Identification of Altered Evoked and Non-Evoked Responses in a Heterologous Mouse Model of Endometriosis-Associated Pain

The aim of this study was to develop and refine a heterologous mouse model of endometriosis-associated pain in which non-evoked responses, more relevant to the patient experience, were evaluated. Immunodeficient female mice (N = 24) were each implanted with four endometriotic human lesions (N = 12) or control tissue fat (N = 12) on the abdominal wall using tissue glue. Evoked pain responses were measured biweekly using von Frey filaments. Non-evoked responses were recorded weekly for 8 weeks using a home cage analysis (HCA). Endpoints were distance traveled, social proximity, time spent in the center vs. outer areas of the cage, drinking, and climbing. Significant differences between groups for von Frey response, climbing, and drinking were detected on days 14, 21, and 35 post implanting surgery, respectively, and sustained for the duration of the experiment. In conclusion, a heterologous mouse model of endometriosis-associated evoked a non-evoked pain was developed to improve the relevance of preclinical models to patient experience as a platform for drug testing

Anatomo-functional and molecular analysis of anxiodepressive consequences of neuropathic pain in a murine model : insights of the anterior cingulate cortex

La douleur neuropathique est un syndrome secondaire à une maladie ou à une lésion affectant le système nerveux somatosensoriel. Environ 30% des patients souffrant de douleurs neuropathiques présentent des troubles de l’humeur. Les causes biologiques de ces comorbidités ne sont pas clairement établies. Grâce à l’utilisation d’un modèle murin de douleur neuropathique, nous avons cherché à comprendre l’apparition des conséquences émotionnelles de cette douleur. Pour cela, nous avons cherché à identifier des régions cérébrales impliquées dans les différentes composantes et conséquences de la douleur ainsi que les modifications moléculaires y prenant place. Nous avons mis en évidence une ségrégation corticale de la douleur avec l’intégration de la composante sensorielle par le cortex insulaire postérieur d’une part et l’intégration de la composante aversive et des conséquences émotionnelles par le cortex cingulaire antérieur d’autre part. Nous avons ensuite montré l’implication de la protéine MKP-1 dans l’expression des comportements de type anxiodépressif dans notre modèle.Neuropathic pain is defined as a pain caused by a lesion or disease of the somatosensory nervous system. Around 30% of neuropathic pain patients develop mood disorders. The biologic bases of these comorbidities are not clearly established. Using a murine model of neuropathic pain, we tried to understand the emotional consequences of neuropathic pain. Thus, we identified cerebral regions involved in the different components of pain and molecular modifications taking place in these regions. We showed a cortical separation of the pain experience with on one hand the integration of the sensory component of pain in the posterior insular cortex and on the other hand the integration of the aversive component and the emotional consequences of pain in the anterior cingulate cortex (ACC). Looking at the molecular modifications in the ACC, we showed that MKP-1, a protein able to dephosphorylate the MAPK, is involved in the development of pain-related mood disorders in our model of neuropathic pain

Analyse anatomo-fonctionnelle et moléculaire des conséquences anxiodépressives de la douleur neuropathique dans un modèle murin : importance du cortex cingulaire antérieur

Neuropathic pain is defined as a pain caused by a lesion or disease of the somatosensory nervous system. Around 30% of neuropathic pain patients develop mood disorders. The biologic bases of these comorbidities are not clearly established. Using a murine model of neuropathic pain, we tried to understand the emotional consequences of neuropathic pain. Thus, we identified cerebral regions involved in the different components of pain and molecular modifications taking place in these regions. We showed a cortical separation of the pain experience with on one hand the integration of the sensory component of pain in the posterior insular cortex and on the other hand the integration of the aversive component and the emotional consequences of pain in the anterior cingulate cortex (ACC). Looking at the molecular modifications in the ACC, we showed that MKP-1, a protein able to dephosphorylate the MAPK, is involved in the development of pain-related mood disorders in our model of neuropathic pain.La douleur neuropathique est un syndrome secondaire à une maladie ou à une lésion affectant le système nerveux somatosensoriel. Environ 30% des patients souffrant de douleurs neuropathiques présentent des troubles de l’humeur. Les causes biologiques de ces comorbidités ne sont pas clairement établies. Grâce à l’utilisation d’un modèle murin de douleur neuropathique, nous avons cherché à comprendre l’apparition des conséquences émotionnelles de cette douleur. Pour cela, nous avons cherché à identifier des régions cérébrales impliquées dans les différentes composantes et conséquences de la douleur ainsi que les modifications moléculaires y prenant place. Nous avons mis en évidence une ségrégation corticale de la douleur avec l’intégration de la composante sensorielle par le cortex insulaire postérieur d’une part et l’intégration de la composante aversive et des conséquences émotionnelles par le cortex cingulaire antérieur d’autre part. Nous avons ensuite montré l’implication de la protéine MKP-1 dans l’expression des comportements de type anxiodépressif dans notre modèle

Longitudinal Effects of Ketamine on Dendritic Architecture In Vivo in the Mouse Medial Frontal Cortex.

A single subanesthetic dose of ketamine, an NMDA receptor antagonist, leads to fast-acting antidepressant effects. In rodent models, systemic ketamine is associated with higher dendritic spine density in the prefrontal cortex, reflecting structural remodeling that may underlie the behavioral changes. However, turnover of dendritic spines is a dynamic process in vivo, and the longitudinal effects of ketamine on structural plasticity remain unclear. The purpose of the current study is to use subcellular resolution optical imaging to determine the time course of dendritic alterations in vivo following systemic ketamine administration in mice. We used two-photon microscopy to visualize repeatedly the same set of dendritic branches in the mouse medial frontal cortex (MFC) before and after a single injection of ketamine or saline. Compared to controls, ketamine-injected mice had higher dendritic spine density in MFC for up to 2 weeks. This prolonged increase in spine density was driven by an elevated spine formation rate, and not by changes in the spine elimination rate. A fraction of the new spines following ketamine injection was persistent, which is indicative of functional synapses. In a few cases, we also observed retraction of distal apical tuft branches on the day immediately after ketamine administration. These results indicate that following systemic ketamine administration, certain dendritic inputs in MFC are removed immediately, while others are added gradually. These dynamic structural modifications are consistent with a model of ketamine action in which the net effect is a rebalancing of synaptic inputs received by frontal cortical neurons

The Anterior Cingulate Cortex Is a Critical Hub for Pain-Induced Depression

International audienc

BDNF parabrachio-amygdaloid pathway in morphine-induced analgesia

In addition to its neurotrophic role, brain-derived neurotrophic factor (BDNF) is involved in a wide array of functions, including anxiety and pain. The central amygdaloid nucleus (CeA) contains a high concentration of BDNF in terminals, originating from the pontine parabrachial nucleus. Since the spino-parabrachio-amygdaloid neural pathway is known to convey nociceptive information, we hypothesized a possible involvement of BDNF in supraspinal pain-related processes. To test this hypothesis, we generated localized deletion of BDNF in the parabrachial nucleus using local bilateral injections of adeno-associated viruses in adult floxed-BDNF mice. Basal thresholds of thermal and mechanical nociceptive responses were not altered by BDNF loss and no behavioural deficit was noticed in anxiety and motor tests. However, BDNF-deleted animals displayed a major decrease in the analgesic effect of morphine. In addition, intra-CeA injections of the BDNF scavenger TrkB-Fc in control mice also decreased morphine-induced analgesia. Finally, the number of c-Fos immunoreactive nuclei after acute morphine injection was decreased by 45% in the extended amygdala of BDNF-deleted animals. The absence of BDNF in the parabrachial nucleus thus altered the parabrachio-amygdaloid pathway. Overall, our study provides evidence that BDNF produced in the parabrachial nucleus modulates the functions of the parabrachio-amygdaloid pathway in opiate analgesia

Cingulate Overexpression of Mitogen-Activated Protein Kinase Phosphatase-1 as a Key Factor for Depression

International audienc

Hyperactivity of Anterior Cingulate Cortex Areas 24a/24b Drives Chronic Pain-Induced Anxiodepressive-like Consequences

International audienc