Biomedical subjects

P Bloms-Funke

Publications and source records attributed to P Bloms-Funke.

9 recordsLinked to original sources

PubMed2000

Agonistic effects of the opioid buprenorphine on the nociceptin/OFQ receptor.

The nociceptin/orphanin FQ (N/OFQ) receptor (e.g. the human ortholog ORL1) has been shown to be pharmacologically distinct from classic opioid receptors. Recently, we have identified buprenorphine as a full ORL1 agonist using a reporter gene assay. For further functional analysis, buprenorphine's effects on ORL1 receptors were investigated using a K(+) channel (GIRK1) assay in Xenopus oocytes and GTPgammaS assay in CHO-K1 membrane preparations. In both assays, buprenorphine behaved as a partial agonist compared to nociceptin itself. The N/OFQ agonism of buprenorphine might contribute to actions of buprenorphine in pain models in vivo beside its mu- or kappa-opioid receptor mediated effects.

Analgesics, Opioid↗

PubMed2000

Kindling causes persistent in vivo changes in firing rates and glutamate sensitivity of central piriform cortex neurons in rats.

The present experiments were undertaken to study whether amygdala kindling induces persistent alterations in the functional status of neurons of the central piriform cortex, a subregion of the piriform cortex identified previously as a site involved in the kindling process. Extracellular, single-unit recordings of piriform cortex neurons were made in anesthetized fully kindled rats at an interval of at least five weeks after the last seizure. Electrode implanted but not kindled rats served as sham controls. An additional group of non-implanted rats was used as naive controls. Spontaneously firing piriform cortex neurons were characterized in all groups by smooth, sharp, biphasic (i.e. positive/negative) action potentials with a duration of 0.8-1.8 ms, and were primarily located at the border between piriform cortex layers II and III. In kindled rats, neurons in the central piriform cortex exhibited a significantly higher firing rate compared to controls. Based on median group values, the increase in basal activity in kindled rats averaged about 90%. The responsiveness of piriform cortex neurons to neurotransmitters was tested by microiontophoretic application of glutamate, N-methyl-D-aspartate and GABA. Piriform cortex neurons of kindled rats exhibited a significantly lower responsiveness to the excitatory effect of glutamate than naive controls. A lowered glutamate responsiveness was also seen in sham controls. No significantly altered transmitter sensitivities of piriform cortex neurons from kindled rats were seen with N-methyl-D-aspartate or GABA. The data indicate that amygdala kindling causes persistent interictal changes in both basal activity and glutamate responsiveness of central piriform cortex neurons which could contribute to the abnormal hyperexcitability characteristic of kindling.

Action Potentials↗

PubMed1999

Extracellular single-unit recordings of piriform cortex neurons in rats: influence of different types of anesthesia and characterization of neurons by pharmacological manipulation of serotonin receptors.

In epilepsy research, there is a growing interest in the role of the piriform cortex (PC) in the development and maintenance of limbic kindling and other types of limbic epileptogenesis leading to complex partial seizures. Neurophysiological studies on PC or amygdala-PC slice preparations from kindled rats showed that kindling of the amygdala induces long-lasting changes in synaptic efficacy in the ipsilateral PC, including spontaneous discharges and enhanced susceptibility of PC neurons to evoked burst responses. These long-lasting electrophysiological changes in the PC during kindling appear to be due, at least in part, to impaired function of gamma-aminobutyric acid (GABA)ergic interneurons. The aim of the present study was to develop an anesthetic protocol allowing electrophysiological single-unit recordings from inhibitory, presumably GABAergic PC interneurons in vivo. In addition to recording of spontaneously active PC neurons, microiontophoretic application of glutamate was used to activate silent neurons. Anesthesia of rats with ketamine/xylazine was not suited for single-unit recordings in the PC because of marked cardiovascular depression. Anesthesia with chloral hydrate allowed recording of spontaneous or glutamate-driven single-unit activity in approximately 40% of all animals. A similar percentage was obtained when recordings were done with the narcotic opioid fentanyl (plus gallamine), after all surgical preparations were performed under anesthesia with repeated administration of the barbiturate methohexital. To avoid brain accumulation of methohexital by repeated applications, we modified the anesthetic protocol in that methohexital was only injected once for initiation of surgical anesthesia, followed by the short-acting anesthetic propofol which does not accumulate upon repeated application. Again, after surgical preparation, electrophysiological recordings were done under fentanyl (plus gallamine). By this procedure, spontaneous or glutamate-driven single-unit activity could be measured in all rats in either layer II or III of the PC. Based on shape and frequency of action potentials, two types of neurons were recorded. The predominant type was similar in its firing characteristics to GABAergic neurons in other brain regions, was mainly located in layer III, and could be suppressed by the serotonin2A receptor antagonist MDL 100,907, suggesting that this type of PC neuron represents inhibitory, putative GABAergic interneurons. This new in vivo preparation may be useful for evaluation of PC neurons in kindled rats.

Action Potentials↗

PubMed1996

The anticonvulsant gabapentin decreases firing rates of substantia nigra pars reticulata neurons.

Gabapentin is a novel anti-epileptic drug which enhances GABA (gamma-aminobutyric acid) turnover in certain brain regions, including substantia nigra. However, the functional consequences of GABA turnover increases in response to gabapentin and their potential involvement in the anticonvulsant action of this drug are not known. In the present study, we examined the effects of gabapentin on the extracellular, single unit activity of nondopaminergic (presumably GABAergic) neurons of the substantia nigra pars reticulata in rats. During the recordings, the animals were infused with the narcotic opioid analgesic fentanyl, associated with a skeletal muscle relaxant and artificial ventilation. The spontaneous firing of substantia nigra pars reticulata neurons was determined up to about 2 h after i.v. or i.p. administration of gabapentin at doses of 15-30 mg/kg. After both routes of administration, gabapentin markedly reduced neuronal firing when administered at a dose of 20-30 mg/kg, while 15 mg/kg were ineffective in this regard. The suppressive effect of gabapentin was rapid in onset (2 min after i.v. and about 20 min after i.p. injection), reached peak values of about 70% below predrug baseline after about 45-60 min, and remained at this level for at least 2 h. Vehicle administration had no effect on substantia nigra pars reticulata neurons. The ability of gabapentin to alter substantia nigra pars reticulata firing does correlate with its known ability to increase nigral GABA turnover. Since a substantial body of evidence suggests that the substantia nigra pars reticulata is a critical site at which decrease of neuronal firing by potentiation of GABAergic influences results in protection against various seizure types, the suppressive effect of gabapentin on substantia nigra pars reticulata activity may contribute to the anticonvulsant action of this drug.

Acetates↗

PubMed1996

The novel antiepileptic drug levetiracetam (ucb L059) induces alterations in GABA metabolism and turnover in discrete areas of rat brain and reduces neuronal activity in substantia nigra pars reticulata.

Levetiracetam ((S)-alpha-2-oxo-pyrrolidine acetamide, ucb L059) is a novel anticonvulsant drug presently in clinical development. Its mechanism of action is unknown although a recently novel specific binding site for [3H]levetiracetam, unique to brain, may be involved. This binding site has yet been characterized, but some evidence suggested a possibly indirect interaction with the GABA system. We therefore examined levetiracetam's effects on GABA metabolism and turnover in several rat brain regions after systemic administration of anticonvulsant doses. Furthermore, in order to study functional effects of levetiracetam on a well defined system of GABAergic neurons in a brain region that has been critically involved in anticonvulsant drug action, we examined levetiracetam's action on spontaneous firing of substantia nigra pars reticulata (SNR) neurons in anesthetized rats. Although levetiracetam did not alter the activity of the GABA synthesizing and degrading enzymes glutamic acid decarboxylase (GAD) and GABA aminotransferase (GABA-T) in vitro, systemic administration induced significant alterations in these enzymes in several brain regions, indicating that these enzyme alterations were no direct drug effects but a consequence of postsynaptic changes in either GABAergic or other neurotransmitter-related systems. In the striatum, levetriacetam, 170 mg/kg i.p., induced a significant increase in GABA-T activity while GAD activity markedly decreased. When GABA turnover was estimated after inhibition of GABA-T by aminooxyacetic acid (AOAA), treatment with levetiracetam (given 15 min prior to injection of AOAA) significantly reduced GABA turnover in the striatum. Since the substantia nigra pars reticulata (SNR) receives a strong GABAergic input from the striatum, we examined if the alterations in GABA metabolism and turnover in the striatum led to functional alterations in neuronal activity in the SNR by recording single unit activity of SNR neurons after i.p. injection of levetiracetam. While injection of vehicle did not affect SNR neuronal activity, a significant decrease in spontaneous neuronal firing was recorded after levetiracetam. Since a substantial body of evidence suggests that the SNR is a critical site at which decrease of neuronal firing results in protection against various seizure types, the suppressive effect of levetiracetam on SNR activity may contribute to the anticonvulsant action of this drug.

4-Aminobutyrate Transaminase↗

PubMed1996

Effects of pentylenetetrazol on GABA receptors expressed in oocytes of Xenopus laevis: extra- and intracellular sites of action.

The convulsive agent pentylenetetrazol (PTZ) antagonized gamma-aminobutyric acid (GABA)-induced membrane currents on RNA-injected Xenopus oocytes with both extra- and intracellular applications. With extracellular administration PTZ enters the cell within a few minutes and reaches concentrations in the millimolar range. The permeability of the plasma membrane makes it possible for systemically applied PTZ to elicit its effect on the GABA-induced currents via extra- as well as intracellular sites of action.

Animals↗

PubMed1995

Effects of the epileptogenic agent strychnine on membrane currents elicited by agonists of the NMDA and non-NMDA receptors in Xenopus oocytes.

The effects of strychnine (STRY) on ion channels activated by N-methyl-D-aspartate (NMDA), kainate (KA), alpha-amino-3-hydroxy-5-methyl-4-isoxazolpropionate (AMPA) and quisqualate (QUIS) were studied using Xenopus oocytes, microinjected with mRNA from rats' brains. STRY reduced NMDA-, KA- and AMPA-induced membrane currents in a dose-dependent manner. The effect was more pronounced with NMDA than with KA and AMPA. QUIS-induced membrane currents were not affected by STRY. The depressive effect of STRY on NMDA responses was voltage dependent. The effect of STRY on the NMDA-induced membrane currents remains unchanged when the concentration of NMDA or glycine was increased. Intracellular injection of STRY did not alter the NMDA response.

Animals↗

PubMed1994

Decrease and increase of responses to glutamate receptor agonists in RNA-injected Xenopus oocytes by the epileptogenic agent pentylenetetrazol: dependence on the agonist concentration.

The effects of the epileptogenic agent pentylenetetrazol (PTZ) on current responses to glutamate (Glu) and to the Glu receptor agonist N-methyl-D-aspartate (NMDA), kainate (KA), alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) and quisqualate (QA) were studied on RNA-injected Xenopus oocytes. PTZ antagonized the reactions to Glu as well as to NMDA, KA, AMPA and QA. With increasing concentration of AMPA, however, the depressive effect of PTZ turned to an augmentation. The complete change from a decreasing to an increasing effect of PTZ with elevated agonist concentration was unique for current responses by AMPA.

Animals↗

PubMed1994

Effects of the epileptogenic agent bicuculline methiodide on membrane currents induced by N-methyl-D-aspartate and kainate (oocyte; Xenopus laevis).

The actions of bicuculline methiodide (BIC) on N-methyl-D-aspartate (NMDA)- and kainate (KA)-activated ion channels were studied using Xenopus oocytes, previously microinjected with RNA from rat brains. BIC reduced NMDA- and, with a lower efficiency, KA-induced membrane currents in a dose-dependent manner. The BIC effect on both agonist responses showed a voltage dependency with a lower grade of reduction at more positive holding potentials. By increasing the concentrations of the agonists, the reduction of the agonist-induced membrane currents by BIC was increased.

Animals↗