Mechanisms convulsive activity

Broom DC, Nitsche JF, Pinter JE, et al. Comparison of receptor mechanisms and efficacy requirements for 5-agonist-induced convulsive activity and antinociception in mice. J Pharmacol Exp Ther 2002 303 723-729. 

Epileptiform activity does not spread randomly throughout the brain, but seems to be generated and propagated by specific anatomical routes (Gale, 1988 Loscher and Ebert, 1996). This suggests ftiat certain propagation pathways may fimction as common denominators for the development of certain t5q>es of epileptiform activity, independent of the ways seizures are triggered. Within the rat brain, there are areas with control mechanisms able to attenuate all aspects of convulsive activity. The localization of such control areas... 

There ate many classes of anticonvulsant agent in use, many associated with side effect HabiUties of unknown etiology. Despite many years of clinical use, the mechanism of action of many anticonvulsant dmgs, with the exception of the BZs, remains unclear and may reflect multiple effects on different systems, the summation of which results in the anticonvulsant activity. The pharmacophore stmctures involved are diverse and as of this writing there is htde evidence for a common mechanism of action. Some consensus is evolving, however, in regard to effects on sodium and potassium channels (16) to reduce CNS excitation owing to convulsive episodes. 

The results demonstrate anticonvulsant properties of PCP and ketamine in two quite different seizure models. On the one hand, ketamine was effective in antagonizing several components of PTZ activity. Others have previously reported anti-PTZ effects of ketamine. However, the present results demonstrate that the anticonvulsant effects of ketamine against PTZ seizures closely resembled the effects of phenobarbital in that both compounds delayed clonic convulsions and prevented tonic extension. Moreover, a low dose of ketamine, which alone showed no anticonvulsant effect or overt behavioral changes, potentiated the anti-PTZ effects of phenobarbita 1. These findings suggest that ketamine possesses selective anticonvulsant properties. The anticonvulsant mechanism of action for phenobarbital is not known. However, the similarities between ketamine and phenobarbital, and the interaction between the two compounds, suggest a common mechanism or site of acti on. 

In conclusion, the in vivo activity of available delta opioids is complex. DPDPE, or even Delt, administered ICV seems to recruit mu receptors and, from all the data, it appears that delta agonists often have mixed mu/ delta activities. More selective delta agonists need to be produced to explore delta receptor pharmacology. The examination of nonanalgesic activities of delta ligands in opioid receptor knockout mice has been very informative while the convulsive effect of SNC 80 seems indeed delta receptor mediated, the addictive activity of Delt most probably results from mu receptor activation and the immunosuppressive action of NTI is mediated by a nonopioid mechanism. 

In addition to locomotor activity, delta opioid agonists produce convulsions in mice [41,43], rats [34,35], and monkeys [44 46], In the past, chemical-induced convulsions induced by camphor or pentylenetetrazol (Metrazol) were used as treatments for depression today, however, ECT is the only convulsant therapy used because the treatment-induced effects are less unpleasant than those produced by chemical convulsants [47]. ECS was demonstrated to have antidepressant-like effects in the forced swim test in rats [3], and ECT is a very effective treatment for depression in humans. Based on these observations, it was proposed that delta opioid agonists produce antidepressant-like effects tough a convulsive- or electroconvulsive shock (ECS)-like mechanism of action [41]. 

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