High-dose Baclofen Research Articles

THE EFFECT OF GABAB RECEPTOR ACTIVATION WITHIN THE VENTRAL TEGMENTAL AREA ON MORPHINE-INDUCED INCENTIVE SENSITIZATION IN FEMALE RATS

Repeated administration of morphine sensitizes animals to the stimulant and rewarding properties of the drug. It may also alter the expression and function of GABA receptors within the ventral tegmental area (VTA), a midbrain region that is implicated in morphine action. In the present study, the effect of activation of GABAB receptor subtypes within the VTA on morphine-induced incentive sensitization in female Wistar rats (250-300 g) was investigated. Female rats (n = 8) were chronically implanted with a 21-gauge cannula in the VTA (V = 8.5, L = 0.9, and A = -4.8 mm from bregma). One week after the surgery, the animals received morphine (5 mg/kg, s.c.) in their home cage for three consecutive days. Five days later, the animals were conditioned with an ineffective dose of morphine in a two compartment un-biased apparatus. Different doses of GABAB receptor agonist, baclofen (1.5, 6, and 12 ng/rat) were administered to the animals 5 min before the test. The results indicated that morphine administration to the animals in three consecutive days produces sensitization in which low doses of morphine (0.5 mg/kg, s.c.) induced CPP. Furthermore, administration of low doses of baclofen (1.5 and 6 ng/rat, i.VTA) enhanced, while higher doses of baclofen (12 ng/rat, i.VTA) reduced the morphine effects. The results indicated that activation of GABAB receptors within the VTA in morphine-sensitized animals produces a biphasic response, which may be due to pre and post GABAB receptor activation.

The GABA B receptor and recognition memory: possible modulation of its behavioral effects by the nitrergic system

Functional activation of the GABA B receptor inhibits learning and memory processes, though discrepant findings, in this context, have also been reported. The present study was designed to investigate the role of the GABA B receptor on recognition memory in the rat. For this purpose, the effects induced by the GABA B agonist baclofen and the GABA B antagonist p-(3-aminopropyl)- p-diethoxymethylphosphinic acid (CGP 35348) on memory were assessed by using the object-recognition task. In addition, the possible involvement of the nitrergic system on GABA B receptor’s effects was also evaluated by using the same behavioral procedure. This is a working-memory paradigm based on the differential exploration of a new and familiar object. In a first dose-response study, baclofen (0.5, 2, and 4 mg/kg, i.p.), dose-dependently impaired animals’ performance in this task, suggesting a modulation of acquisition and storage of information. CGP 35348 (100 and 300 mg/kg, i.p.), counteracted these baclofen-induced performance deficits. The nitric oxide donor molsidomine, at the dose of 4 but not 2 mg/kg, i.p, successfully antagonized the deficits on cognition induced by the highest dose of baclofen (4 mg/kg). These results indicate a) that the GABA B receptor is involved in recognition memory and b) that an NO component modulates the effects of the GABA B receptor on learning and memory.

Effects of intrathecal morphine, baclofen, clonidine and R-PIA on the acute allodynia-like behaviours after spinal cord ischaemia in rats

The present study assessed the efficacy and potency of intrathecal (i.t.) administration of the opiate morphine, the γ-aminobutyric acid-B (GABAB) receptor agonist baclofen, the α2-adrenoceptor agonist clonidine and the adenosine A1-receptor agonist R-phenylisopropyl-adenosine (R-PIA) on the acute allodynia-like behaviour after photochemically induced spinal cord injury (SCI) in rats. Rats displaying allodynia-like behaviours to brushing, von Frey hairs and cold stimulation 1–2 days after photochemically induced SCI were studied. In a cumulative dose regime, morphine (0.1–10 μ g), baclofen (0.1–1 μ g), clonidine (0.1–10 μ g) and R-PIA (0.01–10 nmol) were administered i.t. through an implanted catheter at the lumbar spinal cord. All tested drugs dose-dependently reduced the brushing, von Frey hairs and cold stimulation-induced allodynia-like behaviour. No increase in adverse effects such as motor deficits was found for morphine, clonidine and R-PIA. There was a slight increase in motor impairments at the highest dose of baclofen. For the mechanical allodynia, morphine appeared to be most effective, whereas baclofen, clonidine and R-PIA only provided a partial alleviation. For the cold allodynia, morphine and baclofen were more effective than clonidine and R-PIA. In relieving acute mechanical and cold allodynia-like behaviours in rats 1–2 days after SCI, i.t. morphine and baclofen were superior to clonidine and R-PIA.

Effects of baclofen on maintenance and reinstatement of intravenous cocaine self-administration in rats.

Recent studies suggest that the GABA(B) receptor agonist, baclofen, may be a useful pharmacotherapy for cocaine abuse. To investigate further the effects of baclofen on maintenance and reinstatement of cocaine-reinforced behavior in rats. Two groups of rats were trained to self-administer IV cocaine (0.2 or 0.4 mg/kg per infusion) during daily 7-h sessions under a fixed-ratio 1 schedule. Rats were pretreated with baclofen (1.25, 2.5 or 5 mg/kg IP) or saline before the session for 5 consecutive days. An additional group of rats was trained to self-administer IV cocaine (0.4 mg/kg per infusion) during the first 2 h of daily 7-h sessions. Cocaine was replaced by saline for the remaining 5 h of the session. Once behavior had stabilized over the 7-h period, priming injections of saline (IV), cocaine (3.2 mg/kg IV) or baclofen (1.25 or 2.5 mg/kg IP) were administered prior to hour 4. Injections of baclofen (1.25 or 2.5 mg/kg IP) or saline were also given before priming injections of cocaine. Pretreatment with the two higher doses of baclofen (2.5 and 5 mg/kg) decreased the number of cocaine infusions in both maintenance groups (0.2 and 0.4 mg/kg) over the 5-day treatment period. Baclofen had a greater suppressant effect on responding maintained by the lower dose of cocaine. Priming injections of baclofen (1.25 and 2.5 mg/kg) or saline did not reinstate responding. However, these same doses of baclofen dose-dependently reduced the reinstatement of responding produced by priming injections of cocaine. 1) The magnitude of the suppressant effects of baclofen on maintenance of cocaine self-administration depends upon the maintenance dose, 2) baclofen may be useful in preventing reinstatement of cocaine-seeking behavior, and 3) compared to maintenance, reinstatement of responding is more sensitive to the suppressant effects of baclofen.

Continuous intrathecal baclofen infusions induced a marked increase of the transcranially evoked silent period in a patient with generalized dystonia

We observed a marked prolongation of the transcranially evoked silent period during continuous intrathecal administration of high doses of the gamma-aminobutyric acid (GABA)B receptor agonist baclofen in a patient with generalized dystonia. Size of motor evoked potentials and central conduction time remained unchanged during intrathecal baclofen administration. The selective prolongation of the silent period during high-dose continuous intrathecal baclofen therapy supports the notion that GABAB-ergic intracortical interneurons play a part in the generation of the transcranially evoked silent period. © 1998 John Wiley & Sons, Inc. Muscle Nerve 21:1209–1212, 1998.

Continuous intrathecal baclofen infusions induced a marked increase of the transcranially evoked silent period in a patient with generalized dystonia

We observed a marked prolongation of the transcranially evoked silent period during continuous intrathecal administration of high doses of the gamma-aminobutyric acid (GABA)B receptor agonist baclofen in a patient with generalized dystonia. Size of motor evoked potentials and central conduction time remained unchanged during intrathecal baclofen administration. The selective prolongation of the silent period during high-dose continuous intrathecal baclofen therapy supports the notion that GABA(B)-ergic intracortical interneurons play a part in the generation of the transcranially evoked silent period.

Intrathecal methysergide antagonizes the antinociception, but not the hyperalgesia produced by microinjection of baclofen in the ventromedial medulla of the rat

Microinjection of baclofen, a γ-aminobutyric acid B (GABA B) receptor agonist, in the nucleus raphe magnus (NRM) or nucleus reticularis gigantocellularis pars α (NGCp α) of the rat produces antinociception at doses of 0.1–1.0 ng and hyperalgesia at doses of 30–150 ng in the tail-flick test. The antinociception is proposed to result from disinhibition of spinally-projecting neurons in this region that contain serotonin. The hyperalgesia is proposed to result either from inhibition of these neurons or from disinhibition of a serotonergic pain facilitatory pathway that also originates in this area of the ventromedial medulla. To determine the involvement of bulbospinal serotonergic pathways in the biphasic effects of baclofen, rats were pretreated intrathecally with either 30 μg of methysergide or saline. Ten minutes later, either saline, 0.5 ng or 150 ng of baclofen was microinjected in the NRM and NGCp α, and alterations in nociceptive threshold were assessed by the tail-flick and hot-plate tests. Intrathecal pretreatment with methysergide prevented the increase in tail-flick latency produced by 0.5 ng of baclofen, but did not prevent the decrease in tail-flick latency produced by 150 ng of baclofen. Neither dose of baclofen altered hot-plate latency and this lack of effect was unchanged by methysergide. These data support the idea that the antinociceptive effect of low doses of baclofen in the tail-flick test is mediated by disinhibition of a bulbospinal serotonergic projection and release of serotonin in the spinal cord. These data also suggest that the hyperalgesia produced by high doses of baclofen does not result from disinhibition of a serotonergic pain facilitatory pathway, but rather from direct inhibition of tonically-active pain inhibitory neurons in the NRM and NGCp α.

Sporadic stiffman syndrome in a young girl

A 14-month-old girl had experienced sudden episodes of breath-holding and spasms of the trunk and limb muscles, leading to cyanosis and loss of consciousness since 3 months of age. Her clinical features and electromyography suggested Stiffman syndrome, and her response to high-dose diazepam and baclofen confirmed the diagnosis. Stiffman syndrome is a rare entity, rarer still in childhood. This is the youngest case of sporadic Stiffman syndrome reported in literature. Distinguishing Stiffman syndrome from similar conditions such as Schwartz-Jampel syndrome or neuromyotonia is important because administration of GABAergic agents (valproate, baclofen, diazepam) elicits a good response.

Baclofen, a selective GABA B receptor agonist, dose-dependently impairs spatial learning in rats

The present investigation assessed the effects of the selective GABA B receptor agonist baclofen (1, 3, and 6 mg/kg) on spatial learning in the Morris water maze, an aversively motivated spatial learning task. Potential anxiolytic and sedative effects of baclofen were also assessed in an open field. Baclofen dose-dependently reduced locomotion in the open field but had little effect on thigmotaxia (anxiety). In the water maze, baclofen dose-dependently impaired spatial learning and reduced swim speed. During the probe trial given after training, only rats treated with the highest dose of baclofen (6 mg/kg) failed to show a bias for the correct quadrant. Following four additional retraining trials, a second drug-reversal probe trial was given and it was found that rats switched from saline to the highest dose of baclofen (6 mg/kg) showed a bias for the correct quadrant, as did rats switched from the two lowest doses of baclofen (1 and 3 mg/kg) to saline. Rats switched from the highest dose of baclofen (6 mg/kg) to saline failed to show a quadrant bias. Performance on a visible platform task was not impaired by baclofen at any dose. Together these results suggest that baclofen resembles GABA A agonists/positive modulators in that it impairs spatial learning, but not performance of a previously acquired escape response, but differs in that it does not reduce thigmotaxia (anxiety). Potential mechanisms by which baclofen impairs mnemonic processes are discussed.

Clinical and pharmacokinetic aspects of high dose oral baclofen therapy.

Baclofen is a centrally acting muscle relaxant used for treatment of spasticity. Some patients, to experience adequate symptomatic relief, require dosages of baclofen that significantly exceed the conventional 80 mg daily maximum advocated by the 1992 Physicians' Desk Reference. In this pilot study of baclofen kinetics and dynamics in eleven patients, the safety and efficacy of high dose baclofen was confirmed. The data suggest that the pharmacokinetics of high dose baclofen may vary from those described previously. Time-to-peak plasma levels and plasma half-lives were noted to be substantially longer than prior reports indicate. Baclofen blood levels were observed to rise gradually over time in some patients on a stable dosing regimen, probably a result of impaired renal clearance. These findings may indicate that a change in pattern of prescription is warranted and that a reliable and practical measurement of systemic baclofen levels has a useful role in clinical practice, particularly for the patient with neurogenic bladder and potential renal insufficiency.

A Case of Mania Associated with High-Dose Baclofen Therapy

A Case of Mania Associated with High-Dose Baclofen Therapy

High‐dose oral baclofen

We reviewed a 10% random sample of charts from an outpatient clinic for multiple sclerosis to determine the frequency with which baclofen was prescribed for spasticity in high doses (greater than 80 mg/d). About 20% of patients had taken high-dose baclofen, and 15% were still receiving a high dose. Taking a high dose was not associated with discontinuing treatment.

Effects of GABA Antagonists and Structural GABA Analogues on Baclofen Stimulated Gastric Acid Secretion in the Rat

The effects of GABA receptor antagonists (bicuculline and phaclofen) and structural GABA-analogues on baclofen stimulated gastric acid secretion were studied in standardized perfused rat stomach preparations. Pretreatment with bicuculline, a GABAA-receptor antagonist, in the doses of 1 and 3 mg/kg, subcutaneously, had no influence on the gastric acid response to baclofen. In addition, phaclofen, a GABAB antagonist, in the doses of 3 to 30 mg/kg, intravenously, was found to have no significant effect on the acid response to baclofen. However, GABA-analogues (MOPS and ABA; 10–30 mg/kg, i.v.) and lipophilic GABA derivatives structurally related to beta-amino acids (APPA and APHA; 30 mg/kg, i.v.) significantly counteracted the secretagogue action of baclofen. Further experiments on APPA action showed that the antisecretory effect of APPA could be overcome by higher doses of baclofen. APPA did not affect bethanechol stimulated acid secretion. These results suggest that the secretagogue action of baclofen is independent to GABAA- and GABAB-receptors and that APPA may interact with baclofen in regulation mechanisms of acid secretion, although further investigations are necessary to define the mode of action of APPA on the GABA-ergic system.

Effects of GABA antagonists and structural GABA analogues on baclofen stimulated gastric acid secretion in the rat.

The effects of GABA receptor antagonists (bicuculline and phaclofen) and structural GABA-analogues on baclofen stimulated gastric acid secretion were studied in standardized perfused rat stomach preparations. Pretreatment with bicuculline, a GABAA-receptor antagonist, in the doses of 1 and 3 mg/kg, subcutaneously, had no influence on the gastric acid response to baclofen. In addition, phaclofen, a GABAB antagonist, in the doses of 3 to 30 mg/kg, intravenously, was found to have no significant effect on the acid response to baclofen. However, GABA-analogues (MOPS and ABA; 10-30 mg/kg, i.v.) and lipophilic GABA derivatives structurally related to beta-amino acids (APPA and APHA; 30 mg/kg, i.v.) significantly counteracted the secretagogue action of baclofen. Further experiments on APPA action showed that the antisecretory effect of APPA could be overcome by higher doses of baclofen. APPA did not affect bethanechol stimulated acid secretion. These results suggest that the secretagogue action of baclofen is independent to GABAA- and GABAB-receptors and that APPA may interact with baclofen in regulation mechanisms of acid secretion, although further investigations are necessary to define the mode of action of APPA on the GABA-ergic system.

ラット胃粘膜に対するＧＡＢＡ誘導体（Ｂａｃｌｏｆｅｎ）の潰よう惹起作用

The ulcerogenic action of baclofen, a lipophilic derivative of GABA, was studied in the urethane anesthetized rat in relation to body temperature. Baclofen at the doses of 2, 4 and 8 mg/kg, s.c. induced gastric ulceration in a dose-dependent manner in the hypothermic (body temperature: 28-30 degrees C) rat. Duodenal ulcers were also observed in about 80% of the hypothermic animals treated with the highest dose of baclofen. Baclofen, even at 8 mg/kg, s.c., however, failed to induce gastric ulceration in the normothermic (body temperature: 37-38 degrees C) rat. Histamine, at the secretagogue dose causing acid secretion as potently as 8 mg/kg of baclofen, induced gastric ulcers in both the hypothermic and the normothermic rats. These results indicate that the ulcerogenic effect of baclofen is closely related to the thermoregulation mechanism and may provide important clues for clarifying the pathophysiology of gastroduodenal ulcers induced by hypothermic treatments such as water-immersion stress ulcers or cold exposure ulcers.

Higher doses of baclofen may be needed to relieve cerebral spasticity

Higher doses of baclofen may be needed to relieve cerebral spasticity

Inhibition of sexual reflexes by lumbosacral injection of a GABA B agonist in the male rat

The effects of gamma-aminobutyric acid (GABA) agonists on penile reflexes were investigated. An intrahecal injection of baclofen (0.2, 0.4, or 0.8 μg), a GABA B receptor agonist, into the subarachnoid space of the lumbosacral spinal cord (L5-S1), resulted in a dose-related decrease in the number of animals responding in a penile reflex test. Doses of 0.2 and 0.4 μg of baclofen decreased the number of erections; 0.4 μg also increased the latency to the first glans erection. The highest dose of baclofen (0.8 μg) completely inhibited penile responses in these tests. None of these doses, however, prevented rats from copulating to ejaculation. Antecedent ejaculation, which facilitated the onset of penile reflexes in saline controls, also blocked the inhibitory effects on penile responses by the lower doses (0.2 and 0.4 μg) of baclofen, but was ineffective in animals treated with 0.8 μg. In contrast to the inhibitory effects of baclofen in the lumbosacral cord, an intrathecal injection of baclofen (0.8 μg) at thoracic segments (T8–T10) did not affect penile erections elicited following an ejaculation. The role of spinal GABA A receptors in sexual reflexes was assessed by intrathecal injection of a GABA A agonist, THIP (0.5, 1, or μg), onto the lumbosacral cord. Only at the largest dose of THIP were slight inhibitory effects on penile reflexes observed. Together, these data indicate that stimulation of GABA B receptors in the lumbosacral spinal cord inhibits erectile mechanisms ex copula.

Biphasic dose-response effect of baclofen on haloperidol catalepsy in the rat

Haloperidol-induced catalepsy in rats is reduced by low dose baclofen and is potentiated by high dose baclofen. This biphasic behavioral effect is consistent with reported differences between presynaptic and postsynaptic GABA receptors. Low dose baclofen could have an anti-cholinergic effect by activating presynaptic GABA receptors that inhibit the release of acetylcholine. High dose baclofen could have an antidopamine effect by activating postsynaptic GABA receptors that inhibit the firing of dopamine neurons.

Neuropharmacology in the brain slice: Effects of substance P on neurons in the guinea-pig hypothalamus

1. Effects of substance P on neurons of the guinea-pig hypothalamus in vitro and antagonism between substance P and baclofen were investigated. 2. Substance P depolarized the membrane, increased the input resistance and increases the firing rate of neurons in the medium containing 0 mM Ca 2+ and 12 mM Mg 2+. 3. The excitatory action of substrate P was antagonized by a low dose of baclofen whereas that of acetylcholine and glutamate was not anatagonized even by much higher doses of baclofen.

Further support for the postsynaptic action of substance P and its blockade with baclofen in neurons of the guinea-pig hypothalamus in vitro.

Effects of substance P on neurons of the guinea-pig hypothalamus in vitro and antagonism between substance P and baclofen were investigated. Substance P increased the firing rate of neurons in the medium containing 0 mM Ca2+ and 12 mM Mg2+. The excitatory action of substance P was antagonized by a low dose of baclofen whereas that of acetylcholine was not antagonized even by much higher doses of baclofen.