The cannabinoid CB2 receptor-specific agonist AM1241 increases pentylenetetrazole-induced seizure severity in Wistar rats.
The potential efficacy of cannabinoid receptor ligands for the treatment of epilepsy remains controversial; cannabis components that act via cannabinoid type 1 (CB1) receptors produce anticonvulsant effects in animal models despite treatment with the CB receptor agonist reliably inducing convulsions in various species. Moreover, the potential role of cannabinoid receptor type 2 (CB2) to modulate seizures remains under-investigated. This study assessed the effects of the selective CB2 receptor agonist, AM1241, on pentylenetetrazole (PTZ)-induced seizures in rats. A stereotactically placed guide cannula was surgically implanted into the right lateral ventricle in adult Wistar rats which, 5-6days later, received an acute intracerebroventricular (i.c.v.) microinfusion of AM1241 (0.01, 1 or 10μg/2μl or vehicle) 5min before intraperitoneal (i.p.) injection of PTZ (70mg/kg). Rats were observed for 30min and the seizure severity behavior measured using a modified Racine's scale. Additional groups of rats were pretreated with a single low dose of the selective CB2 receptor antagonist, AM630 (dose 1mg/kg; i.p.), or vehicle, 30min prior to i.c.v. microinfusion of AM1241 (1μg/2μl). AM1241 administration significantly increased tonic-clonic seizure incidence and severity while also decreasing the onset of generalized seizures (AM1241 1 and 10μg/2μl). Pretreatment with AM630 prevented the proconvulsant effects of AM1241. This study shows, for the first time, that selective activation of CB2 receptors can increase generalized seizure susceptibility and suggests that pathological hyperexcitability phenomena can be differentially regulated by targeting CB1 and CB2 receptors.
Programa de Pós- graduação em Neurociências, Centro de Ciências Biológicas, Universidade Federal de Santa Catarina, Florianópolis, SC, Brazil; Centro de Neurociências Aplicadas, Hospital Universitário, Universidade Federal de Santa Catarina, Florianópolis, SC, Brazil. Electronic address: decarvalhocr@gmail.com.
Cristiane R
CR
de Carvalho
Centro de Neurociências Aplicadas, Hospital Universitário, Universidade Federal de Santa Catarina, Florianópolis, SC, Brazil; Programa de Pós- graduação em Ciências Médicas, Centro de Ciências da Saúde, Universidade Federal de Santa Catarina, Florianópolis, SC, Brazil.
Alexandre A
AA
Hoeller
Centro de Neurociências Aplicadas, Hospital Universitário, Universidade Federal de Santa Catarina, Florianópolis, SC, Brazil.
Pedro L C
PL
Franco
Centro de Neurociências Aplicadas, Hospital Universitário, Universidade Federal de Santa Catarina, Florianópolis, SC, Brazil.
Athos P S
AP
Martini
Centro de Neurociências Aplicadas, Hospital Universitário, Universidade Federal de Santa Catarina, Florianópolis, SC, Brazil; Programa de Pós- graduação em Ciências Médicas, Centro de Ciências da Saúde, Universidade Federal de Santa Catarina, Florianópolis, SC, Brazil.
Flávia M S
FM
Soares
Centro de Neurociências Aplicadas, Hospital Universitário, Universidade Federal de Santa Catarina, Florianópolis, SC, Brazil; Programa de Pós- graduação em Ciências Médicas, Centro de Ciências da Saúde, Universidade Federal de Santa Catarina, Florianópolis, SC, Brazil; Serviço de Neurologia, Departamento de Clínica Médica, Hospital Universitário, Universidade Federal de Santa Catarina, Florianópolis, SC, Brazil.
Katia
K
Lin
Centro de Neurociências Aplicadas, Hospital Universitário, Universidade Federal de Santa Catarina, Florianópolis, SC, Brazil; Departamento de Farmacologia, Universidade Federal de Santa Catarina, Florianópolis, SC, Brazil.
Rui D
RD
Prediger
School of Chemistry, Food and Nutritional Sciences, and Pharmacy, The University of Reading, Reading, Berkshire RG6 6AP, UK.
Benjamin J
BJ
Whalley
Programa de Pós- graduação em Neurociências, Centro de Ciências Biológicas, Universidade Federal de Santa Catarina, Florianópolis, SC, Brazil; Centro de Neurociências Aplicadas, Hospital Universitário, Universidade Federal de Santa Catarina, Florianópolis, SC, Brazil; Programa de Pós- graduação em Ciências Médicas, Centro de Ciências da Saúde, Universidade Federal de Santa Catarina, Florianópolis, SC, Brazil; Serviço de Neurologia, Departamento de Clínica Médica, Hospital Universitário, Universidade Federal de Santa Catarina, Florianópolis, SC, Brazil.
Roger
R
Walz
D000818:Animals; D063386:Cannabinoid Receptor Agonists / Q000494:pharmacology*; D002186:Cannabinoids / Q000494:pharmacology; D002408:Catheters, Indwelling; D003292:Convulsants / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D007274:Injections, Intraperitoneal; D008297:Male; D008845:Microinjections; D010433:Pentylenetetrazole / Q000494:pharmacology*; D017208:Rats, Wistar; D043885:Receptor, Cannabinoid, CB2 / Q000819:agonists* / Q000378:metabolism; D012640:Seizures / Q000139:chemically induced* / Q000378:metabolism / Q000401:mortality; D012720:Severity of Illness Index
C439263:AM 1241; D063386:Cannabinoid Receptor Agonists; D002186:Cannabinoids; C469526:Cnr2 protein, rat; D003292:Convulsants; D043885:Receptor, Cannabinoid, CB2; D010433:Pentylenetetrazole
CB2 cannabinoid receptors; Epilepsy; Pentylenetetrazole; Proconvulsant; Seizures