Antinociception produced by systemic R(+)-baclofen hydrochloride is attenuated by CGP 35348 administered to the spinal cord or ventromedial medulla of rats

This study examined the sites in the central nervous system at which subcutaneously-administered R(+) - baclofen hydrochloride (baclofen), the most active isomer of this prototypic γ-aminobutyric acid (GABAB receptor agonist, acts to produce antinociception in the rat. To determine whether baclofen acts in the spinal cord, either saline or the GABAB receptor antagonist CGP 35348 was injected intrathecally in rats pretreated 24 min earlier with 1 or 3 mg/kg s.c. baclofen. Intrathecal (i.t.) injection of 3 or 10 μg of CGP 35348 antagonized the increase in tail-flick and hot-plate latency produced by either dose of baclofen. To determine whether baclofen acts at sites in the ventromedial medulla (VMM), either saline or CGP 35348 was microinjected in the nucleus raphe magnus or nucleus reticularis gigantocellularis pars a of rats pretreated 24 min earlier with 1 or 3 mg/kg s.c. baclofen. Microinjection of 0.5 or 3 μg of CGP 35348 at sites in the VMM produced at best only a very modest attenuation of the antinociceptive effects of baclofen. These data suggest that systemically-administered baclofen acts at sites in both the spinal cord and the VMM, but that its antinociceptive effects are likely to be mediated to a greater extent by a spinal, rather than medullary site of action. However, a definitive comparison of the relative contribution of GABAB receptors in these two regions is precluded by differences in the diffusion and concentrations of the antagonist in the spinal cord and brainstem. Finally, microinjection of 0.5 or 3.0 μg of CGP 35348 in the nucleus raphe magnus or nucleus reticularis gigantocellularis pars a of saline-pretreated rats did not alter tail-flick or hot-plate latency. This finding suggests that, unlike GABA_A receptors, GABAB receptors do not mediate the tonic GABAergic input to neurons in these nuclei.     

Spinal interneurons play a minor role in generating ongoing renal sympathetic nerve activity in spinally intact rats

The purpose of the present study was to determine whether spinal interneurons play a role in the regulation of sympathetic activity in spinally intact rats. In acutely spinally transected rats, we have described a population of spinal interneurons that, by virtue of correlations between their ongoing firing rates and the magnitude of ongoing renal sympathetic nerve activity (RSNA), are candidates for generators of sympathetic activity. Further evidence for a sympathetic role for these neurons comes from our observation that cervical spinal stimulation that reduces RSNA also reduces their discharge rates. In chloralose-anesthetized, spinally intact and spinally transected rats, we recorded ongoing RSNA and the ongoing activities of T₁₀ dorsal horn and intermediate zone interneurons, and we determined the incidence of sympathetically related neurons in these rats by cross-correlating their activities with RSNA. The incidence of correlated neurons was much smaller in spinally intact than in spinally transected rats. We stimulated the dorsolateral, C_2–3 spinal cord before and after acute C₁ spinal transection. Dorsolateral cervical stimulation in spinally transected rats reduced both RSNA and the activities of most T₁₀ interneurons, but stimulation in spinally intact rats increased RSNA while still reducing the activities of most T₁₀ interneurons. Both the low incidence of sympathetically correlated spinal neurons in intact rats and the dissociation between the effects of cervical stimulation on RSNA and the discharge rates of spinal interneurons argue against these neurons playing a major role in regulating sympathetic activity in intact rats.     

Actions of (-)-baclofen on rat dorsal horn neurons.

The actions of a gamma-aminobutyric acid B (GABAB) agonist, (-)-baclofen, on the electrophysiological properties of neurons and synaptic transmission in the spinal dorsal horn (laminae I-IV) were examined by using intracellular recordings in spinal cord slice from young rats. In addition, the effects of baclofen on the dorsal root stimulation-evoked outflow of glutamate and aspartate from the spinal dorsal horn were examined by using high performance liquid chromatography (HPLC) with flourimetric detection. Superfusion of baclofen (5 nM to 10 microM) hyperpolarized, in a stereoselective and bicuculline-insensitive manner, the majority (86%) of tested neurons. The hyperpolarization was associated with a decrease in membrane resistance and persisted in a nominally zero-Ca2+, 10 mM Mg(2+)- or a TTX-containing solution. Our findings indicate that the hyperpolarizing effect of baclofen is probably due to an increase in conductance to potassium ions. Baclofen decreased the direct excitability of dorsal horn neurons, enhanced accommodation of spike discharge, and reduced the duration of Ca(2+)-dependent action potentials. Baclofen depressed, or blocked, excitatory postsynaptic potentials evoked by electrical stimulation of the dorsal roots. Spontaneously occurring synaptic potentials were also reversibly depressed by baclofen. Whereas baclofen did not produce any consistent change in the rate of the basal outflow of glutamate and aspartate, the stimulation-evoked release of the amino acids was blocked. The present results suggest that baclofen, by activating GABAB receptors, may modulate spinal afferent processing in the superficial dorsal horn by at least two mechanisms: (1) baclofen depresses excitatory synaptic transmission primarily by a presynaptic mechanism involving a decrease in the release of excitatory amino acids, and (2) at higher concentrations, the hyperpolarization and increased membrane conductance may contribute to the depressant effect of baclofen on excitatory synaptic transmission in the rat spinal dorsal horn.     

The analgesic effects of the GABAB receptor agonist,baclofen, in a rodent model of functional dyspepsia

Background The amino acid γ‐aminobutyric acid (GABA) is an important modulator of pain but its role in visceral pain syndromes is just beginning to be studied. Our aims were to investigate the effect and mechanism of action of the GABA_B receptor agonist, baclofen, on gastric hypersensitivity in a validated rat model of functional dyspepsia (FD). Methods 10‐day‐old male rats received 0.2 mL of 0.1% iodoacetamide in 2% sucrose daily by oral gavages for 6 days. Control group received 2% sucrose. At 8–10 weeks rats treated with baclofen (0.3, 1, and 3 mg kg^?1 bw) or saline were tested for behavioral and electromyographic (EMG) visceromotor responses; gastric spinal afferent nerve activity to graded gastric distention and Fos protein expression in dorsal horn of spinal cord segments T8–T10 to noxious gastric distention. Key Results Baclofen administration was associated with a significant attenuation of the behavioral and EMG responses (at 1 and 3 mg kg^?1) and expression of Fos in T8 and T9 segments in neonatal iodoacetamide sensitized rats. However, baclofen administration did not significantly affect splanchnic nerve activity to gastric distention. Baclofen (3mg kg^?1) also significantly reduced the expression of spinal Fos in response to gastric distention in control rats to a lesser extent than sensitized rats. Conclusions & Inferences Baclofen is effective in attenuating pain associated responses in an experimental model of FD and appears to act by central mechanisms. These results provide a basis for clinical trials of this drug in FD patients.     

Bicuculline-Induced Rhythmic EEG Episodes: Gender Differences and the Effects of Ethosuximide and Baclofen Treatment

Summary: Purpose: There are gender differences in the expression of seizures. We tested rhythmic EEG episodes induced by low doses of bicuculline in rats for gender differences. To verify the validity of these discharges as a model of absence seizures in both male and female rats, we tested the antiabsence drug ethosuximide (ESM) and a γ-aminobutyric acid (GABA_B)-receptor agonist, baclofen, which may exacerbate absence seizures. Methods: Adult rats of both sexes were used. Under general anesthesia, EEG electrodes were implanted over frontal and occipital cortex, and some females were ovariectomized. After recovery, male, intact female rats, and female rats ovariectomized and ovariectomized rats with estradiol replacement were compared for occurrence of rhythmic EEG episodes (～6 cycles/ s) induced by 2.5 mgkg of bicucullin?, s.c. Because of gender differences in sensitivity to bicuculline, further pharmacologic effects of ESM (125 and 250 mgkg, i.p.) and baclofen (2 mgkg, i.p.) were tested separately in male (3.0 mgkg of bicuculline), and female (2.5 mgkg of bicuculline) rats. Results: After the identical dose of bicuculline, s.c., male and female rats differed in the incidence of rhythmic episodes and in the latency to onset of the first as well as the generalized episode. Female rats with natural or exogenous estrogens (but not ovariectomized rats) developed EEG episodes more often than did males, and this effect could be attributed to the presence of estrogens. ESM pretreatment suppressed the episodes, whereas baclofen enhanced their occurrence, as well as the total duration of episodes without gender-specific differences. Conclusions: The study demonstrates gender differences (related probably to the presence of circulating estrogens) in the susceptibility of rats to develop rhythmic EEG episodes induced by threshold doses of bicuculline. This activity has some features of an acute absence seizure model.     

The antinociceptive action of an α2-adrenoceptor agonist in the spinal dorsal horn is due to a direct spinal action and not to activation of Descending Inhibition

In this electrophysiological study we tried to find out whether the spinal antinociceptive effect of a supraspinaly administered α₂-adrenoceptor agonist is due to a direct spinal effect or to activation of descending inhibition. The responses to wide-dynamic range (WDR) neurons of the spinal dorsal horn were studied following application of medetomidine, a selective α₂-adrenergic agonist, into the rostroventromedial medulla (RVM) or directly onto the spinal cord of the Intact and in spinal rats. The noxious electrical stimuli were applied to the ipsilateral receptive field in the plantar region of the hind paw, and responses mediated by A- and C-fibers to WDR neurons were separately evaluated. The reversal of medetomidine-induced effects was attempted by a systemic administration of atipamezole, a selective α₂-adronoceptor antagonist. Medetomldine injection into the RVM produced a dose-dependent, atipamezole-reversible attenuation of the C-fiber-mediated responses to WDR neurons of the spinal dorsal horn in both intact and spinal rats. Paradoxically, the spinal aMFnociceptive effect of supraspinally administered medstomidine was stronger in spinal rats. The A-fiber-mediated responses were significantly less attenuated by medetomidine than the C-fiber-mediated responses to the WDR neurons. Also a direct application of medetomidine onto the spinal cord produced a dose-dependent, atipamezole-reversible attenuation of the C-fiber-mediated responses, and this effect was identical in intact and in spinal rats. The medetomidins doses producing spinal antinociception were considerably lower with a direct spinal application than with a supraspinal application. These results indicate that spinal antinocicsption following spinal or supraspinal application of an α₂-adrenergic agonist is due to a direct activation of spinal α₂-adrenoceptors and not to descending inhibition. Activation of supraspinal α₂-adrenoceptors counteracts the spinal antinociceptive effect.     

Role of inhibitory mechanisms in trigeminal neuralgia

Segmental inhibition was elicited in the spinal trigeminal nucleus of cats by delivering a conditioning stimulus to the maxillary nerve 100 msec before the test stimulus. Carbamazepine, baclofen, and phenytoin markedly facilitated this segmental inhibition, as well as depressing the response to an unconditioned maxillary nerve stimulus. Phenobarbital, on the other hand, usually depressed the segmental inhibition. These results suggest that drugs that relieve trigeminal neuralgia both facilitate inhibitory mechanisms and depress excitatory mechanisms in the spinal trigeminal nucleus. The facilitation of inhibitory mechanisms appears to be at least as important as the depression of excitatory mechanisms and suggests that a failure of inhibitory mechanisms may play a significant role in the pathogenesis of trigeminal neuralgia.     

Effect of spinal cord injury and of intrathecal baclofen on brainstem reflexes

Reorganization of neural circuits within the central nervous system following injury appears to be a means of compensatory mechanism for loss of function. Reorganization following spinal cord injury is known to evoke changes at the cortical and spinal cord levels. Recent studies, however, provide evidence of enhanced brainstem reflexes and alterations in excitatory and inhibitory interneuronal brainstem circuits, suggesting that reorganization following spinal cord injury occurs also at the brainstem level. Reversal of these changes by continuous intrathecal baclofen infusion to normal levels or beyond indicates strong GABAergic involvement. Rapid changes in the blink reflex and its prepulse inhibition following intrathecal baclofen bolus application that parallel clinical changes in muscle hypertonia suggest a muscle tone regulating effect of baclofen at the brainstem level. Enhanced brainstem reflexes in spinal cord injury patients may be the consequence of decreased GABA-mediated inhibition and/or strengthening of facilitatory connections due to either direct or indirect plastic changes occurring at the brainstem level. Modulation of brainstem reflexes by baclofen may foster the understanding of pathophysiological mechanisms underlying diseases with increased brainstem activity. Rehabilitation after central nervous system injury will always be a challenge, but understanding the mechanisms of reorganization of undamaged neural pathways may help to develop better strategies for enhancing neuronal plasticity and for implementing neuronal reorganization into carefully planned therapy.     

Stimulation of spinal serotonergic receptors facilitates seminal emission and suppresses penile erectile reflexes

Penile erection and ejaculation are produced by spinal reflexes subject to tonic control from the brain. This study examines the possible involvement of serotonergic transmission in the supraspinal modulation of such reflexes. The effects of two drugs which facilitate serotonergic transmission by different mechanisms, namely the direct receptor agonist, 5-methoxy-N,N'-dimethyltryptamine (5-MeODMT), and the reuptake inhibitor, zimelidine, were compared in intact and spinal rats. Results show that serotonergic stimulation in intact rats by either drug produces a dose-related increase in the incidence of seminal emission as well as a definite decrease of the display of erectile responses. In the spinal animals 5-MeODMT treatment reproduced both effects. By contrast, zimelidine, which needs functional nerve endings to exert its agonistic action, was ineffective in the spinal rats. This is interpreted to exclude a peripheral mechanism for the effects of the serotonin agonists on penile reflexes of intact animals and makes a strong case for a spinal site of action. We postulate the existence of serotonergic receptors located in the lower segments of the spinal cord which, when stimulated, trigger seminal emission and suppress erection.     

Continuous Intrathecal Baclofen Infusion by a Programmable Pump in 131 Consecutive Patients with Severe Spasticity of Spinal Origin

We began this study to determine the efficacy and safety of intrathecal baclofen (ITB) delivered by a programmable pump for the treatment of severe spasticity of spinal cord origin. One hundred fifty two patients with severe spasticity of spinal origin, refractory to oral baclofen, or who experienced intolerable side‐effects were given a test dose of ITB. Only those who had a satisfactory response were considered to be appropriate for pump implantation. All but one of the 152 patients had a satisfactory response, and the pump was implanted in 131 patients. Pre‐ and postoperative spasticity scores were compared and analyzed. The mean Ashworth score for rigidity decreased from 4.2 preoperatively to 1.3 (p < 0.0005) on ITB. The spasm score decreased from a mean of 3.4 to 0.6 (p < 0.0005). Reduction of spasticity resulted in improved levels of physical activity, decreased pain, and augmentation of sleep. Drug‐related complications included constipation, muscular hypotonia, urinary retention, erectile dysfunction, nausea, dizziness, drowsiness, hypotension and bradycardia as well as tolerance to baclofen. Some patients experienced post‐spinal puncture headaches. Catheter‐related problems included occlusions, breaks, punctures, and dislodgments. Superficial pump pocket infection, pocket erosion, cerebrospinal fluid (CSF) leak, post‐spinal puncture headache, and meningitis were some of the procedure‐related complications. Two pumps flipped and another pump valve was stuck. We conclude that long‐term intrathecal baclofen by an implanted programmable pump is a safe and effective method of treating severe intractable spinal spasticity.     

Safety and Efficacy of Intrathecal Baclofen Infusion by Implantable Pump for the Treatment of Severe Spinal Spasticity: A Spanish Multicenter Study

Objective. To assess long‐term efficacy, safety and functional benefit of intrathecal baclofen for severe spinal spasticity. Materials and Methods. This prospective multicenter study was performed in two stages: the first one consisted of an intrathecal bolus injection of baclofen, and the second of a continuous intrathecal baclofen infusion by means of an implantable pump. The sample consisted of 72 adult patients with severe spinal spasticity. Sixty‐four were implanted and followed for 36 months. Muscular tone, spasms, and functional scales were evaluated before and periodically after administration of the drug, with a follow‐up period of 36 months. Results. A very significant decrease in tone and spasms was observed in all cases (p < 0.001). Tolerance appeared during the first 12 months, increasing doses from a mean initial dose of 83.2 μg (range 25–200 μg) to a mean final dose of 270 μg (range 25–800 μg). Later on, efficacy remained stable, except in cases of mechanical problems of the infusion system.     

Effects of baclofen on mechanical noxious and innocuous transmission in the spinal dorsal horn of the adult rat: in vivo patch‐clamp analysis

The effects of a GABA_B agonist, baclofen, on mechanical noxious and innocuous synaptic transmission in the substantia gelatinosa (SG) were investigated in adult rats with the in vivo patch‐clamp technique. Under current‐clamp conditions, perfusion with baclofen (10 μm ) on the surface of the spinal cord caused hyperpolarisation of SG neurons and a decrease in the number of action potentials elicited by pinch and touch stimuli applied to the receptive field of the ipsilateral hindlimb. The suppression of action potentials was preserved under blockade of postsynaptic G‐proteins, although baclofen‐induced hyperpolarisation was completely blocked. These findings suggest presynaptic effects of baclofen on the induced action potentials. Under voltage‐clamp conditions, application of baclofen reduced the frequency, but not the amplitude, of miniature excitatory postsynaptic currents (mEPSCs), whereas the GABA_B receptor antagonist CGP55845 increased the frequency of mEPSCs without affecting the amplitude. Furthermore, application of a GABA uptake inhibitor, nipecotic acid, decreased the frequency of mEPSCs; this effect was blocked by CGP55845, but not by the GABA_A antagonist bicuculline. Both the frequency and the amplitude of the pinch‐evoked barrage of excitatory postsynaptic currents (EPSCs) were suppressed by baclofen in a dose‐dependent manner. The frequency and amplitude of touch‐evoked EPSCs was also suppressed by baclofen, but the suppression was significantly smaller than that of pinch‐evoked EPSCs. We conclude that mechanical noxious transmission is presynaptically blocked through GABA_B receptors in the SG, and is more effectively suppressed than innocuous transmission, which may account for a part of the mechanism of the efficient analgesic effects of baclofen.     

Effects of GABAB receptor agonists and antagonists on the bulbar respiratory network in cat

We examined the involvement of the GABA_B receptor in central respiratory mechanisms. Respiratory neurons (RNs) from the ventral respiratory group in the medulla of the cat were subjected to iontophoretic applications of the GABA_B receptor agonist baclofen and the antagonists saclofen and CGP 35348.In all types of RNs baclofen decreased the firing rate. This reduction was antagonized by CGP 35348. Application of either antagonist increased the spontaneous discharge in both inspiratory and expiratory RNs. CGP 35348 excited 57% of the neurons tested, on the average by 34% with ejection currents of 100 nA. Saclofen excited 6 of 9 neurons tested. Baclofen administered systemically (8–12 mg/kg i.v.) to either anesthetized, decerebrate or intact freely moving cats, induced a selective lengthening of the inspiratory phase, an effect comparable to the apneusis induced by the NMDA antagonist MK-801. Baclofen also produced either a pronounced decrease in the amplitude of phrenic nerve discharge or an apnea, both of which were reversed by increasing paCO₂. The results suggest that endogenously released GABA acting on GABA_B receptors may be involved in the control of respiratory neuronal discharge.     

Differential effects of apomorphine on spinal reflex activity following 6-hydroxydopamine or long-term haloperidol pretreatment

Summary The thermal cutaneous evoked tail flick response was measured both before and after intrathecal injection of R-apomorphine in spinal rats and in rats with an intact neuraxis pretreated with either long-term haloperidol or intrathecal 6-hydroxydopamine. Intrathecal R-apomorphine produced a dose-dependent increase of tail flick latency in spinal rats but not in intact rats. Long-term haloperidol treatment increased the effect of R-apomorphine in spinal rats while 6-OHDA decreased it. The present findings provide further evidence for the modulatory role of spinal DA receptor populations on spinal reflex activity. Pretreatment with long-term haloperidol or 6-OHDA may alter the conformational status of spinal DA receptors in opposite directions and thereby change the responsiveness of receptors to R-apomorphine.     

Phaclofen antagonizes the depressant effect of baclofen on spinal reflex transmission in rats

The action of phaclofen, the phosphonic acid derivative of baclofen, on baclofen-induced suppression of spinal reflex transmission was tested in anaesthetized rats. Intrathecal (i.th.) injection of phaclofen, 100 nmol, antagonized the depressant effect of baclofen, 2 nmol, on spinal Hoffmann (H)-reflexes and polysynaptic flexor reflexes but ha on the action of muscimol, 20 nmol. The antagonistic effect of phaclofen on baclofen-induced depression of H-reflexes was dose-dependent in doses ranging from 1 to 100 nmol. When administered alone, phaclofen, 100 nmol, was devoid of stimulatory or depressant effects on spinal reflexes. These results indicate that phaclofen specifically antagonizes the reflex suppressant action of baclofen. The lack of intrinsic action of phaclofen suggests that there is no endogenous tonic inhibition mediated by GABAB receptors under the present experimental conditions.     

Effects ofp-chlorophenylalanine and a monoamine oxidase inhibitor on the 5-hydroxytryptamine in the spinal cord after transection

Summary Treatment with the monoamine oxidase inhibitor nialamide (500 mg/kg i.p., 2.5 and 5 h) produced in the caudal and cranial half of the spinal cord an increase in 5-hydroxytryptamine which was of the same magnitude in intact rats and in rats acutely spinalized midthoracically. Similar results were obtained after reserpine pretreatment. The nialamide-induced increase in 5-hydroxytryptamine caudal to a transection was slightly reduced after 2 days and completely inhibited after 3 weeks.Treatment with the tryptophan hydroxylase inhibitorp-chlorophenylalanine (319 mg/kg i.p., 24 h) or its methylester HCl (400 mg/kg i.p., 24 h) reduced the concentration of 5-hydroxytryptamine in the spinal cord by about 70 per cent in both halves of the intact cord and in the cranial half of the cut cord but by only about 30 per cent caudal to an acute transection. The nialamide-induced increase in 5-hydroxytryptamine of a transected spinal cord was inhibited to the same extent cranial and caudal to the lesion 24 h after treatment withp-chlorophenylalanine.In conclusion, the changes in 5-hydroxytryptamine concentrations induced byp-chlorophenylalanine are dependent on nerve impulses in contrast to those induced by nialamide. Thep-chlorophenylalanine does not have to be incorporated into newly synthesized tryptophan hydroxylase in order to inhibit the enzyme.     

Gabaergic mechanisms in antinociception

GABAergic mechanisms appear to be involved in antinociceptive processes. Generally, peripheral administration of GABAergic agents increases the antinociceptive effect of morphine, but central administration inhibits this effect, suggesting that multiple interactions may occur. GABAergic agents also can produce antinociception directly. Muscimol and THIP (GABA_A agonists) act at supraspinal sites to produce antinociception, but do not appear to interact with bicueulline sensitive receptors. Baclofen (a GABA_B agonist) acts at both supraspinal and spinal sites. Supraspinal mechanisms Include inhibition of ascending noradrenergic and dopaminergic pathways but activation of descending noradrenergic pathways. The spinal mechanism may involve postsynaptic inhibition of the effect of substance P. D-Baclofen is an antagonist at spinal baclofen receptors. Antinociception produced by inhibitors of GABA-transaminase is not reduced by bicuculline in most studies, while manipulations which increase the antinociceptive effect of baclofen do not alter or block the effect of GABA-transaminase inhibitors. An understanding of the role of GABA_A and GABA_B receptors in antinociception will require clarification of some curious pharmacological actions of bicuculline and the use of a specific GABA_B receptor antagonist.     

Inhibitory effect of intrathecal glycine on the micturition reflex in normal and spinal cord injury rats

We examined the influence of lumbosacral glycinergic neurons on the spinobulbospinal and spinal micturition reflexes. Female rats were divided into intact rats, rats with acute injury to the lower thoracic spinal cord (SCI), and rats with chronic SCI. Under urethane anesthesia, isovolumetric cystometry was performed in each group before and after intrathecal (IT) injection of glycine or strychnine into the lumbosacral cord level. The glutamate and glycine levels of the lumbosacral cord were measured after injection of glycine or strychnine in intact and chronic SCI rats. Expression of strychnine-sensitive glycine receptor alpha-1 (GlyR alpha1) mRNA in the lumbosacral cord was also assessed in both rats. In chronic SCI rats, the interval and amplitude of bladder contractions were shorter and smaller when compared with intact rats. IT glycine (0.1-100 microg) prolonged the interval and decreased the amplitude of bladder contractions in both intact rats and chronic SCI rats. IT strychnine (0.01-10 microg) elevated the baseline pressure in intact rats and induced bladder contraction in acute SCI rats. On amino acid analysis, IT glycine (0.01-100 microg) decreased the glutamate level of the lumbosacral cord in intact rats, but not in chronic SCI rats. The glycine level of the lumbosacral cord was 54% lower in chronic SCI rats when compared with intact rats, while the GlyR alpha1 mRNA level did not change after SCI. These results suggest that glycinergic neurons may have an important inhibitory effect on the spinobulbospinal and spinal micturition reflexes at the level of the lumbosacral cord.     

Baclofen infused in rat hippocampal formation impairs spatial learning

Recent studies show that baclofen, a selective GABA_B agonist, impairs different kinds of learning. In the present study we investigated the effect of microinfused baclofen into the hippocampus of male Wistar rats, on the performance in the Morris water maze. Rats of 8–10 weeks of age were implanted with cannulae aimed bilaterally at the hippocampal formation. Baclofen (1 μl of 0.2 mM, 2.0 mM, and 20.0 mM) or sterilized saline was microinfused 1 h before each daily session (3 trials/session, 1 session/day) for 4 days. On the fifth day, the animals did not receive drug or saline injections and the retention of the location of the escape platform was tested in a 30 s free swim trial. Results from the free swim trial indicate that the doses of baclofen used during training affected the ability of the rats to swim to the target quadrant. Although no significant difference compared with the saline group was observed, the experimental rats showed a more generalized swim trajectory in the area of the target and both adjacent quadrants. Moreover, 1μl of 20.0 mM baclofen also impaired the acquisition. We suggest that baclofen has an impairing action on spatial learning, although more studies should be conducted to reach a more precise conclusion. Hippocampus 1998;8:109–113. © 1998 Wiley-Liss, Inc.     

Biphasic effects of systemically administered GABA antagonists on Cardiac vagal activity

Systemic administration of the GABA antagonist picrotoxin 6.0 mg/kg i.v. elicited hypertension and a fall in sinus rate wita return to baseline levels in intact rats. Antagonists of GABA act in the supraspinal CNS to augment sympathetic outflow to the heart and vasculature. Therefore, in this study the spinal cord was transected prior to drug administration in order to eliminate sympathetically mediated effects. In spinal rats, picrotoxin 6.0 mg/kg evoked a biphasic sinus rate response characterized by an initial decrease followed by an increase above baseline sinus rate. Bilateral vagotomy or atropine pretreatment blocked sinus rate changes elicited by picrotoxin, demonstrating that these effects were vagally mediated. Midcollicular decerebration altered the biphasic sinus rate response by preventing the late rise but not the initial decrease in sinus rate. Infusion of another GABA antagonist, bicuculline, elicited a similar biphasic sinus rate response, althougthe time-course was shorter. Unexpectedly, picrotoxin or bicuculline administration in spinal rats caused an increase in mean blood pressure whicwas prevented by decerebration and different from that observed in intact rats witrespect to time course. In spinal rats pretreatment wita vasopressin antagonist,d(CH₂)₅Tyr(Me)AVP, blocked the pressor response induced by picrotoxin infusion without altering the biphasic changes in sinus rate. These results suggest that, in the rat: (1) two GABAergic inhibitory mechanisms at different levels of the neuraxis exert opposite effects on cardiac vagal activity; and (2) GABA antagonists may elevate arterial pressure by a mechanism distinct from their previously described sympathoexcitatiry effects.