Pain hypersensitivity in a pharmacological mouse model of attention-deficit/hyperactivity disorder.

Clinical evidence suggests that pain hypersensitivity develops in patients with attention-deficit/hyperactivity disorder (ADHD). However, the mechanisms and neural circuits involved in these interactions remain unknown because of the paucity of studies in animal models. We previously validated a mouse model of ADHD obtained by neonatal 6-hydroxydopamine (6-OHDA) injection. Here, we have demonstrated that 6-OHDA mice exhibit a marked sensitization to thermal and mechanical stimuli, suggesting that phenotypes associated with ADHD include increased nociception. Moreover, sensitization to pathological inflammatory stimulus is amplified in 6-OHDA mice as compared to shams. In this ADHD model, spinal dorsal horn neuron hyperexcitability was observed. Furthermore, ADHD-related hyperactivity and anxiety, but not inattention and impulsivity, are worsened in persistent inflammatory conditions. By combining in vivo electrophysiology, optogenetics, and behavioral analyses, we demonstrated that anterior cingulate cortex (ACC) hyperactivity alters the ACC-posterior insula circuit and triggers changes in spinal networks that underlie nociceptive sensitization. Altogether, our results point to shared mechanisms underlying the comorbidity between ADHD and nociceptive sensitization. This interaction reinforces nociceptive sensitization and hyperactivity, suggesting that overlapping ACC circuits may be targeted to develop better treatments.

Human Foot Outperforms the Hand in Mechanical Pain Discrimination.

Tactile discrimination has been extensively studied, but mechanical pain discrimination remains poorly characterized. Here, we measured the capacity for mechanical pain discrimination using a two-alternative forced choice paradigm, with force-calibrated indentation stimuli (Semmes-Weinstein monofilaments) applied to the hand and foot dorsa of healthy human volunteers. In order to characterize the relationship between peripheral nociceptor activity and pain perception, we recorded single-unit activity from myelinated (A) and unmyelinated (C) mechanosensitive nociceptors in the skin using microneurography. At the perceptual level, we found that the foot was better at discriminating noxious forces than the hand, which stands in contrast to that for innocuous force discrimination, where the hand performed better than the foot. This observation of superior mechanical pain discrimination on the foot compared to the hand could not be explained by the responsiveness of individual nociceptors. We found no significant difference in the discrimination performance of either the myelinated or unmyelinated class of nociceptors between skin regions. This suggests the possibility that other factors such as skin biophysics, receptor density or central mechanisms may underlie these regional differences.

The role of the anterior cingulate cortex in aggression and impulsivity.

Aggression is a complex social behavior that evolved in the context of defending a territory, fighting for limited resources, and competing for mates and protection. Although aggression considered as a negative or undesirable emotion is an essential part of many species' repertoire of social behaviors. For humans, the motivations, actions, and limits of aggressive acts are not always clear. However, uncontrolled aggression may have destructive consequences, and it develops inappropriately into violence. At the neural level, several studies demonstrated that aggression is related to cortical abnormalities, including the anterior cingulate cortex (ACC). This review summarizes the state of the literature regarding the involvement of ACC in the neurobiology of aggression and impulsivity. We will first review structural and neuroanatomical studies, including volumetric and functional investigations of aggression. Next, we will discuss the neurochemical and neuropharmacological studies of aggression related to the ACC. We will focus mainly on the gamma-aminobutyric acid/glutamate balance, as well as the serotoninergic system. Finally, we will try to integrate these results and reconcile discrepancies in the field and suggest recommendations for future studies. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Single-Soma Deep RNA sequencing of Human DRG Neurons Reveals Novel Molecular and Cellular Mechanisms Underlying Somatosensation.

The versatility of somatosensation arises from heterogeneous dorsal root ganglion (DRG) neurons. However, soma transcriptomes of individual human DRG (hDRG) neurons-critical in-formation to decipher their functions-are lacking due to technical difficulties. Here, we developed a novel approach to isolate individual hDRG neuron somas for deep RNA sequencing (RNA-seq). On average, >9,000 unique genes per neuron were detected, and 16 neuronal types were identified. Cross-species analyses revealed remarkable divergence among pain-sensing neurons and the existence of human-specific nociceptor types. Our deep RNA-seq dataset was especially powerful for providing insight into the molecular mechanisms underlying human somatosensation and identifying high potential novel drug targets. Our dataset also guided the selection of molecular markers to visualize different types of human afferents and the discovery of novel functional properties using single-cell in vivo electrophysiological recordings. In summary, by employing a novel soma sequencing method, we generated an unprecedented hDRG neuron atlas, providing new insights into human somatosensation, establishing a critical foundation for translational work, and clarifying human species-species properties.

PIEZO2-dependent rapid pain system in humans and mice.

The PIEZO2 ion channel is critical for transducing light touch into neural signals but is not considered necessary for transducing acute pain in humans. Here, we discovered an exception - a form of mechanical pain evoked by hair pulling. Based on observations in a rare group of individuals with PIEZO2 deficiency syndrome, we demonstrated that hair-pull pain is dependent on PIEZO2 transduction. Studies in control participants showed that hair-pull pain triggered a distinct nocifensive response, including a nociceptive reflex. Observations in rare Aß deafferented individuals and nerve conduction block studies in control participants revealed that hair-pull pain perception is dependent on Aß input. Single-unit axonal recordings revealed that a class of cooling-responsive myelinated nociceptors in human skin is selectively tuned to painful hair-pull stimuli. Further, we pharmacologically mapped these nociceptors to a specific transcriptomic class. Finally, using functional imaging in mice, we demonstrated that in a homologous nociceptor, Piezo2 is necessary for high-sensitivity, robust activation by hair-pull stimuli. Together, we have demonstrated that hair-pulling evokes a distinct type of pain with conserved behavioral, neural, and molecular features across humans and mice.

Switch of serotonergic descending inhibition into facilitation by a spinal chloride imbalance in neuropathic pain.

Descending control from the brain to the spinal cord shapes our pain experience, ranging from powerful analgesia to extreme sensitivity. Increasing evidence from both preclinical and clinical studies points to an imbalance toward descending facilitation as a substrate of pathological pain, but the underlying mechanisms remain unknown. We used an optogenetic approach to manipulate serotonin (5-HT) neurons of the nucleus raphe magnus that project to the dorsal horn of the spinal cord. We found that 5-HT neurons exert an analgesic action in naïve mice that becomes proalgesic in an experimental model of neuropathic pain. We show that spinal KCC2 hypofunction turns this descending inhibitory control into paradoxical facilitation; KCC2 enhancers restored 5-HT-mediated descending inhibition and analgesia. Last, combining selective serotonin reuptake inhibitors (SSRIs) with a KCC2 enhancer yields effective analgesia against nerve injury-induced pain hypersensitivity. This uncovers a previously unidentified therapeutic path for SSRIs against neuropathic pain.

Bidirectional effects of Topiramate on anterior cingulate cortex region related aggressive behavior.

Topiramate, an antiepileptic drug, has been found to be useful for the treatment of aggression in clinical populations as well as in animal models of aggression. However, increases in aggression were also observed under lower doses of Topiramate. Subsequently, Topiramate produced an inverted U-shaped dose response curve, with increases in aggression at low doses, whereas higher doses engendered anti-aggressive effects. In our previous study, we demonstrated that Topiramate modulates brain activity in the prefrontal areas involved in the modulation of the subcortical circuit mediating aggression, and we found indirect evidence that the anterior cingulate cortex (ACC) could be a key site where Topiramate may exert its dose-response effects on aggression. In this study, we performed site-directed injections of Topiramate (0.1 and 0.3 mM) into the ACC on offensive behaviors in isolation-inducedaggression paradigm. By using the resident-intruder test, we demonstrated that Topiramate microinfusion into the ACC at low doses produced increases in aggression, as evidenced by shorter attack latencies (p < 0.01) and increased attack duration (p < 0.01), without affecting the social behavior. In contrast, higher doses engendered anti-aggressive effects, by increasing the attack latencies (p < 0.001), decreasing attack number (p < 0.001) and decreasing attack duration (p < 0.001), as well as an increase in the social behavior. Our findings supported that Topiramate at higher concentrations appeared more efficient to decrease aggression in treated mice. Therefore, we suggest that the ACC is a key brain region in which Topiramate may exert its dose-response effects on aggressive and antisocial behaviors observed in populations with psychotic disorders.

The effects of Topiramate on isolation-induced aggression: a behavioral and immunohistochemical study in mice.

Topiramate, an antiepileptic drug, has been found to be useful for the treatment of aggression in clinical populations. Most preclinical studies related to Topiramate have been focused exclusively on the quantitative aspects of the aggressive behavior between mice. However, there is still limited knowledge regarding the effects of Topiramate on neuronal mechanisms occurring in aggressive mice. The present work aims to understand further the effects of the antiepileptic drug Topiramate on aggressive behaviors, and on the neural correlates underlying such behaviors. To achieve this, we combined the resident-intruder model of isolation-induced aggression in mice with two drug regimens of Topiramate administration (30.0 mg/kg; acute and sub-chronic treatments). Our data showed that both acute and subchronic treatments decreased the intensity of agonistic encounters and reinforced social behavior. By using C-fos immunoreactivity, we investigated the neuronal activation of several brain regions involved in aggressive behavior following subchronic treatment. We found that Topiramate produced activation in several cortical areas and in the lateral septum of resident brain mice compared with their controls. However, Topiramate induced inhibition in the medial nucleus of the amygdala, the dorsomedial nucleus of the periaqueductal gray, and especially in the anterior hypothalamic nucleus. Finally, we performed microinfusion of Topiramate (0.1 and 0.3 mM) into the lateral septum and anterior hypothalamus on offensive behaviors in isolation-induced-aggression paradigm. Interestingly, the microinfusion of Topiramate into the lateral septum has the capacity to alleviate aggressive behavior, without affecting social behavior. However, the microinfusion of Topiramate into the anterior hypothalamus decreased aggressive behavior and slightly reinforced social behavior. Our observations supported that the dose of 0.1 mM of Topiramate appeared more efficacy to treat aggression in adult mice. These pharmacological characteristics may account for Topiramate efficacy on aggressive symptoms in psychiatric patients.

Neonatal 6-OHDA Lesion Model in Mouse Induces Cognitive Dysfunctions of Attention-Deficit/Hyperactivity Disorder (ADHD) During Young Age.

Attention-deficit/hyperactivity disorder (ADHD) is a syndrome characterized by impaired attention, impulsivity and hyperactivity in children. These symptoms are often maintained in adults. During adolescence, prefrontal cortex develops connectivity with other brain regions to engage executive functions such as, latent inhibition, attention and inhibitory control. In our previous work, we demonstrated the validity of the neonatal 6-Hydroxydopamine (6-OHDA) mouse model, a classical neurodevelopmental model mimicking major symptoms of the human ADHD pathology. In order to evaluate pathological forms of executive functions and impulsive behavior in 6-OHDA mice during young age, we first tested latent inhibition (LI) after weaning, and then we evaluated the impulsive behavior using a cliff avoidance reaction test. Our results demonstrated that 6-OHDA mice showed disruption in latent inhibition, suggesting a deficit in selective attention, and displayed repetitive peering-down behavior, indicating a maladaptive impulsive behavior. Subsequently, to assess impulsivity and attention in young mice, we performed a modified 5-choice serial reaction time task test (5-CSRTT), optimizing the degree of food restriction for young animals and shortening the training duration. This test allowed us to demonstrate a deficit in inhibitory control and a loss of accuracy of 6-OHDA mice in the 5-CSRTT. In conclusion, we demonstrated that the 6-OHDA mouse model reproduces human symptoms of ADHD in childhood and early adulthood periods, as seen in human. Taken together, the 6-OHDA mouse model will be useful alongside other animal models to understand the neurobiological mechanisms underlying complex, heterogeneous neurological disorders.

Anticonvulsive and neuroprotective effects of aqueous and methanolic extracts of Anacyclus pyrethrum root in kainic acid-induced-status epilepticus in mice.

PURPOSE: Epilepsy is a chronic neurological disorder characterized by spontaneous and recurrent seizures. The currently available synthetic antiepileptic drugs have a limited efficacy and are associated with a wide range of side effects. In Ayurveda, Anacyclus pyrethrum root (APR) has been used as a traditional antiepileptic remedy. The aim of the present study is to evaluate the anticonvulsive and neuroprotective effects of aqueous and methanol extracts of Anacyclus pyrethrum root (AEAPR and MEAPR) on experimental model of status epilepticus (SE). METHODS: Twenty four male mice were divided into four groups. The control and KA groups had free access to tap water for 5 days before the intraperitoneal injection of distillated water or kainic acid (KA; 30 mg/kg), respectively. In the treated groups, mice received extracts solutions MEAPR and AEAPR in drinking water at the concentration of 5 g/l for 5 days. At the fifth day, animals received intraperitoneal injection of KA. The behavioral changes latency of seizures, the number of wet dog shakes (WDS) and the mortality were observed over 6 h. Thereafter, the mice were sacrificed for immunohistochemical studies. RESULTS: Pretreatment with MEAPR and AEAPR decreases significantly the frequency of WDS (32.5% and 43.9%, p < 0.01; respectively), and increases considerably the latent period (77.9% and 91.9%, p<0.01; respectively) between the injection of the KA and the appearance of the SE as compared to the KA group. The duration and severity of seizure in the MEAPR or AEAPR-pretreated groups were significantly lower (p < 0.01 and p < 0.05 or p < 0.01; respectively) than those in the KA group. These behavioral results were confirmed by the immunohistochemical study at the level of the hippocampus, in which the c-FOS and GFAP expression of both MEAPR and AEAPR-treated animals largely reduced (p < 0.001) the number of labelled cells with respect to the group, which received the KA alone. CONCLUSION: Our results showed that the MEAPR and AEAPR have anticonvulsive effect and putative neuroprotective effect against seizures induced by KA. Further studies are required to identify its active ingredients responsible for the observed effects.

Neonatal 6-OHDA lesion model in mouse induces Attention-Deficit/ Hyperactivity Disorder (ADHD)-like behaviour.

Attention-deficit/hyperactivity disorder (ADHD) is a common neurodevelopmental disorder characterized by impaired attention, impulsivity and hyperactivity. The "neonatal 6-hydroxydopamine" (6-OHDA) lesion is a commonly used model of ADHD in rat. However, a comprehensive assessment of ADHD-like symptoms is still missing, and data in mouse remain largely unavailable. Our aim was to analyse symptoms of ADHD in the mouse neonatal 6-OHDA model. 6-OHDA mice exhibited the major ADHD-like symptoms, i.e. hyperactivity (open field), attention deficit and impulsivity (five-choice serial reaction time task). Further, the model revealed discrete co-existing symptoms, i.e. anxiety-like (elevated plus maze test) and antisocial (social interaction) behaviours and decreased cognitive functioning (novel object recognition). The efficacy of methylphenidate, a classical psychostimulant used in the treatment of ADHD, was also evaluated. A histological analysis further supports the model validity by indicating dopamine depletion, changes in cortical thickness and abnormalities in anterior cingulate cortex neurons. A principal component analysis of the behaviour profile confirms that the 6-OHDA mouse model displayed good face and predictive validity. We conclude that neonatal dopamine depletion results in behavioural and morphological changes similar to those seen in patients and therefore could be used as a model for studying ADHD pathophysiological mechanisms and identifying therapeutic targets.

Anti-inflammatory, Antinociceptive, and Antioxidant Activities of Methanol and Aqueous Extracts of Anacyclus pyrethrum Roots.

Anacyclus pyrethrum (L.) is a plant widely used in Moroccan traditional medicine to treat inflammatory and painful diseases. The objective of the present study was to evaluate the antinociceptive, anti-inflammatory and antioxidant activities of aqueous and methanol extracts of Anacyclus pyrethrum roots (AEAPR and MEAPR). The anti-inflammatory effect of AEAPR and MEAPR was determined in xylene-induced ear edema and Complete Freund's Adjuvant (CFA)-induced paw edema. The antinociceptive activity of AEAPR and MEAPR (125, 250, and 500 mg/kg) administered by gavage was examined in mice by using acetic acid-induced writhing, hot plate, and formalin tests, and the mechanical allodynia were assessed in CFA-induced paw edema. In addition, the in vitro antioxidant activities of the extracts were determined by using 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging method, ferric reducing power and ß-carotene-linoleic acid assay systems. AEAPR and MEAPR produced significant reductions in CFA-induced paw edema and xylene-induced ear edema. A single oral administration of these extracts at 250 and 500 mg/kg significantly reduced mechanical hypersensitivity induced by CFA, which had begun 1 h 30 after the treatment, and was maintained till 7 h. Chronic treatment with both extracts significantly reduced mechanical hypersensitivity in persistent pain conditions induced by CFA. Acute pretreatment with AEAPR or MEAPR at high dose caused a significant decrease in the number of abdominal writhes induced by acetic acid injection (52.2 and 56.7%, respectively), a marked increase of the paw withdrawal latency in the hot plate test, and also a significant inhibition of both phases of the formalin test. This antinociceptive effect was partially reversed by naloxone pretreatment in the hot plate and formalin tests. Additionally, a significant scavenging activity in DPPH, reducing power and protection capacity of ß-carotene was observed in testing antioxidant assays. The present study suggests that AEAPR and MEAPR possess potent anti-inflammatory, antinociceptive and antioxidant effects which could be related to the presence of alkaloids and phenols in the plant. In addition, the antinociceptive effect of APR extracts seems to partly involve the opioid system. Taken together, these results suggest that Anacylcus pyrethrum may indeed be useful in the treatment of pain and inflammatory disorders in humans.

Acute and chronic glue sniffing effects and consequences of withdrawal on aggressive behavior.

Drug abuse act on brain mechanisms that cause a high-risk individual to engage in aggressive and violent behavior. While a drug-violence relationship exists, the nature of this relationship is often complex, with intoxication, neurotoxic, and withdrawal effects often being confused and/or confounded. Glue sniffing is often a springboard to the abuse of more addictive drugs. Despite its high prevalence and serious consequences, we know relatively little about the aggressive behavioral effects of volatile inhalants abuse, especially glue. The aim of the present study was to investigate the link between the duration of glue exposure, a common substance abuse problem in Morocco, and the level of aggressive behavior during withdrawal. For this we used the isolation-induced aggression model "residents" in three groups of mice. The first group served as control resident animals (n=10, without exposure); the second group as experimental resident mice (n=10) tested before and after acute (first day) and chronic exposure to the glue, and at 1 and 2weeks of withdrawal; and the third group of 10 intruder animals. The results showed that the number of attacks decreased (halved) and the latency of the first attack increased (doubled) following acute glue sniffing. However, the effects of chronic exposure and of 1week of withdrawal led to an increase in the intensity of agonistic encounters. After 2weeks of withdrawal, the intensity of aggressive behavior decreased again. These results indicated that chronic glue exposure and the first week of withdrawal are associated with increased aggression in mice.