RESUMEN
Developmental bisphenol A (BPA) exposure has been implicated in adverse behavior and learning deficits. The mode of action underlying these effects is unclear. The objectives of this study were to identify whether low-dose, developmental BPA exposure affects larval zebrafish locomotor behavior and whether learning deficits occur in adults exposed during development. Two control compounds, 17ß-estradiol (an estrogen receptor ligand) and GSK4716 (a synthetic estrogen-related receptor gamma ligand), were included. Larval toxicity assays were used to determine appropriate BPA, 17ß-estradiol, and GSK4716 concentrations for behavior testing. BPA tissue uptake was analyzed using HPLC and lower doses were extrapolated using a linear regression analysis. Larval behavior tests were conducted using a ViewPoint Zebrabox. Adult learning tests were conducted using a custom-built T-maze. BPA exposure to <30µM was non-teratogenic. Neurodevelopmental BPA exposure to 0.01, 0.1, or 1µM led to larval hyperactivity or learning deficits in adult zebrafish. Exposure to 0.1µM 17ß-estradiol or GSK4716 also led to larval hyperactivity. This study demonstrates the efficacy of using the zebrafish model for studying the neurobehavioral effects of low-dose developmental BPA exposure.
Asunto(s)
Disruptores Endocrinos/toxicidad , Contaminantes Ambientales/toxicidad , Hipercinesia/inducido químicamente , Discapacidades para el Aprendizaje/inducido químicamente , Discapacidades para el Aprendizaje/psicología , Fenoles/toxicidad , Pez Cebra/fisiología , Animales , Conducta Animal/efectos de los fármacos , Compuestos de Bencidrilo , Cromatografía Líquida de Alta Presión , Relación Dosis-Respuesta a Droga , Embrión no Mamífero/metabolismo , Disruptores Endocrinos/farmacocinética , Contaminantes Ambientales/farmacocinética , Estradiol/farmacología , Hidrazinas/farmacología , Larva , Aprendizaje por Laberinto/efectos de los fármacos , Fenoles/farmacocinética , Receptores de Estrógenos/efectos de los fármacos , Receptores Acoplados a Proteínas G/efectos de los fármacos , Aprendizaje Inverso/efectos de los fármacos , Teratógenos/toxicidadRESUMEN
BACKGROUND CONTEXT: There is increasing evidence for a role of the cannabinoid (CB) system in the development of neuropathic pain (NP) after spinal cord injury (SCI). The nonspecific CB1 and CB2 receptor agonists, WIN 55, 212-2 (WIN), have previously been shown to alleviate both mechanical and thermal hyperalgesia (TH) after peripheral nerve injury. PURPOSE: The present study was designed to identify the CB receptors involved in the antihyperalgesic effect of WIN by using selective antagonists for CB1 and CB2 receptors. STUDY DESIGN: This is an in vivo and behavioral study using a moderate T9 contusion SCI. After injury, TH of the hind paws was measured on postinjury days 21 through 42. METHODS: Sprague-Dawley rats underwent a contusion SCI using the Multicenter Animal Spinal Cord Injury Study (MASCIS) weight-drop impactor, which induced a moderate T9 SCI. Only animals showing consistent plantar stepping and consistent forelimb and hind limb coordination (Basso, Beattie, and Bresnahan score=15) were tested for TH. Animals exhibiting decreased withdrawal latency time, indicating TH, on or before Day 42, were selected for pharmacological intervention. Animals not exhibiting TH did not receive pharmacological intervention and were sacrificed. Rats underwent hind paw testing before any drug administration (after injury), 45 minutes after selective CB antagonist (AM 251 or AM 630) administration (postantagonist) and again 45 minutes after WIN administration (post-WIN). There were a total of seven treatment groups: saline vehicle control; Dimethyl sulfoxide (DMSO) vehicle control; low-dose WIN (0.2 mg/kg); and high-dose WIN (2.0 mg/kg); AM 251 (3 mg/kg) and AM 630 (1 mg/kg) were given subcutaneously in a total volume of 0.5 mL. Followed by intraperitoneal injection of WIN after each antagonist, sham-operated rats repeated pharmacological intervention used with treatment Groups 5 and 6. RESULTS: Thermal hyperalgesia was significantly ameliorated in a dose-dependent manner with systemically administered WIN. Cannabinoid receptor Type 1 antagonist AM 251 pretreatment did not affect the antihyperalgesic effect of WIN. By contrast, pretreatment with the CB2 receptor antagonist AM 630 significantly attenuated the effect of WIN. CONCLUSION: Taken together, these results suggest a role of the CB2 receptor in modulating SCI-induced TH. Selective activation of the CB2 receptor could potentially lead to analgesic effects on NP while avoiding psychotropic side effects in patients with SCI.