Icilin-evoked behavioral stimulation is attenuated by alpha2-adrenoceptor activation.

Icilin is a transient receptor potential cation channel subfamily M (TRPM8) agonist that produces behavioral activation in rats and mice. Its hallmark overt pharmacological effect is wet-dog shakes (WDS) in rats. The vigorous shaking associated with icilin is dependent on NMDA receptor activation and nitric oxide production, but little else is known about the biological systems that modulate the behavioral phenomenon. The present study investigated the hypothesis that alpha(2)-adrenoceptor activation inhibits icilin-induced WDS. Rats injected with icilin (0.5, 1, 2.5, 5mg/kg, i.p.) displayed dose-related WDS that were inhibited by pretreatment with a fixed dose of clonidine (0.15 mg/kg, s.c.). Shaking behavior caused by a fixed dose (2.5mg/kg) of icilin was also inhibited in a dose-related manner by clonidine pretreatment (0.03-0.15 mg/kg, s.c.) and reduced by clonidine posttreatment (0.15 mg/kg, s.c.). Pretreatment with a peripherally restricted alpha(2)-adrenoceptor agonist, ST91 (0.075, 0.15 mg/kg), also decreased the incidence of shaking elicited by 2.5mg/kg of icilin. Pretreatment with yohimbine (2mg/kg, i.p.) enhanced the shaking induced by a low dose of icilin (0.5mg/kg). The imidazoline site agonists, agmatine (150mg/kg, i.p.) and 2-BFI (7 mg/kg, i.p.), did not affect icilin-evoked shaking. These results suggest that alpha(2)-adrenoceptor activation inhibits shaking induced by icilin and that increases in peripheral, as well as central, alpha(2)-adrenoceptor signaling oppose the behavioral stimulant effect of icilin.

Topiramate antagonizes NMDA- and AMPA-induced seizure-like activity in planarians.

The mechanism of anticonvulsant action of topiramate includes inhibition of glutamate-activated ion channels. The evidence is most convincing for direct inhibitory action at the ionotropic AMPA (alpha-Amino-3-hydroxy-5-methylisoxazole-4-propionic acid) and kainate ((2S,3S,4S)-3-(Carboxymethyl)-4-prop-1-en-2-ylpyrrolidine-2-carboxylic acid) glutamate receptor subtypes. Less direct connection has been made to the NMDA (N-Methyl-d-aspartate) subtype. In the present study, we demonstrate that NMDA and AMPA produce concentration-dependent seizure-like activity in planarians, a type of flatworm which possesses mammalian-like neurotransmitters. In contrast, planarians exposed to the inhibitory amino acid, glycine, did not display pSLA. For combination experiments, topiramate significantly reduced planarian seizure-like activity (pSLA) produced by NMDA or AMPA. Additionally, NMDA-induced pSLA was antagonized by either an NMDA receptor antagonist (MK-801) or AMPA receptor antagonist (DNQX), thus suggesting that NMDA-induced pSLA was mediated by NMDA and non-NMDA receptors. The present results provide pharmacologic evidence of a functional inhibitory action of topiramate on glutamate receptor activity in invertebrates and provide a sensitive, quantifiable end-point for studying anti-seizure pharmacology.