大鼠不同脑区微量注射蝇蕈醇与氯苯氨丁酸镇痛作用比较

目的观察并比较GABAa受体激动剂蝇蕈醇及GABAb受体激动剂氯苯氨丁酸在大鼠不同脑区的镇痛作用。方法实验分侧脑室、室旁核和海马三组 ,每组又分成生理盐水对照组、蝇蕈醇组及氯苯氨丁酸组 ,分别经侧脑室、海马和室旁核”微量注射生理盐水或药物 ( 1× 1 0 - 3 mol·L- 1,1 μl) ,在大鼠甩尾测痛模型上”测定大鼠的痛阈。结果微量注射蝇蕈醇和氯苯氨丁酸在不同脑区均可不同程度地提高大鼠的痛阈 (与生理盐水对照组相比 ,P <0 .0 5或P <0 .0 1或P <0 .0 0 1 ) ,虽然蝇蕈醇与氯苯氨丁酸在侧脑室和室旁核的镇痛作用无显著性差异 (P >0 .0 5 ) ,但氯苯氨丁酸在海马的镇痛作用明显强于蝇蕈醇(P <0 .0 0 1 )。比较药物在不同脑区的镇痛作用发现 ,氯苯氨丁酸在海马和室旁核的镇痛作用无明显区别 ,但均强于侧脑室 ;而蝇蕈醇在室旁核最强 ,其次为海马、侧脑室。结论经侧脑室、海马或室旁核微量注射蝇蕈醇或氯苯氨丁酸均能降低大鼠对痛的感受性。氯苯氨丁酸在海马和室旁核可产生较强的镇痛作用 ,而蝇蕈醇在室旁核镇痛作用较明显 ,其次为海马     

Baclofen Pretreatment Attenuates the Suppressant Effect of Intraperitoneal Administration of Cholecystokinin (CCK) on Food Intake in Rats

The aim of this study was to investigate whether pretreatment with the GABAB receptor agonist baclofen could prevent the inhibitory effect of systemically administered cholecystokinin (CCK) on food intake in rats. Baclofen (2 mg/kg, SC) administered 60 min prior to IP injection of CCK (5 μg/kg) significantly attenuated the suppressant effect of the peptide on feeding in nondeprived rats (Experiment 1) and rats that had been deprived of food for 22 h (Experiment 2). Baclofen had no significant effects on food intake when administered alone. The results suggest that the inhibitory effect of exogenous peripheral CCK on food intake may be dependent on an interaction with a GABAB-receptor mediated mechanism. Copyright © 1996 Elsevier Science Inc.     

Age-Specific Effects of Baclofen on Pentylenetetrazol-Induced Seizures in Developing Rats

Summary: Purpose : To determine whether seizures have age-specific features, we studied the role of γ-aminobutyric acid, (GABAB) transmission in rats of various ages (9, 15, 30, and 60 postnatal days). Methods: We used a GABA, receptor agonist baclofen (2 or 5 mg/kg intraperitoneally, i.p.) and a GABA_B receptor antagonist CGP 35348 (100 or 600 mg/kg i.p.) in the pentylenetetrazol (PTZ)-induced model of clonic and tonic-clonic seizures (100 mg/kg subcutaneously, s.c.).
Results : Whereas baclofen was anticonvulsant and CGP 35348 proconvulsant in most animals, there were distinct age-related differences in the effectiveness of these drugs and the antagonist had some anticonvulsant activity in adults. Furthermore, the two drugs acting at GABA_B receptors had a different profile of action in clonic seizures as compared with tonic-clonic seizures.
Conclusions : The differences in the age-specific action of the GABA_B agonist and antagonist suggest that different GABA_B receptor subsets may mediate the drug effects. The results indicate that putative antiepileptic drugs (AEDs) must be tested during development because it may not be possible to extrapolate age-specific anticonvulsant effects from studies in adult animals.     

Potential involvement of a baclofen-sensitive autoreceptor in the modulation of the release of endogenous GABA from rat brain slices in vitro

Summary The effects of the GABA_A agonist, muscimol, and of the enantiomers of the GABA_B agonist, baclofen, on the release of endogenous GABA from slices of the rat cerebral cortex, striatum and hippocampus were measured by means of a HPLC method with electrochemical detection. Moreover, the effect of the GABA_A antagonist, bicuculline, and of the frequency of stimulation were studied in cortical slices. The amount of endogenous GABA released per impulse from cortical slices decreased by about 50% when the frequency was increased from 0.25 Hz to 1 Hz. This might indicate that GABA inhibited its own release. (–)-Baclofen at 1 and 10 M, but not its (+)-enantiomer, markedly inhibited the release of endogenous GABA, to a similar extent in all 3 areas investigated. The effect of (–)-baclofen was dependent on the frequency of stimulation: at lower frequencies (0.25 and 0.5 Hz) it was more marked than at a higher one (4 Hz). This would be expected from the results showing that the release of endogenous GABA decreases with increasing frequency, which suggests that this amino acid inhibits its own release. Muscimol at 10 M, on the other hand, was ineffective in all 3 areas at a stimulation frequency of 0.5 Hz. Bicuculline (10 M) at 4 Hz, at which autosuppression of GABA release is maximal did not enhance the release of endogenous GABA from cortical slices. With cerebellar or nigral slices, no adequate stimulation-induced release of endogenous GABA could be obtained under comparable conditions. These data are compatible with, but do not prove the existence of GABAB-type presynaptic autoreceptors modulating the release of this amino acid. More definite conclusions may possibly be drawn when a GABAB antagonist becomes available, which is expected to enhance GABA release under appropriate conditions.Presented in part at the 3rd Brit. Meeting on Electrochemical detection in Pharmacology and Neurochemistry, Cambridge, March 30–April 1, 1987Send offprint requests to P. C. Waldmeier     

Baclofen: reduction of presynaptic calcium influx in the cat spinal cord in vivo

 In the ventral horn of the lumbar spinal cord of cats anaesthetised with pentobarbitone sodium, microelectrophoretically administered (–)-baclofen, but not (+)-baclofen, reversibly reduced the duration of the orthodromic action potential of muscle group Ia afferent terminations, but not those of muscle group I afferent myelinated fibres. The presumably submicromolar concentrations are already known to reversibly reduce excitatory transmitter release from muscle group Ia afferent terminations. Action potential durations were estimated from threshold recovery curves after an orthodromic impulse using an extracellular microstimulation technique. Both of these presynaptic effects of (–)-baclofen were blocked by baclofen antagonists, and neither appeared to be reduced by the potassium channel blocking agents tetraethylammonium and 4-aminopyridine. Tetraethylammonium and 4-aminopyridine also did not significantly modify the reduction by (–)-baclofen of monosynaptic field potentials in the lumbar cord of rats anaesthetised with pentobarbitone sodium. In the cat the maximum reduction by (–)-baclofen of termination action potentials was considerably less than that produced by cadmium ions, which, unlike (–)-baclofen, also reduced the action potential duration of group I myelinated fibres. These findings are consistent with a reduction by (–)-baclofen of the influx of calcium through voltage-activated channels in the membrane of group Ia terminations, a proposal which also accounts for the reduction by (–)-baclofen of the release of GABA at axo-axonic depolarizing synapses on these terminations. The results are discussed in relation to the mode of action of (–)-baclofen and the different sensitivities of transmitter release at various central synapses. Received: 30 May 1996 / Accepted: 11 September 1996     

A pharmacological study of group I muscle afferent terminals and synaptic excitation in the intermediate nucleus and Clarke's column of the cat spinal cord

Summary When administered microelectrophoretically GABA and piperidine-4-sulphonic acid depolarized the central terminations of muscle group Ia and Ib afferent fibres in the lumbar intermediate nucleus and Clarke's column of cats anaesthetised with pentobarbitone sodium. Both this depolarization, and primary afferent depolarization, generated by impulses in other primary afferent fibres which produce prolonged bicuculline-sensitive inhibition of the firing of group I afferent fibre-excited interneurones in the intermediate nucleus and cells in Clarke's column, are reduced by microelectrophoretic bicuculline methochloride. Systemically administered (±)-baclofen hydrochloride (maximum dose 8 mg kg^–1) depressed the monosynaptic excitation of Clarke's column neurones by impulses in muscle and cutaneous afferent fibres. Microelectrophoretically administered (–)-baclofen reduced the bicuculline-sensitive primary afferent depolarization of group I terminations without, however, reducing the depolarizing action of GABA or piperidine-4-sulphonic acid. The depression by (–)-baclofen of the group I monosynaptic excitation of intermediate nucleus neurones is not reduced by concentrations of bicuculline methochloride adequate to suppress prolonged inhibition of these neurones     

The effects of compounds related to γ-aminobutyrate and benzodiazepine receptors on behavioural responses to anxiogenic stimuli in the rat: Punished barpressing

Rats were trained to press a bar for sucrose reward on a random-interval (RI) schedule and footshock punishment was then introduced for 3-min intrusion periods (signalled by a tone) on an independent RI schedule. Shock intensity was individually adjusted to produce stable intermediate levels of response suppression during the tone for each animal. Groups of animals were then allocated to a number of separate experiments in which they were systemically injected with anxiolytics (chlordiazepoxide HCl or sodium amylobarbitone), GABA antagonists (picrotoxin or bicuculline), the GABA_A agonist muscimol, the GABA_B agonist baclofen, an antagonist (RO 15-1788) at the benzodiazepine receptor and, an inverse agonist (FG 7142) at this receptor. The results showed that the alleviation of punishment-induced suppression of barpressing produced by chlordiazepoxide was blocked or partially blocked by RO 15-1788, picrotoxin and bicuculline but not by FG 7142; that picrotoxin (but not FG 7142) increased the suppression of responding by punishment; that neither muscimol nor baclofen affected responding on their own, but their combination weakly but reliably released punished responding from suppression; and that the anti-punishment effect of amylobarbitone was unaffected by either picrotoxin or bicuculline, though the barbiturate reversed the punishment-enhancing effect of picrotoxin. These results are discussed in the light of the hypothesis that anxiolytic behavioural effects are due to increased GABAergic inhibition.     

Desensitization to substance P following intrathecal injection

Summary The intrathecal injection of substance P (SP) (2.5–15 g) has been shown to produce hyperalgesia in the rat tail flick test. Repeated injection of SP (7.5 or 15 g) or pretreatment with two of these doses produces desensitization to this hyperalgesic response. Desensitization is doserelated with respect to degree and duration. This phenomenon is relatively specific because the hyperalgesic response to methysergide, a serotonin receptor antagonist, is unaffected, while that produced by phentolamine, an adrenergic receptor antagonist, is much less affected than that of SP. Pretreatment with a desensitizing regimen of SP potentiates the antinociceptive effect of morphine and baclofen when they are tested immediately after the regimen but if a 30 min delay is permitted, an inhibition of their effects is observed. These results support the notion that the spinal antinociceptive effect of morphine and baclofen is due to an interaction with SP mechanisms in the spinal cord, the nature of which may be more complex than is presently understood. Desensitization produces no change in baseline responsiveness in the tail flick test. This suggests that the hyperalgesic response to SP is due either to an action at a site other than the primary afferent synapse, or if it is at this site either compensatory mechanisms occur or SP is not the primary determinant of tail flick latency but may play a modulatory role.     

Interactions between naloxone and GABA in the control of locomotor activity in the rat

Summary It was found that naloxone causes a small but significant reduction of motility. The GABA_B agonist baclofen and the GABA transaminase inhibitor-acetylenic GABA (GAG) also reduced locomotor activity. When a subeffective dose of baclofen was combined with naloxone 0.8 or 3.2 mg/kg, baclofen significantly inhibited motility beyond the inhibition caused by naloxone + saline. GAG, in a dose of 12.5 mg/kg, was also potentiated by naloxone, 3.2 mg/kg. The locomotion reducing effects of naloxone could be blocked by either picrotoxin or bicuculline. It is concluded that GABAergic mechanisms participate in the inhibition of locomotor activity provoked by naloxone. The possibility that this drug disinhibits GABAergic neurons is discussed.     

电针加强海马微量注射蝇蕈碱与氯苯氨丁酸的镇痛作用

目的观察电针对大鼠海马微量注射GABA受体激动剂蝇蕈碱（Mus）和氯苯氨丁酸(Bac)镇痛作用的影响。方法实验分生理盐水对照组、药物组和电针+药物组,在2分钟内将1μlMus或Bac（1×10-3mol.L-1）注射入海马,取双侧足三里进行电针,用甩尾法测定大鼠的痛阈。结果从给药后5min至60min,Mus或Bac均能明显提高大鼠的痛阈（P＜0.01）,20min时作用最显著,痛阈分别提高0.386±0.062mA和0.549±0.116mA。电针能加强Mus和Bac的镇痛作用（P＜0.05或P＜0.01）,痛阈最大提高值分别为0.603±0.117mA和0.704±0.099mA。结论海马微量注射Mus或Bac能产生镇痛作用,并且电针能加强其镇痛作用。