Differential Effects of Phenobarbital and Pentobarbital on Isolated Nervous Tissue

Vazquez, A. J.; Diamond, Bruce I.; Sabelli, Hector

doi:10.1111/j.1528-1157.1975.tb04742.x

Cited by 7 publications

(1 citation statement)

References 17 publications

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“…As could be expected from their CNS‐depressing activity, barbiturates reduce neuronal membrane excitability in various invertebrate and vertebrate preparations (cf., Jurna, 1985). For instance, at high concentrations, pentobarbital and phenobarbital were shown to block the generation of action potentials in nerve fibers (Heinbecker & Bartley, 1940; Schoepfle, 1957; Vazquez et al., 1975; Sabelli et al., 1977). Phenobarbital was demonstrated to reduce repetitive spike discharges in frog nerve fibers (Toman, 1949, 1952) and to hyperpolarize neuronal membranes (Takeuchi, 1968).…”

Section: Effects Of Barbiturates On Neuronal Membrane Excitabilitymentioning

confidence: 99%

How theories evolved concerning the mechanism of action of barbiturates

2012

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Summary The barbiturate phenobarbital has been in use in the treatment of epilepsy for 100 years. It has long been recognized that barbiturates act by prolonging and potentiating the action of γ‐aminobutyric acid (GABA) on GABAA receptors and at higher concentrations directly activating the receptors. A large body of data supports the concept that GABAA receptors are the primary central nervous system target for barbiturates, including the finding that transgenic mice with a point mutation in the β3 GABAA‐receptor subunit exhibit diminished sensitivity to the sedative and immobilizing actions of the anesthetic barbiturate pentobarbital. Although phenobarbital is only modestly less potent as a GABAA‐receptor modulator than pentobarbital, phenobarbital is minimally sedating at effective anticonvulsant doses. Possible explanations for the reduced sedative effect of phenobarbital include more regionally restricted action; partial agonist activity; reduced propensity to directly activate GABAA receptors (possibly including extrasynaptic receptors containing δ subunits); and reduced activity at other ion channel targets, including voltage‐gated calcium channels. In recent years, substantial progress has been made in defining the structural features of GABAA receptors responsible for gating and allosteric modulation by drugs. Although the precise sites of action of barbiturates have not yet been defined, the second and third transmembrane domains of the β subunit appear to be critical; binding may involve a pocket formed by β‐subunit methionine 286 as well as α‐subunit methionine 236. In addition to effects on GABAA receptors, barbiturates block AMPA/kainate receptors, and they inhibit glutamate release through an effect on P/Q‐type high‐voltage activated calcium channels. The combination of these various actions likely accounts for their diverse clinical activities. Despite the remarkable progress of the last century, there is still much to learn about the actions of barbiturates that can be applied to the discovery of new, more therapeutically useful agents.

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