhedonia-like behavior. These findings illustrate the major influence that the tVTA exerts on the dopamine system, modulating the motor and non-motor symptoms related to a partial loss of dopamine cells

Peripheral Delta Opioid Receptors Mediate Formoterol Anti-allodynic Effect in a Mouse Model of Neuropathic Pain.

Neuropathic pain is a challenging condition for which current therapies often remain unsatisfactory. Chronic administration of β2 adrenergic agonists, including formoterol currently used to treat asthma and chronic obstructive pulmonary disease, alleviates mechanical allodynia in the sciatic nerve cuff model of neuropathic pain. The limited clinical data currently available also suggest that formoterol would be a suitable candidate for drug repurposing. The antiallodynic action of β2 adrenergic agonists is known to require activation of the delta-opioid (DOP) receptor but better knowledge of the molecular mechanisms involved is necessary. Using a mouse line in which DOP receptors were selectively ablated in neurons expressing Nav1.8 sodium channels (DOP cKO), we showed that these DOP peripheral receptors were necessary for the antiallodynic action of the β2 adrenergic agonist formoterol in the cuff model. Using a knock-in mouse line expressing a fluorescent version of the DOP receptor fused with the enhanced green fluorescent protein (DOPeGFP), we established in a previous study, that mechanical allodynia is associated with a smaller percentage of DOPeGFP positive small peptidergic sensory neurons in dorsal root ganglia (DRG), with a reduced density of DOPeGFP positive free nerve endings in the skin and with increased DOPeGFP expression at the cell surface. Here, we showed that the density of DOPeGFP positive free nerve endings in the skin is partially restored and no increase in DOPeGFP translocation to the plasma membrane is observed in mice in which mechanical pain is alleviated upon chronic oral administration of formoterol. This study, therefore, extends our previous results by confirming that changes in the mechanical threshold are associated with changes in peripheral DOP profile. It also highlights the common impact on DOP receptors between serotonin noradrenaline reuptake inhibitors such as duloxetine and the β2 mimetic formoterol.journal article20192020 02 14importe

ADN forense: problemas éticos y jurídicos

Coordinació: María Casado y Margarita GuillénLos análisis genéticos afectan a derechos fundamentales, por lo que el uso de esta información debe estar supeditado a vías de control democrático. En la actualidad, la lucha contra grandes delitos, como por ejemplo el terrorismo, aparentemente legitima a invadir derechos antes considerados intangibles. La presente obra, fruto del trabajo multidisciplinar llevado a cabo por juristas, filósofos, biólogos, técnicos y médicos, tiene por objetivo poner de manifiesto cuáles son los problemas ético-jurídicos derivados de la obtención, el análisis y el almacenamiento del ADN, así como sus usos judiciales y extrajudiciales. Ante el difícil equilibrio entre libertad individual y seguridad colectiva, este libro ayuda a comprender los conflictos que subyacen en el manejo de una herramienta informativa tan poderosa como son las muestras y los perfiles del ADN

The antiallodynic action of pregabalin in neuropathic pain is independent from the opioid system.

BACKGROUND: Clinical management of neuropathic pain, which is pain arising as a consequence of a lesion or a disease affecting the somatosensory system, partly relies on the use of anticonvulsant drugs such as gabapentinoids. Therapeutic action of gabapentinoids such as gabapentin and pregabalin, which act by the inhibition of calcium currents through interaction with the α2δ-1 subunit of voltage-dependent calcium channels, is well documented. However, some aspects of the downstream mechanisms are still to be uncovered. Using behavioral, genetic, and pharmacological approaches, we tested whether opioid receptors are necessary for the antiallodynic action of acute and/or long-term pregabalin treatment in the specific context of neuropathic pain. RESULTS: Using the cuff model of neuropathic pain in mice, we show that acute pregabalin administration at high dose has a transitory antiallodynic action, while prolonged oral pregabalin treatment leads to sustained antiallodynic action, consistent with clinical observations. We show that pregabalin remains fully effective in μ-opioid receptor, in δ-opioid receptor and in κ-opioid receptor deficient mice, either female or male, and its antiallodynic action is not affected by acute naloxone. Our work also shows that long-term pregabalin treatment suppresses tumor necrosis factor-α overproduction induced by sciatic nerve constriction in the lumbar dorsal root ganglia. CONCLUSIONS: We demonstrate that neither acute nor long-term antiallodynic effect of pregabalin in a context of neuropathic pain is mediated by the endogenous opioid system, which differs from opioid treatment of pain and antidepressant treatment of neuropathic pain. Our data are also supportive of an impact of gabapentinoid treatment on the neuroimmune aspect of neuropathic pain.journal articleresearch support, non-u.s. gov't20162016 03 29importe

When chronic pain can suppress the opioid kick: new insights from preclinical research.

Comment on : Opioid facilitation of rewarding electrical brain stimulation is suppressed in rats with neuropathic pain. [Anesthesiology. 2011

La queue GABAergique de l aire tegmentale ventrale (Un nouveau centre de contrôle des systèmes dopaminergiques)

Les systèmes dopaminergiques (DA) mésencéphaliques jouent un rôle clé dans de nombreuses fonctions cérébrales. A l origine de ces systèmes, se trouve notamment l aire tegmentale ventrale (VTA). Dans les années 2000, une nouvelle sous-région de la VTA a été identifiée et nommée tVTA. Essentiellement GABAergique, elle accumule le facteur de transcription DeltaFosB en réponse à la cocaïne ou aux amphétamines. Nous avons réalisé chez le rat un criblage d une vingtaine de molécules pour évaluer leur capacité à exprimer FosB dans la tVTA. Les résultats montrent que l induction de FosB dans la tVTA est spécifique aux psychostimulants et n a lieu que dans les neurones GABAergiques. Notre travail a également permis de délimiter les frontières neuroanatomiques de la tVTA et d analyser les connexions de cette région. Les afférences sont nombreuses et essentiellement similaires à celles de la VTA, suggérant l appartenance de la tVTA à la VTA. Par contre, les efférences sont plus restreintes. La tVTA projette surtout vers les groupes DA A9 et A10. Ces projections sont GABAergiques et forment des appositions avec les somas des neurones DA de la VTA, notamment ceux projetant vers le noyau accumbens. Enfin, en utilisant l électrophysiologie in vivo, nous avons démontré que la stimulation de la tVTA inhibe les neurones DA de la VTA. Ces résultats ont permis de définir une nouvelle région cérébrale pouvant être un centre de contrôle des systèmes dopaminergiques. Cette découverte devrait déboucher sur de nombreuses études permettant de mieux comprendre comment la tVTA participe à la physiologie et aux pathologies des systèmes dopaminergiques.The midbrain dopaminergic systems play a key role in various brain functions, and the ventral tegmental area (VTA) is one of the main structure from which these systems originate. In the years 2000, a new subregion of the VTA was identified and named tVTA for tail of the VTA . Essentially GABAergic, this region accumulates the transcription factor DeltaFosB in response to cocaine or amphetamines. In rats, we did a screening of twenty molecules to assess their capacity to express FosB in the tVTA. The results indicate that the induction of FosB in the tVTA is specific to psychostimulant drugs and occurs only in GABAergic neurons. Our work also allowed to delineate the neuroanatomical boundaries of the tVTA and to analyze the connections of this new brain region. Its afferents are numerous and essentially similar to those of the VTA, suggesting that the tVTA belongs to the VTA. On the contrary, the efferents are more restricted. The tVTA projects mainly to the A9 and A10 dopaminergic cell groups. These projections are GABAergic and tVTA fibers do appositions with the soma of DA neurons in the VTA, including those projecting to the nucleus accumbens. Finally, using in vivo electrophysiology, we demonstrated that the stimulation of the tVTA inhibits DA neurons of the VTA. These results allowed us to identify a new brain region that may be a control center of the dopaminergic systems. This discovery should lead to numerous studies to understand how the tVTA is involved in the physiology and pathology of the dopaminergic systems.STRASBOURG-Sc. et Techniques (674822102) / SudocSudocFranceF

Effets thérapeutiques des antidépresseurs dans un modèle murin de douleur neuropathique

STRASBOURG-Sc. et Techniques (674822102) / SudocSudocFranceF

Fos response of the tail of the ventral tegmental area to food restriction entails a prediction error processing

The tail of the ventral tegmental area (tVTA) or rostromedial tegmental nucleus (RMTg) receives lateral habenula inputs and projects heavily to midbrain dopamine neurons. Midbrain dopamine and lateral habenula neurons participate in learning processes predicting the outcomes of actions, placing the tVTA in a critical location into prediction error pathways. tVTA GABA neurons show electrophysiological inhibition or activation after reward and aversive stimuli, respectively, and their predictive cues. tVTA molecular recruitment, however, is not elicited by all aversive stimuli. Indeed, precipitated opioid withdrawal, repeated footshocks or food restriction raise tVTA Fos expression, whereas various other unpleasant, stressful or painful stimuli does not elicit that molecular response. However, the basis of that difference remains unknown. In the present study, we tried to disentangle whether the tVTA c-Fos induction observed after food restriction was due to the aversive state of food restriction or to procedure-related reward prediction error. To this end, male Sprague-Dawley rats were food-restricted for 7–8 days. During this period, animals were handled and weighed every day before feeding. On the test day, rats underwent several behavioral procedures to explore the impact of food restriction and food-predictive cue exposure on tVTA c-Fos expression. We showed that food restriction per se was not able to recruit c-Fos in the tVTA. On the contrary, the food-predicting cues induced c-Fos locally in the absence of feeding, whereas the food-predicting cues followed by feeding evoked lower c-Fos expression. Overall, our results support the proposed involvement of the tVTA in reward prediction error.This research was supported by the Centre National de la Recherche Scientifique (contract UPR3212, France), , Université de Strasbourg and its Neuropôle (France), the Agence Nationale de la Recherche (ANR-11-sv4-002; ANR-15-CE37-0005-02, France), the Generalitat Valenciana (GV/2020/173, Spain) and Universitat Jaume I (UJI-A2019-14, Spain)