RESUMEN
ß-site amyloid precursor protein-cleaving enzyme 1 (BACE1) is considered a therapeutic target to combat Alzheimer's disease by reducing ß-amyloid in the brain. To date, all clinical trials involving the inhibition of BACE1 have been discontinued due to a lack of efficacy or undesirable side effects such as cognitive worsening. The latter could have been the result of the inhibition of BACE at the synapse where it is expressed in high amounts. We have previously shown that prolonged inhibition of BACE interferes with structural synaptic plasticity, most likely due to the diminished processing of the physiological BACE substrate Seizure protein 6 (Sez6) which is exclusively processed by BACE1 and is required for dendritic spine plasticity. Given that BACE1 has significant amino acid similarity with its homolog BACE2, the inhibition of BACE2 may cause some of the side effects, as most BACE inhibitors do not discriminate between the two. In this study, we used newly developed BACE inhibitors that have a different chemotype from previously developed inhibitors and a high selectivity for BACE1 over BACE2. By using longitudinal in vivo two-photon microscopy, we investigated the effect on dendritic spine dynamics of pyramidal layer V neurons in the somatosensory cortex in mice treated with highly selective BACE1 inhibitors. Treatment with those inhibitors showed a reduction in soluble Sez6 (sSez6) levels to 27% (elenbecestat, Biogen, Eisai Co., Ltd., Tokyo, Japan), 17% (Shionogi compound 1) and 39% (Shionogi compound 2), compared to animals fed with vehicle pellets. We observed a significant decrease in the number of dendritic spines with Shionogi compound 1 after 21 days of treatment but not with Shionogi compound 2 or with elenbecestat, which did not show cognitive worsening in clinical trials. In conclusion, highly selective BACE1 inhibitors do alter dendritic spine density similar to non-selective inhibitors if soluble (sSez6) levels drop too much. Low-dose BACE1 inhibition might be reasonable if dosing is carefully adjusted to the amount of Sez6 cleavage, which can be easily monitored during the first week of treatment.
Asunto(s)
Enfermedad de Alzheimer , Ácido Aspártico Endopeptidasas , Animales , Ratones , Ácido Aspártico Endopeptidasas/metabolismo , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Espinas Dendríticas/metabolismo , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/metabolismo , Péptidos beta-Amiloides/metabolismo , Proteínas del Tejido Nervioso/metabolismoRESUMEN
Previously, studies using human neuroimaging and excitotoxic lesions in non-human primate have demonstrated an important role of ventrolateral prefrontal cortex (vlPFC) in higher order cognitive functions such as cognitive flexibility and the planning of behavioral sequences. In the present experiments, we tested effects on performance of temporary inactivation (using GABA receptor agonists) and dopamine (DA) D2 and 5-HT2A-receptor (R) blockade of vlPFC via local intracerebral infusions in the marmoset. We trained common marmosets to perform spatial self-ordered sequencing tasks in which one cohort of animals performed two and three response sequences on a continuously varying spatial array of response options on a touch-sensitive screen. Inactivation of vlPFC produced a marked disruption of accuracy of sequencing which also exhibited significant error perseveration. There were somewhat contrasting effects of D2 and 5-HT2A-R blockade, with the former producing error perseveration on incorrect trials, though not significantly impairing accuracy overall, and the latter significantly impairing accuracy but not error perseveration. A second cohort of marmosets were directly compared on performance of fixed versus variable spatial arrays. Inactivation of vlPFC again impaired self-ordered sequencing, but only with varying, and not fixed spatial arrays, the latter leading to the consistent use of fewer, preferred sequences. These findings add to evidence that vlPFC is implicated in goal-directed behavior that requires higher-order response heuristics that can be applied flexibly over different (variable), as compared with fixed stimulus exemplars. They also show that dopaminergic and serotonergic chemomodulation has distinctive effects on such performance.SIGNIFICANCE STATEMENT This investigation employing local intracerebral infusions to inactivate the lateral prefrontal cortex (PFC) of the New World marmoset reveals the important role of this region in self-ordered response sequencing in variable but not fixed spatial arrays. These novel findings emphasize the higher order functions of this region, contributing to cognitive flexibility and planning of goal directed behavior. The investigation also reports for the first time somewhat contrasting neuromodulatory deficits produced by infusions of dopamine (DA) D2 and 5-HT2A receptor (R) antagonists into the same region, of possible significance for understanding cognitive deficits produced by anti-psychotic drugs.
Asunto(s)
Dopamina/fisiología , Corteza Prefrontal/fisiología , Desempeño Psicomotor/fisiología , Serotonina/fisiología , Ácido gamma-Aminobutírico/fisiología , Animales , Antipsicóticos/efectos adversos , Baclofeno/farmacología , Callithrix , Trastornos del Conocimiento/inducido químicamente , Antagonistas de los Receptores de Dopamina D2/farmacología , Fluorobencenos/farmacología , Agonistas del GABA/farmacología , Objetivos , Memoria a Corto Plazo/fisiología , Muscimol/farmacología , Piperidinas/farmacología , Corteza Prefrontal/efectos de los fármacos , Desempeño Psicomotor/efectos de los fármacos , Antagonistas del Receptor de Serotonina 5-HT2/farmacología , Conducta Espacial , Sulpirida/farmacologíaRESUMEN
Fronto-striatal circuitry involving the orbitofrontal cortex has been identified as mediating successful reversal of stimulus-outcome contingencies. The region of the striatum that most contributes to reversal learning remains unclear, with studies in primates implicating both caudate nucleus and putamen. We trained four marmosets on a touchscreen-based serial reversal task and implanted each with cannulae targeting both putamen and caudate bilaterally. This allowed reversible inactivation of the two areas within the same monkeys, but across separate sessions, to directly investigate their respective contributions to reversal performance. Behavioral sensitivity to the GABAA agonist muscimol varied across subjects and between brain regions, so each marmoset received a range of doses. Intermediate doses of intra-putamen muscimol selectively impaired reversal performance, leaving the baseline discrimination phase unchanged. There was no effect of low doses and high doses were generally disruptive. By contrast, low doses of intra-caudate muscimol improved reversal performance, while high doses impaired both reversal and baseline discrimination performance. These data provide evidence for a specific role of the putamen in serial reversal learning, which may reflect the more habitual nature of repeated reversals using the same stimulus pair.
Asunto(s)
Aprendizaje Discriminativo/fisiología , Putamen/fisiología , Aprendizaje Inverso/fisiología , Animales , Callithrix , Masculino , Estimulación Luminosa/métodosRESUMEN
Dopamine exerts various effects including movement coordination and reward. It is useful to understand the quantitative relationship between drug pharmacokinetics and target engagement such as the change in occupancy and dopamine level in brain for the proper treatment of dopamine-related diseases. This study was aimed at developing a pharmacokinetic-pharmacodynamic (PK-PD) model based on dopamine transporter (DAT) occupancies that could describe changes in extracellular dopamine levels in brain after administration of methylphenidate (a DAT inhibitor) to rat. First, uptake of fluorescent substrates was studied in DAT-expressing human embryonic kidney 293 cells and concentration dependently inhibited by methylphenidate. By analyzing the uptake of fluorescent substrates in the presence or absence of methylphenidate, a mathematical model could estimate the association and dissociation rate constants of methylphenidate for DAT. Next, we measured the concentrations of methylphenidate in plasma and cerebrospinal fluid (CSF) and extracellular dopamine levels in the nucleus accumbens after single intraperitoneal administration of methylphenidate. The concentrations of methylphenidate in plasma increased almost dose proportionally and the CSF-to-plasma concentration ratio was similar among evaluated dose. The extracellular dopamine levels also increased with dose. These data were analyzed using the mechanism-based PK-PD model, which incorporates dopamine biosynthesis, release from a synapse, reuptake via DAT into a synapse, and elimination from a synapse. Methylphenidate concentrations in plasma and dopamine profiles predicted by the PK-PD model were close to in vivo observations. In conclusion, our mechanism-based PK-PD model can accurately describe dopamine levels in the brain after administration of methylphenidate to rats.
Asunto(s)
Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/metabolismo , Dopamina/metabolismo , Metilfenidato/farmacología , Metilfenidato/farmacocinética , Animales , Transporte Biológico/efectos de los fármacos , Masculino , Modelos Animales , RatasRESUMEN
RATIONALE: Phosphodiesterase 4D negative allosteric modulators (PDE4D NAMs) enhance memory and cognitive function in animal models without emetic-like side effects. However, the relationship between increased cyclic adenosine monophosphate (cAMP) signaling and the effects of PDE4D NAM remains elusive. OBJECTIVE: To investigate the roles of hippocampal cAMP metabolism and synaptic activation in the effects of D159687, a PDE4D NAM, under baseline and learning-stimulated conditions. RESULTS: At 3 mg/kg, D159687 enhanced memory formation and consolidation in contextual fear conditioning; however, neither lower (0.3 mg/kg) nor higher (30 mg/kg) doses induced memory-enhancing effects. A biphasic (bell-shaped) dose-response effect was also observed in a scopolamine-induced model of amnesia in the Y-maze, whereas D159687 dose-dependently caused an emetic-like effect in the xylazine/ketamine anesthesia test. At 3 mg/kg, D159687 increased cAMP levels in the hippocampal CA1 region after conditioning in the fear conditioning test, but not in the home-cage or conditioning cage (i.e., context only). By contrast, 30 mg/kg of D159687 increased hippocampal cAMP levels under all conditions. Although both 3 and 30 mg/kg of D159687 upregulated learning-induced Fos expression in the hippocampal CA1 30 min after conditioning, 3 mg/kg, but not 30 mg/kg, of D159687 induced phosphorylation of synaptic plasticity-related proteins such as cAMP-responsive element-binding protein, synaptosomal-associated protein 25 kDa, and the N-methyl-D-aspartate receptor subunit NR2A. CONCLUSIONS: Our findings suggest that learning-stimulated conditions can alter the effects of a PDE4D NAM on hippocampal cAMP levels and imply that a PDE4D NAM exerts biphasic memory-enhancing effects associated with synaptic plasticity-related signaling activation.
Asunto(s)
Compuestos de Bencidrilo , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 4 , Compuestos de Fenilurea , Inhibidores de Fosfodiesterasa 4 , Animales , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 4/metabolismo , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 4/farmacología , Eméticos/metabolismo , Eméticos/farmacología , Inhibidores de Fosfodiesterasa 4/farmacología , Inhibidores de Fosfodiesterasa 4/uso terapéutico , Transducción de Señal , HipocampoRESUMEN
Psychosis is a distressing symptom commonly occurring in people with dementia. To treat Parkinson's disease psychosis, pimavanserin (1), a 5-HT2A receptor inverse agonist having minimal 5-HT2C receptor affinity and no dopamine D2 receptor affinity, was approved in the United States, but not for dementia-related psychosis due to limited efficacy issues. Herein, we report on the identification of a potent and dual 5-HT2A and 5-HT2C receptor inverse agonist 8 having minimal hERG inhibition, after having demonstrated the involvement of both 5-HT2A and 5-HT2C receptors to deliver antipsychotic efficacy in an MK-801-induced locomotor model and having conducted 5-HT2A and 5-HT2C occupancy studies including a surrogate method. The introduction of a spirocyclopropyl group boosting 5-HT2C affinity in 1 followed by further optimization to control lipophilicity resulted in balanced dual potency and metabolic stability, and mitigating hERG inhibition led to 8 that showed significant antipsychotic efficacy due to the involvement of both receptors.
Asunto(s)
Antipsicóticos , Demencia , Trastornos Psicóticos , Receptor de Serotonina 5-HT2A , Receptor de Serotonina 5-HT2C , Agonistas del Receptor de Serotonina 5-HT2 , Antipsicóticos/farmacología , Antipsicóticos/uso terapéutico , Antipsicóticos/química , Antipsicóticos/síntesis química , Animales , Receptor de Serotonina 5-HT2A/metabolismo , Humanos , Trastornos Psicóticos/tratamiento farmacológico , Agonistas del Receptor de Serotonina 5-HT2/farmacología , Agonistas del Receptor de Serotonina 5-HT2/uso terapéutico , Agonistas del Receptor de Serotonina 5-HT2/química , Receptor de Serotonina 5-HT2C/metabolismo , Demencia/tratamiento farmacológico , Relación Estructura-Actividad , Masculino , Agonismo Inverso de Drogas , Canal de Potasio ERG1/metabolismo , Canal de Potasio ERG1/antagonistas & inhibidores , Ratas , Ratones , Piperidinas/farmacología , Piperidinas/uso terapéutico , Piperidinas/química , Ratas Sprague-Dawley , Canales de Potasio Éter-A-Go-Go/antagonistas & inhibidores , Canales de Potasio Éter-A-Go-Go/metabolismo , Urea/análogos & derivadosRESUMEN
The ß-secretase ß-site APP cleaving enzyme (BACE1) is a central drug target for Alzheimer's disease. Clinically tested, BACE1-directed inhibitors also block the homologous protease BACE2. Yet little is known about physiological BACE2 substrates and functions in vivo. Here, we identify BACE2 as the protease shedding the lymphangiogenic vascular endothelial growth factor receptor 3 (VEGFR3). Inactivation of BACE2, but not BACE1, inhibited shedding of VEGFR3 from primary human lymphatic endothelial cells (LECs) and reduced release of the shed, soluble VEGFR3 (sVEGFR3) ectodomain into the blood of mice, nonhuman primates, and humans. Functionally, BACE2 inactivation increased full-length VEGFR3 and enhanced VEGFR3 signaling in LECs and also in vivo in zebrafish, where enhanced migration of LECs was observed. Thus, this study identifies BACE2 as a modulator of lymphangiogenic VEGFR3 signaling and demonstrates the utility of sVEGFR3 as a pharmacodynamic plasma marker for BACE2 activity in vivo, a prerequisite for developing BACE1-selective inhibitors for safer prevention of Alzheimer's disease.
Asunto(s)
Enfermedad de Alzheimer , Secretasas de la Proteína Precursora del Amiloide , Ácido Aspártico Endopeptidasas , Transducción de Señal , Receptor 3 de Factores de Crecimiento Endotelial Vascular , Pez Cebra , Animales , Humanos , Ratones , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/patología , Enfermedad de Alzheimer/enzimología , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Secretasas de la Proteína Precursora del Amiloide/genética , Secretasas de la Proteína Precursora del Amiloide/antagonistas & inhibidores , Ácido Aspártico Endopeptidasas/metabolismo , Ácido Aspártico Endopeptidasas/genética , Ácido Aspártico Endopeptidasas/antagonistas & inhibidores , Células Endoteliales/metabolismo , Células Endoteliales/enzimología , Células Endoteliales/patología , Receptor 3 de Factores de Crecimiento Endotelial Vascular/metabolismo , Receptor 3 de Factores de Crecimiento Endotelial Vascular/genética , Pez Cebra/metabolismo , Pez Cebra/genética , Proteínas de Pez Cebra/genética , Proteínas de Pez Cebra/metabolismoRESUMEN
Given that histone acetylation via histone acetyltransferases (HATs) and histone deacetylases (HDACs) is significant in memory formation, HDAC2 has been thoroughly investigated as a potential therapeutic target for the treatment of cognitive dysfunction. Although HDAC inhibitors have been discovered through in vitro enzyme assay, off-target effects on other HDACs are common due to their conserved catalytic domains. Each HDAC could be regulated by specific intracellular molecular mechanisms, raising the possibility that a cell-based assay could identify selective inhibitors targeting specific HDACs through their regulatory mechanisms. Here, we propose a versatile, cell-based reporter system for screening HDAC2 inhibitors. Through RNA-sequencing from human cultured neuronal cells, we determined that expression of a transcriptional repressor, inhibitor of DNA binding 1 (ID1), is increased by knockdown of HDAC2. We also established the knock-in neuronal cell lines of a bioluminescence reporter gene to ID1. The knock-in cell lines showed significant reporter activity by known HDAC inhibitors and by HDAC2-knockdown but not by HDAC1-knockdown. Thus, our neuronal cell-based reporter system is a promising method for screening the specific inhibitors of HDAC2 but not HDAC1, by potentially targeting not only HDAC2, but also the regulatory mechanisms of HDAC2 in neurons.
Asunto(s)
Inhibidores de Histona Desacetilasas , Proyectos de Investigación , Humanos , Inhibidores de Histona Desacetilasas/farmacología , Histona Desacetilasa 2/genéticaRESUMEN
Impaired detection of causal relationships between actions and their outcomes can lead to maladaptive behavior. However, causal roles of specific prefrontal cortex (PFC) sub-regions and the caudate nucleus in mediating such relationships in primates are unclear. We inactivated and overactivated five PFC sub-regions, reversibly and pharmacologically: areas 24 (perigenual anterior cingulate cortex), 32 (medial PFC), 11 (anterior orbitofrontal cortex, OFC), 14 (rostral ventromedial PFC/medial OFC), and 14-25 (caudal ventromedial PFC) and the anteromedial caudate to examine their role in expressing learned action-outcome contingencies using a contingency degradation paradigm in marmoset monkeys. Area 24 or caudate inactivation impaired the response to contingency change, while area 11 inactivation enhanced it, and inactivation of areas 14, 32, or 14-25 had no effect. Overactivation of areas 11 and 24 impaired this response. These findings demonstrate the distinct roles of PFC sub-regions in goal-directed behavior and illuminate the candidate neurobehavioral substrates of psychiatric disorders, including obsessive-compulsive disorder.
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Conducta Animal/fisiología , Objetivos , Corteza Prefrontal/fisiología , Animales , Callithrix , Aprendizaje/fisiologíaRESUMEN
Clinical studies have shown that microduplications at 7q36.3, containing VIPR2, confer significant risk for schizophrenia and autism spectrum disorder (ASD). VIPR2 gene encodes the VPAC2 receptor for vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase-activating polypeptide (PACAP). Lymphocytes from patients with these mutations exhibited higher VIPR2 gene expression and VIP-induced cAMP responsiveness, but mechanisms by which overactive VPAC2 signaling may lead to these psychiatric disorders are unknown. We have previously found that repeated administration of a selective VPAC2 receptor agonist Ro25-1553 in the mouse during early postnatal development caused synaptic alterations in the prefrontal cortex and sensorimotor gating deficits. In this study, we aimed to clarify the effects of VPAC2 receptor activation on neurite outgrowth in cultured primary mouse cortical neurons. Ro25-1553 and VIP caused reductions in total numbers and lengths of both neuronal dendrites and axons, while PACAP38 facilitated elongation of dendrites, but not axons. These effects of Ro25-1553 and VIP were blocked by a VPAC2 receptor antagonist PG99-465 and abolished in VPAC2 receptor-deficient mice. Additionally, Ro25-1553-induced decreases in axon and dendritic outgrowth in wild-type mice were blocked by a protein kinase A (PKA) inhibitor H89, but not by a PKC inhibitor GF109203X or a mitogen-activated protein kinase (MAPK) kinase (MEK) inhibitor U0126. PACAP38- induced facilitation of dendritic outgrowth was blocked by U0126. These results suggest that activation of the VPAC2 receptor impairs neurite outgrowth and decreases branching of cortical neurons by a PKA-dependent mechanism. These findings also imply that the VIPR2-linkage to mental health disorders may be due in part to deficits in neuronal maturation induced by VPAC2 receptor overactivation.
RESUMEN
Impulsive choice behavior, which can be assessed using the delay discounting task, is a characteristic of various psychiatric disorders, including attention-deficit/hyperactivity disorder (ADHD). Guanfacine is a selective α2A-adrenergic receptor agonist that is clinically effective in treating ADHD. However, there is no clear evidence that systemic guanfacine administration reduces impulsive choice behavior in the delay discounting task in rats. In the present study, we examined the effect of systemic guanfacine administration on food-motivated impulsive choice behavior in rats and the neuronal mechanism underlying this effect. Repeated administration of either guanfacine, methylphenidate, or atomoxetine significantly enhanced impulse control, increasing the number of times the rats chose a large but delayed reward in a dose-dependent manner. The effect of guanfacine was significantly blocked by pretreatment with an α2A-adrenergic receptor antagonist. Furthermore, the effect of guanfacine remained unaffected in rats pretreated with a selective noradrenergic neurotoxin, consistent with a post-synaptic action. In contrast, the effect of atomoxetine on impulsive choice behavior was attenuated by pretreatment with the noradrenergic neurotoxin. These results provide the first evidence that systemically administered guanfacine reduces impulsive choice behavior in rats and that direct stimulation of postsynaptic, rather than presynaptic, α2A-adrenergic receptors is involved in this effect.
Asunto(s)
Agonistas de Receptores Adrenérgicos alfa 2/farmacología , Conducta de Elección/efectos de los fármacos , Conducta Alimentaria/efectos de los fármacos , Guanfacina/farmacología , Conducta Impulsiva/efectos de los fármacos , Motivación/efectos de los fármacos , Antagonistas de Receptores Adrenérgicos alfa 2/farmacología , Animales , Clorhidrato de Atomoxetina/farmacología , Conducta de Elección/fisiología , Relación Dosis-Respuesta a Droga , Conducta Alimentaria/fisiología , Conducta Alimentaria/psicología , Alimentos , Conducta Impulsiva/fisiología , Masculino , Metilfenidato/farmacología , Motivación/fisiología , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Distribución Aleatoria , Ratas Wistar , Receptores Adrenérgicos alfa 2/metabolismoRESUMEN
Effects of prokineticins (PKs), a novel family of bioactive peptides with a mitogenic action to endothelial cells of the endocrine gland and testis, on astrocytic functions were examined. Mouse cultured astrocytes expressed PK-R1 type PK receptors, while there was little expression of the PK-R2 type. PKs caused increases in astrocytic cytosolic Ca2+ levels and BrdU incorporation. Increases in Ca2+ levels by PK-2 were diminished by U73122 (a phospholipase C inhibitor). PK-induced BrdU incorporation was inhibited by U73122, GF109203 (a protein kinase C inhibitor) and PD98059 (a MEK/ERK inhibitor). These results indicate that PK receptors are expressed in astrocytes and regulate astrocytic proliferation.
Asunto(s)
Astrocitos/metabolismo , Proliferación Celular , Expresión Génica/fisiología , Receptores Acoplados a Proteínas G/metabolismo , Animales , Animales Recién Nacidos , Astrocitos/efectos de los fármacos , Bromodesoxiuridina/metabolismo , Calcio/metabolismo , Células Cultivadas , Cerebelo/citología , Relación Dosis-Respuesta a Droga , Embrión de Mamíferos , Inhibidores Enzimáticos/farmacología , Estrenos/farmacología , Flavonoides/farmacología , Hormonas Gastrointestinales/farmacología , Ratones , Neuropéptidos/farmacología , Pirrolidinonas/farmacología , Receptores Acoplados a Proteínas G/genética , Factor de Crecimiento Endotelial Vascular Derivado de Glándula Endocrina/farmacologíaRESUMEN
RATIONALE: Isolation rearing in rodents causes not only abnormal behaviors which resemble the clinical symptoms of schizophrenia but also hypoalgesia in thermal nociception models. However, the mechanism of the hypoalgesia is not known. OBJECTIVES: The present study investigated the effect of isolation rearing on acute pain and the descending pain inhibitory pathways in mice. RESULTS: Rearing in isolation for 6 weeks from post-weaning reduced pain sensitivity in the hot plate test and acetic acid-induced writhing test. Isolation rearing also reduced the intraplantar capsaicin-induced licking behavior. Capsaicin increased c-Fos expression, a neuronal activity marker, in the spinal cord and primary somatosensory cortex both in group- and isolation-reared mice, but this effect did not differ between groups. On the other hand, c-Fos expression in the anterior cingulate cortex, periaqueductal gray matter, and rostral ventromedial medulla, but not in the spinal cord or somatosensory cortex, was enhanced by isolation rearing. Systemic administration of WAY100635 (serotonin (5-HT)1A receptor antagonist), but not of ketanserin (5-HT2 receptor antagonist), prazosin (α1-adrenoceptor antagonist), or yohimbine (α2-adrenoceptor antagonist), attenuated isolation rearing-induced hypoalgesia in capsaicin-induced licking behavior. Attenuation of isolation rearing-induced hypoalgesia was also observed following the intrathecal injection of WAY100635. Naloxone, an opioid receptor antagonist, did not affect the hypoalgesia in isolation-reared mice. CONCLUSIONS: These findings suggest that isolation rearing causes hypoalgesia in mouse models of acute pain and imply that the spinal 5-HT1A receptor activation probably through descending serotonergic inhibitory pathway is involved in isolation rearing-induced hypoalgesia.
Asunto(s)
Dolor Agudo/fisiopatología , Receptor de Serotonina 5-HT1A/metabolismo , Aislamiento Social , Médula Espinal/metabolismo , Ácido Acético/toxicidad , Animales , Conducta Animal/efectos de los fármacos , Capsaicina/farmacología , Modelos Animales de Enfermedad , Masculino , Ratones , Dimensión del Dolor , Umbral del Dolor , Proteínas Proto-Oncogénicas c-fos/metabolismo , Corteza Somatosensorial/metabolismoRESUMEN
Social isolation rearing in mice after weaning reduces pain sensitivity to acute pain, and this hypoalgesia is mediated by the descending serotonergic pain inhibitory system in which the spinal serotonin (5-HT)1A receptor is involved. However, it is not known whether isolation rearing affects pain sensitivity to neuropathic or inflammatory chronic pain. In this study, we examined the effects of isolation rearing on chronic pain induced by Freund's complete adjuvant (FCA) and partial sciatic nerve ligation using the von Frey test (to assess mechanical allodynia) and the plantar test (to assess thermal hyperalgesia). In the FCA model, isolation rearing reduced mechanical allodynia, but not thermal hyperalgesia. In contrast, isolation rearing had no effect on allodynia or hyperalgesia in the sciatic nerve ligation model. The isolation rearing-induced inhibition of allodynia was alleviated by intrathecal injection of WAY100635, a selective 5-HT1A receptor antagonist. FCA increased 5-HT turnover and decreased 5-HT1A receptor expression in the spinal cord of group-reared mice, while it did not have these effects in isolation-reared mice. These results suggest that FCA suppresses the serotonergic pain inhibitory system selectively in group-reared mice. Moreover, systemic administration of osemozotan, a selective 5-HT1A receptor agonist, inhibited FCA-induced mechanical allodynia in group-reared mice, and this effect of the drug was suppressed by intrathecal injection of WAY100635. Collectively, these findings suggest that isolation rearing selectively reduces FCA-induced mechanical allodynia in mice and that this effect is mediated by the activation of spinal 5-HT1A receptors.