We studied the effects of GABA receptor agonists microinjections in medullary raphé on the mechanically induced tracheobronchial cough response in anesthetized, unparalyzed, spontaneously breathing cats. The results suggest that GABA-ergic inhibition significantly contributes to the regulation of cough reflex by action of both GABA(A) and GABA(B) receptors. The data are consistent with inhomogeneous occurrence of GABA-ergic neurons in medullary raphé and their different involvement in the cough reflex control. Cells within rostral nucleus raphéobscurus with dominant role of GABA(A) receptors and neurons of rostral nucleus raphépallidus and caudal nucleus raphémagnus with dominant role of GABA(B) receptors participate in regulation of cough expiratory efforts. These cough control elements are distinct from cough gating mechanism. GABA-ergic inhibition in the raphé caudal to obex had insignificant effect on cough. Contradictory findings for GABA, muscimol and baclofen administration in medullary raphé suggest involvement of coordinated activity of GABA on multiple receptors affecting raphé neurons and/or the local neuronal circuits in the raphé modulating cough motor drive.

• MeSH
• agonisté receptorů GABA-A farmakologie   terapeutické užití   MeSH
• agonisté receptorů GABA-B farmakologie   terapeutické užití   MeSH
• baklofen farmakologie   terapeutické užití   MeSH
• kašel farmakoterapie   patofyziologie   MeSH
• kočky MeSH
• medulla oblongata účinky léků   fyziologie   MeSH
• muscimol farmakologie   terapeutické užití   MeSH
• nuclei raphe účinky léků   fyziologie   MeSH
• receptory GABA-A fyziologie   MeSH
• receptory GABA-B fyziologie   MeSH
• reflex účinky léků   fyziologie   MeSH
• zvířata MeSH
• Check Tag
• kočky MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

Activation of GABA(B) receptors leads to longer inhibitory postsynaptic potentials than activation of GABA(A) receptors. Therefore GABA(B) receptors may be a target for anticonvulsant therapy. The present study examined possible effects of GABA(B) receptor agonist SKF97541 on cortical and hippocampal epileptic afterdischarges (ADs). Epileptic ADs elicited by electrical stimulation of sensorimotor cortex or dorsal hippocampus were studied in adult male Wistar rats. Stimulation series were applied 6 times with 10- or 20-min interval. Either interval was efficient for reliable elicitation of cortical ADs but stimulation at 10-min intervals did not reliably elicit hippocampal ADs, many stimulations were without effect. SKF97541 in dose 1 mg/kg significantly prolonged cortical ADs. Duration of hippocampal ADs was not significantly changed by either dose of SKF97541 in spite of a marked myorelaxant effect of the higher dose. Our present data demonstrated that neither cortical nor hippocampal ADs in adult rats were suppressed by GABA(B) receptor agonist SKF97541. Proconvulsant effect on cortical ADs indicates a different role in these two brain structures. In addition, duration of refractory period for electrically-induced ADs in these two structures in adult rats is different.

• MeSH
• agonisté receptorů GABA-B farmakologie   MeSH
• elektroencefalografie účinky léků   MeSH
• epilepsie patofyziologie   MeSH
• hipokampus patofyziologie   MeSH
• krysa rodu rattus MeSH
• mozková kůra patofyziologie   MeSH
• organofosforové sloučeniny farmakologie   MeSH
• potkani Wistar MeSH
• pyramidové buňky účinky léků   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

OBJECTIVE: The cutaneous silent period (SP) is a spinal inhibitory reflex, which suppresses activity in spinal motor nuclei. Transcranial magnetic stimulation (TMS) elicits a cortical SP, which represents GABA(B) receptor-mediated inhibition of cortical excitability. Baclofen as a strong GABA(B) agonist effectively reduces muscle hypertonia, however, it is not known whether intrathecal baclofen (ITB) may modulate spinal inhibitory circuits. METHODS: We evaluated clinical and neurophysiological effects of ITB in ten patients with severe spasticity due to spinal cord injury (n = 9) and chronic progressive multiple sclerosis (n = 1). Neurophysiological assessment included H reflex and cutaneous and cortical SPs, before and 15, 30, 60, 90, 120, and 180 min after ITB bolus administration. RESULTS: ITB suppressed soleus H reflex as early as 15 min after lumbar bolus injection; MAS scores declined after 1 h. Cortical SP end latency and duration increased progressively with a significant maximum 3h following ITB bolus, whereas cutaneous SP latency and duration did not change significantly. CONCLUSION: The present findings suggest that baclofen does not affect the cutaneous SP, but prolongs the cortical SP. SIGNIFICANCE: The spinal inhibitory circuitry of the cutaneous SP is not modulated by GABA(B) receptor-mediated activity, in contrast to the cortical inhibitory circuitry of the cortical SP, which is subject to powerful GABA(B) control.

• MeSH
• agonisté receptorů GABA-B aplikace a dávkování   farmakologie   MeSH
• baklofen aplikace a dávkování   farmakologie   MeSH
• časové faktory MeSH
• dospělí MeSH
• H-reflex účinky léků   fyziologie   MeSH
• kosterní svaly inervace   MeSH
• lidé středního věku MeSH
• lidé MeSH
• míšní nervy účinky léků   patofyziologie   MeSH
• mozková kůra účinky léků   patofyziologie   MeSH
• poranění páteře komplikace   MeSH
• reakční čas účinky léků   fyziologie   MeSH
• reflex účinky léků   fyziologie   MeSH
• roztroušená skleróza komplikace   MeSH
• spinální injekce MeSH
• svalová spasticita etiologie   patofyziologie   MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• klinické zkoušky MeSH
• práce podpořená grantem MeSH
• srovnávací studie MeSH

Our data indicate the significant intrinsic efficacy of GABA(B)-receptors in rat brain cortex already at birth (PD1, PD2). Subsequently, baclofen- and SKF97541-stimulated G-protein activity, measured by agonist-stimulated, high-affinity [(35)S]GTPgammaS binding assay, was increased; the highest level of both baclofen and SKF97541-stimulated [(35)S]GTPgammaS binding was detected between PD10 and PD15. In older rats, baclofen- and SKF97541-stimulated [(35)S]GTPgammaS binding was continuously decreased so, that the level in adult, 90-days old animals, was not different from that in newborn animals. The potency of G-protein response to baclofen (characterized by EC(50) values) was also high at birth but unchanged by further postnatal development. An individual variance among different agonists was observed in this respect as the potency of SKF97541 response was decreased between the birth and adulthood. Accordingly, the highest plasma membrane density of GABA(B)-R, determined by saturation binding assay with antagonist [(3)H]CGP54626, was measured in 1-day old animals (2.27+/-0.08 pmol · mg(-1)). The further development was reflected in a decrease of [(3)H]CGP54626 binding as the B(max) values of 1.38+/-0.05 and 0.93+/-0.04 pmol · mg(-1) were determined in PM isolated from 13- and 90-days old rats, respectively.

• MeSH
• agonisté receptorů GABA-B farmakologie   MeSH
• baklofen farmakologie   MeSH
• buněčná membrána účinky léků   metabolismus   MeSH
• časové faktory MeSH
• krysa rodu rattus MeSH
• mozková kůra růst a vývoj   metabolismus   MeSH
• novorozená zvířata MeSH
• organofosforové sloučeniny farmakologie   MeSH
• receptory GABA-B metabolismus   MeSH
• signální transdukce * MeSH
• vazebná místa MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

GABA(B) receptors mediate inhibition at early stages of development but mixed anti-and proconvulsant action of their agonists affecting all receptors was found in immature rats. Positive allosteric modulators of GABA(B) receptors potentiate only already active GABA(B) receptors and therefore more specific action is expected. Possible anticonvulsant action of CGP7930 was studied in a model of pentetrazol-induced seizures previously used for studies with agonists baclofen and SKF97541. Pentetrazol (100mg/kg) was administered subcutaneously in male rats 7, 12, 18, 25 and 90 days old pretreated with CGP7930 in doses 1-40 mg/kg i.p. High doses of CGP7930 suppressed generalized tonic-clonic seizures in all five age groups. Animals 18 and less days old exhibited a specific suppression of the tonic phase after lower doses of CGP7930. Twelve-day-old rats were the most sensitive to anticonvulsant effect of CGP7930 (even the 2-mg/kg dose suppressed the tonic phase whereas 20-mg/kg dose was active in other age groups). Minimal clonic seizures (mS) were moderately potentiated by low doses of CGP7930 in 18-day-old but suppressed by the highest dose in 25-day-old rats. The 60-mg/kg dose of PTZ induced only mS in 4 out of 9 25-day-old rats; the 40-mg/kg dose of CGP7930 combined with this lower dose of PTZ resulted in the only proconvulsant effect--generalized tonic-clonic seizures appeared in two rats. Results from 12-day-old rats suggest a possibility to find an age-specific anticonvulsant among positive allosteric modulators of GABA(B) receptors.

• MeSH
• agonisté receptorů GABA-B farmakologie   terapeutické užití   MeSH
• antikonvulziva farmakologie   terapeutické užití   MeSH
• fenoly farmakologie   terapeutické užití   MeSH
• injekce subkutánní MeSH
• krysa rodu rattus MeSH
• pentylentetrazol toxicita   MeSH
• potkani Wistar MeSH
• receptory GABA-B fyziologie   MeSH
• věkové faktory MeSH
• záchvaty chemicky indukované   patofyziologie   prevence a kontrola   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

• Klíčová slova
• epileptický záchvat,
• MeSH
• agonisté receptorů GABA-B aplikace a dávkování   farmakologie   MeSH
• elektrická stimulace přístrojové vybavení   škodlivé účinky   MeSH
• epilepsie komplexní parciální farmakoterapie   MeSH
• hipokampus patofyziologie   MeSH
• modely u zvířat MeSH
• organofosforové sloučeniny aplikace a dávkování   farmakologie   MeSH
• potkani Wistar MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• zvířata MeSH