Modulation of tonic immobility by GABAA and GABAB receptors of the medial amygdala.

Tonic immobility (TI) is a temporary state of profound motor inhibition associated with great danger as the attack of a predator. Previous studies carried out in our laboratory evidenced high Fos-IR in the posteroventral region of the medial nucleus of the amygdala (MEA) after induction of the TI response. Here, we investigated the effects of GABAA and GABAB of the MEA on TI duration. Intra-MEA injections of the GABAA agonist muscimol and GABAB agonist baclofen reduced TI response, while intra-MEA injections of the GABAA antagonist bicuculline and GABAB antagonist phaclofen increased the TI response. Moreover, the effects observed with muscimol and baclofen administrations into MEA were blocked by pretreatment with bicuculline and phaclofen (at ineffective doses per se). Finally, the activation of GABAA and GABAB receptors in the MEA did not alter the spontaneous motor activity in the open field test. These data support the role of the GABAergic system of the MEA in the modulation of innate fear.

Inhibition of Transient Receptor Potential Melastatin 3 ion channels by G-protein ßγ subunits.

Transient receptor potential melastatin 3 (TRPM3) channels are activated by heat, and chemical ligands such as pregnenolone sulphate (PregS) and CIM0216. Here, we show that activation of receptors coupled to heterotrimeric Gi/o proteins inhibits TRPM3 channels. This inhibition was alleviated by co-expression of proteins that bind the ßγ subunits of heterotrimeric G-proteins (Gßγ). Co-expression of Gßγ, but not constitutively active Gαi or Gαo, inhibited TRPM3 currents. TRPM3 co-immunoprecipitated with Gß, and purified Gßγ proteins applied to excised inside-out patches inhibited TRPM3 currents, indicating a direct effect. Baclofen and somatostatin, agonists of Gi-coupled receptors, inhibited Ca2+ signals induced by PregS and CIM0216 in mouse dorsal root ganglion (DRG) neurons. The GABAB receptor agonist baclofen also inhibited inward currents induced by CIM0216 in DRG neurons, and nocifensive responses elicited by this TRPM3 agonist in mice. Our data uncover a novel signaling mechanism regulating TRPM3 channels.

G protein ßγ subunits inhibit TRPM3 ion channels in sensory neurons.

Transient receptor potential (TRP) ion channels in peripheral sensory neurons are functionally regulated by hydrolysis of the phosphoinositide PI(4,5)P2 and changes in the level of protein kinase mediated phosphorylation following activation of various G protein coupled receptors. We now show that the activity of TRPM3 expressed in mouse dorsal root ganglion (DRG) neurons is inhibited by agonists of the Gi-coupled µ opioid, GABA-B and NPY receptors. These agonist effects are mediated by direct inhibition of TRPM3 by Gßγ subunits, rather than by a canonical cAMP mediated mechanism. The activity of TRPM3 in DRG neurons is also negatively modulated by tonic, constitutive GPCR activity as TRPM3 responses can be potentiated by GPCR inverse agonists. GPCR regulation of TRPM3 is also seen in vivo where Gi/o GPCRs agonists inhibited and inverse agonists potentiated TRPM3 mediated nociceptive behavioural responses.

Inhibition of baclofen-induced hypothermia in mice by the novel GABAB antagonist CGP 35348.

This study shows that the selective GABAB antagonist CGP 35348 had no effect on body temperature in mice in doses up to 300 mg/kg i.p. However, the highest dose abolished the hypothermia induced by the GABAB agonist baclofen (10 mg/kg i.p.) but not that produced by the GABA-mimetic progabide (200 mg/kg i.p.); the benzodiazepine agonist loprazolam (3 mg/kg i.p.); the alpha 2-agonist UK 14,304 (1 mg/kg i.p.) nor the mu-opioid agonist morphine (30 mg/kg i.p.). These findings, showing selective antagonism of GABAB receptors by CGP 35348, confirm that this compound may be a valuable tool for exploration of GABAB receptor function in vivo.

Baclofen activates two distinct receptors in the rat spinal cord and guinea pig ileum.

Following intrathecal injection, pretreatment with both D-baclofen and 5-aminovaleric acid (5-AV) inhibited the antinociceptive effect of L-baclofen, but homotaurine (3-aminopropane sulphonic acid, APS) was inactive as an antagonist (rank order D-baclofen greater than 5-AV greater than APS = 0). In an established GABAB system, the electrically stimulated guinea pig longitudinal muscle myenteric plexus preparation, APS and 5-AV but not D-baclofen reduced the inhibitory effect of L-baclofen (APS = 5-AV greater than D-baclofen = 0). Receptors with which baclofen interacts in the spinal cord to produce antinociception differ from GABAB receptors with respect to the rank order of potency of antagonists as well as close structural analogs, and these criteria could be used for characterization of such receptors.

CGP 55845A: a potent antagonist of GABAB receptors in the CA1 region of rat hippocampus.

The new GABAB receptor antagonist CGP 55845A was tested on pre- and post-synaptic GABAB receptors in the hippocampus. CGP 55845A (1 microM) blocked (-)-baclofen (5-10 microM)-induced postsynaptic hyperpolarization and depression of evoked IPSPs and EPSPs. It also blocked three physiological consequences of GABAB receptor activation: the late IPSP, paired-pulse depression of IPSCs, and heterosynaptic depression of EPSPs. Therefore, CGP 55845A is an antagonist at pre- and post-synaptic GABAB receptors in the hippocampus and is approximately three orders of magnitude more potent than previously described GABAB receptor antagonists.

Substance P, injected intrathecally, antagonizes the spinal antinociceptive effect of morphine, baclofen and noradrenaline.

The effect of substance P on the antinociceptive effect of morphine, baclofen and noradrenaline in the spinal cord was examined in the tail-flick and hot plate tests, after intrathecal administration. Substance P (5-20 micrograms) produced a dose-related antagonism of the effect of all three agents, which persisted for the entire time-course of the antinociceptive effect in each case. The rank order of potency of substance P and related peptides in antagonizing the antinociceptive effect of morphine, was substance P greater than physalaemin greater than eledoisin greater than eledoisin-related peptide. A similar order of potency was observed against noradrenaline, except that physalaemin appeared to be the most potent. The intrathecal administration of these peptides did not alter reaction latencies in the tail-flick test when baseline values were 2-3 sec, but produced a significant decrease in latency (hyperalgesia) when baseline values were 6-8 sec. There was a slight increase in reaction latency in the hot plate test. The specificity of the antagonism was examined by determining the effect of phentolamine on the antinociceptive effect of morphine and baclofen. Although phentolamine (30 micrograms) produced comparable hyperalgesia to substance P, it did not significantly alter the antinociceptive effect of morphine or baclofen. These results suggest that alterations in the function of substance P in the spinal cord may contribute to the spinal antinociceptive effects of morphine, baclofen and noradrenaline. The effects of substance P on nociception in the spinal cord appear to be mediated by substance P type receptors.

Antagonism of baclofen-induced depression of whole-cell synaptic currents in spinal dorsal horn neurones by the potent GABAB antagonist CGP55845.

The potencies of two GABAB receptor antagonists P-[3-aminopropyl]- P-diethoxymethyl-phosphinic acid (CGP35348) and the novel compound 3-N[1-(S)-(3,4-dichlorophenyl)ethyl]amino-2-(S)-hydroxypropyl-P- benzyl-phosphinic acid (CGP55845) have been compared in an in vitro spinal cord preparation. They have been tested as antagonists of baclofen-induced depression of EPSCs of patch-clamped dorsal horn neurons following electrical stimulation of dorsal roots. Mean EC50 values for the depressant action of baclofen were increased by 50- and 140-fold respectively in the presence of CGP35348 (200 microM) (n = 5) and CGP55845 (100 nM) (n = 4). This potency of CGP55845 is > 1000-fold higher than that reported previously for other GABAB receptor antagonists.

Pindolol antagonizes the effects on hippocampal rhythmical slow activity of clonidine, baclofen and 8-OH-DPAT, but not chlordiazepoxide and sodium amylobarbitone.

Buspirone, benzodiazepines, barbiturates and ethanol all reliably reduce the frequency of reticular-elicited hippocampal rhythmical slow activity. In the present experiments we tested a number of drugs which are not usually used for treating generalized anxiety disorders but which have been reported to have some anxiolytic properties. Clonidine (0.3 mg/kg, i.p.), baclofen (6 mg/kg, i.p.) and 8-hydroxy-di-n-propylamino tetralin (8-OH-DPAT) (2.5 mg/kg, i.p.) all reduced the frequency of rhythmical slow activity. The effect of all three drugs was reduced by the 5-hydroxytryptamine 1a antagonist pindolol (2 mg/kg, i.p.). Pindolol had no effect on the reduction in rhythmical slow activity produced by sodium amylobarbitone, as has been previously reported for the benzodiazepine chlordiazepoxide. Flumazenil (10 mg/kg, i.p.), a benzodiazepine receptor antagonist, reduced the effects of chlordiazepoxide (5 mg/kg, i.p.), but not buspirone (10 mg/kg, i.p.). A combination of the selective beta 1 adrenergic receptor antagonist metoprolol (20 mg/kg, i.p.) and the beta 2 adrenergic receptor antagonist ICI 118,551 (4 mg/kg, i.p.) did not reduce the effects of either buspirone (10 mg/kg, i.p.) or diazepam (1 mg/kg, i.p.). These data show that there are at least two separate routes through which anxiolytic agents reduce the frequency of hippocampal rhythmical slow activity. Buspirone, clonidine, baclofen and 8-OH-DPAT act via a system dependent on 5-hydroxytryptamine 1a receptor activation. Benzodiazepines act via activation of the benzodiazepine receptor and probably share with barbiturates action at the GABA-benzodiazepine-chloride ionophore complex but do not produce their effects, directly or indirectly, by 5-hydroxytryptamine 1a receptor activation.

Systemic baclofen stimulates gastric motility and secretion via a central action in the rat.

Intravenous (0.5 mg kg-1) or subcutaneous (2-16 mg kg-1) administration of the gamma-aminobutyric acid (GABA) analogue baclofen resulted in a stimulation of gastric motility and secretion in the rat, anaesthetized with urethane. The motility response to subcutaneous injection was dose-related. This effect was abolished by vagotomy or atropine. There was no response to baclofen in decerebrate animals. These results indicate that systemic baclofen, probably acting at a site rostral to the brainstem, stimulates gastric motility and acid secretion by a vagally-dependent mechanism.

Pharmacologically distinct GABAB receptors that mediate inhibition of GABA and glutamate release in human neocortex.

1. The release of endogenous gamma-aminobutyric acid (GABA) and glutamic acid in the human brain has been investigated in synaptosomal preparations from fresh neocortical samples obtained from patients undergoing neurosurgery to reach deeply located tumours. 2. The basal outflows of GABA and glutamate from superfused synaptosomes were largely increased during depolarization with 15 mM KCl. The K(+)-evoked overflows of both amino acids were almost totally dependent on the presence of Ca(2+) in the superfusion medium. 3. The GABAB receptor agonist (-)-baclofen (1, 3 or 10 microM) inhibited the overflows of GABA and glutamate in a concentration-dependent manner. The inhibition caused by 10 microM of the agonist ranged from 45-50%. 5. The effect of three selective GABAB receptor antagonists on the inhibition of the K(+)-evoked GABA and glutamate overflows elicited by 10 microM (-)-baclofen was investigated. Phaclofen antagonized (by about 50% at 100 microM; almost totally at 300 microM) the effect of (-)-baclofen on GABA overflow but did not modify the inhibition of glutamate release. The effect of (-)-baclofen on the K(+)-evoked GABA overflow was unaffected by 3-amino-propyl (diethoxymethyl)phosphinic acid (CGP 35348; 10 or 100 microM); however, CGP 35348 (10 or 100 microM) antagonized (-)-baclofen (complete blockade at 100 microM) at the heteroreceptors on glutamatergic terminals. Finally, [3-[[(3,4-dichlorophenyl) methyl]amino]propyl] (diethoxymethyl) phosphinic aid (CGP 52432), 1 microM, blocked the GABAB autoreceptor, but was ineffective at the heteroreceptors. The selectivity of CGP 52423 was lost at 30 microM, as the compound, at this concentration, inhibited completely the (-)-baclofen effect on both GABA and glutamate release. 5. It is concluded that GABA and glutamate release evoked by depolarization of human neocortex nerve terminals can be affected differentially through pharmacologically distinct GABAB receptors.

CGP 35348, a new GABAB antagonist, prevents antinociception and muscle-relaxant effect induced by baclofen.

1. CGP 35348, a new GABAB antagonist, was examined on antinociception induced by (+/-)-baclofen by use of the hot plate and writhing tests in mice and the paw pressure test in rats. CGP 35348 was also studied in mice on (+/-)-baclofen-induced impairment of rota-rod performance. 2. CGP 35348, injected either i.p. (60-100 mg kg-1 in mouse) or intracerebroventricularly (i.c.v.) (0.5-2.5 micrograms per mouse; 25 micrograms per rat) prevented (+/-)-baclofen-induced antinociception. 3. CGP 35348 did not modify oxotremorine- and morphine-induced antinociception in mice and rats. 4. CGP 35348 (2.5 micrograms i.c.v. per mouse) also prevented (+/-)-baclofen-induced impairment of the rota-rod test. 5. Two other GABAB antagonists, phaclofen (50 micrograms i.c.v. per mouse) and 2-OH-saclofen (2.5 micrograms-10 micrograms i.c.v. per mouse) did not modify (+/-)-baclofen-induced antinociception. 7. These results suggest that, at present, CGP 35348 is the only compound able to antagonize (+/-)-baclofen-induced antinociception.

Electrophysiological actions of GABAB agonists and antagonists in rat dorso-lateral septal neurones in vitro.

1. The actions of GABAB-receptor agonists and antagonists on rat dorso-lateral septal neurones in vitro were recorded with intracellular microelectrodes. 2. In the presence of 1 microM tetrodotoxin to prevent indirect neuronal effects caused by action potential-dependent neurotransmitter release, bath application of baclofen (0.1-30 microM) or SK&F 97541 (0.01-3 microM) evoked concentration-dependent hyperpolarizations which reversed close to the potassium equilibrium potential; the EC50S were 0.55 and 0.05 microM, respectively. No significant desensitization was observed during prolonged agonist exposure (< or = 10 min). 3. Hyperpolarizations induced by baclofen were antagonized in a competitive manner by the following GABAB-receptors antagonists (calculated pA2 values in parentheses): CGP 36742 (4.0), 2-OH saclofen (4.2), CGP 35348 (4.5), CGP 52432 (6.7) and CGP 55845A (8.3). Responses to SK&F 97541 were also antagonized by CGP 55845A (pA2 = 8.4). 4. The amplitude of the late, GABAB receptor-mediated inhibitory postsynaptic potential (i.p.s.p.) was reduced by the GABAB antagonists as follows (means +/- s.e.mean): CGP 55845A (1 microM) 91 +/- 5%, CGP 52432 (1 microM) 64 +/- 5%, CGP 35348 (100 microM) 82 +/- 5%, CGP 36742 (100 microM) 76 +/- 8%, and 2-OH saclofen (100 microM) 68 +/- 3%. 5. It is concluded that neurones in the rat dorso-lateral septal nucleus express conventional GABAB receptors, which are involved in the generation of slow inhibitory postsynaptic potentials. CGP 55845A is the most potent GABAB receptor antagonist described in this brain area.

Peripheral and central sites of action of GABA-B agonists to inhibit the cough reflex in the cat and guinea pig.

1. The GABA-B receptor agonists baclofen and 3-aminopropylphosphinic acid (3-APPi) have antitussive activity in the cat and guinea pig. The purpose of this study was to investigate the sites of action of these GABA-B receptor agonists to inhibit the cough reflex. 2. Single intracerebroventricular (i.c.v.) cannulas were placed in the lateral ventricles of anaesthetized guinea pigs. Approximately 1 week later, the animals were exposed to aerosols of capsaicin (0.3 mM) to elicit coughing. Coughs were detected with a microphone and counted. 3. Cough was produced in anaesthetized cats by mechanical stimulation of the intrathoracic trachea and was recorded from electromyograms of respiratory muscle activity. Cannulas were placed for intravenous (i.v.) or, in separate groups of animals, intravertebral arterial (i.a.) administration of baclofen, 3-APPi, the centrally active antitussive drug codeine or the peripherally active antitussive drug BW443c. Dose-response relationships for i.v. and i.a. administration of each drug were generated to determine a ratio of i.v. ED50 to i.a. ED50, known as the effective dose ratio (EDR). The EDR will be 20 or greater for a centrally acting drug. 4. In the guinea pig, baclofen (3 mg kg-1, s.c.) and 3-APPi (10 mg kg-1, s.c.) inhibited capsaicin-induced cough by 50% and 35% respectively. The antitussive activity of baclofen was completely blocked by i.c.v. administration of the GABA-B receptor antagonist CGP 35348 (10 micrograms). Conversely, the antitussive effect of 3-APPi was unaffected by i.c.v. CGP 35348. However, systemic administration of CGP 35348 (30 mg kg-1, s.c.) completely blocked the antitussive activity of 3-APPi (10 mg kg-1, s.c.). In separate experiments baclofen alone (1 microg, i.c.v.) inhibited capsaicin-induced cough by 78%. 3-APPi (10 and 100 microg, i.c.v.) had no effect on capsaicin-induced cough in the guinea pig.5. In the cat, potencies (ED50) of the standards and GABA-B agonists by the i.v. route were: codeine(0.34 mg kg-1), BW443C (0.17 mg kg-1), baclofen (0.63 mg kg-1) and 3-APPi (2.3 mg kg-1). Potencies of these drugs by the i.a. route were: codeine, 0.013 mg kg-1; BW443C, 0.06mg kg-1; baclofen,0.016mg kg-1; and 3-APPi, 0.87 mg kg-1. The EDRs for each drug were: codeine, 26; BW443C, 3;baclofen, 39; and 3-APPi, 3.6 We conclude that in both the cat and guinea pig baclofen inhibits cough by a central site of action,while 3-APPi inhibits cough by a peripheral site of action.

Effects of baclofen on synaptically-induced cell firing in the rat hippocampal slice.

The effects of baclofen on the synaptically-induced firing of pyramidal and granule cell populations were tested in the rat hippocampal slice. Population spikes were evoked by stimulating excitatory pathways in the presence and absence of bath-applied drug. (+/-)-Baclofen (20 microM) completely blocked the firing of CA1 or CA3 hippocampal pyramidal cells subsequent to stimulation of projections that originate in area CA3. In contrast, the firing of dentate granule cells evoked by stimulation of the perforant path fibres was depressed by only 46% and baclofen did not affect the monosynaptic firing of CA3 pyramidal cells evoked by mossy fibre stimulation. These results are consistent with the effects of baclofen on the corresponding extracellularly-recorded excitatory postsynaptic potentials (e.p.s.ps). The Schaffer collateral-commissural population spike in area CA1 was depressed by (-)-baclofen (EC50 = 2.8 microM), GABA (EC50 = 2.2 mM) and 3-aminopropanesulphonic acid (3-APS) (EC50 = 0.34 mM). (-)-Baclofen was 180 times as potent as (+)-baclofen. Bicuculline methiodide (100 microM) did not reverse the depressant action of (-)-baclofen. GABA-induced depressions were antagonized to only a small degree, whilst the effect of 3-APS was readily reversed. Raising the concentration of bicuculline from 100 microM to 500 microM did not further reverse the action of GABA. The effects of (-)-baclofen and 3-APS on the relationship between extracellular e.p.s.p. and population spike were tested by stimulation of the Schaffer collateral-commissural fibres in area CA1. (-)-Baclofen shifted the 'input/output' curve to the right at a concentration of 1 microM, but less or not at all at 3 microM. In contrast, increasing the concentration of 3-APS shifted this curve farther to the right.

GABA, glutamate and substance P-like immunoreactivity release: effects of novel GABAB antagonists.

1. The effects of various GABA receptor ligands on the electrically-evoked release of endogenous GABA, glutamate and substance P-like immunoreactivity from the dorsal horn of rat isolated spinal cord were examined. 2. Exogenous GABA (10-300 microM) significantly decreased the evoked, but not basal, release of endogenous glutamate in a concentration-dependent manner. The GABAA agonist, isoguvacine (1-100 microM), failed to decrease the release of glutamate although it did reduce the release of GABA. Baclofen (0.1-1000 microM), the GABAB agonist, reduced the release of GABA and glutamate in a stereospecific and concentration-dependent manner. 3. The actions of five GABAB antagonists on these release systems were compared. CGP36742, CGP52432, CGP55845A and CGP57250A significantly increased the evoked release of GABA and glutamate. They also reversed the effects of (-)-baclofen in a concentration-dependent manner. On the other hand, while CGP56999A had no effect on glutamate release, it was an effective antagonist of the baclofen-induced inhibition of GABA and substance P release. 4. These results suggest that GABAB receptors on nerve terminals within the dorsal horn spinal cord may be heterogeneous. However, this is based solely on the data obtained with CGP56999A which affected only GABA and substance P, but not glutamate, release.

The role of GABAB receptors in mediating the stimulatory effects of ethanol in mice.

Recently, the GABAB receptor antagonist phaclofen has been shown to attenuate the stimulation of locomotor activity induced by ethanol (Allan and Harris 1989). In the present study, the effects of a range of recently developed GABAB receptor antagonists (phaclofen, 2-hydroxysaclofen, beta-phenyl-beta-alanine, CGP 35348) and the GABAB receptor agonist baclofen, were studied for their ability to block the locomotor stimulation induced by a low dose of ethanol administered IP to mice (1.75 g/kg). Results showed that phaclofen, 2-hydroxysaclofen, BPBA and baclofen all dose-dependently decreased ethanol-induced locomotor activity, and, of these, baclofen and BPBA did so at doses which did not attenuate locomotor activity when administered alone. CGP 35348 had no effect on the activity produced by ethanol. The action of baclofen on ethanol-induced activity appeared to be GABAB receptor mediated, as the effects were stereospecific and were reversed by the antagonist, CGP 35348. However phaclofen, 2-hydroxysaclofen and BPBA failed to reverse the effects of baclofen. These results suggest that the GABAB receptor may modulate locomotor stimulation induced by low doses of ethanol, and furthermore, that agonist, rather than antagonist activity at the GABAB receptor is responsible for this reduction. The GABAB receptor subtype responsible for modulating the effects of ethanol may have properties different from those GABAB receptors characterised to date.

Increase in mouse brain dopamine content by baclofen: effects of apomorphine and neuroleptics.

Baclofen, like gamma-butyrolactone, causes a dose-dependent increase in the concentration of dopamine in the mouse brain without affecting the content of norepinephrine. This increase is antagonized by apomorphine. Haloperidol but not pimozide counteracts this effect of apomorphine and dose-dependently enhances the increase in brain dopamine produced by baclofen. The results suggest that baclofen reduces impulse flow in dopaminergic neurons in a manner similar to that produced by gamma-butyrolactone.

The GABA(B) antagonist CGP56433A attenuates the effect of baclofen on cocaine but not heroin self-administration in the rat.

RATIONALE: Several reports have demonstrated that the gamma-aminobutyric acid (GABA)(B) agonist baclofen attenuates the reinforcing effects of cocaine in rats, and recent evidence indicates that it might have a similar effect on heroin self-administration. OBJECTIVES: The specific GABA(B) receptor antagonist CGP56433A was used to further evaluate the involvement of GABA(B) receptors in the baclofen-induced suppression of cocaine and heroin self-administration. METHODS: In the first series of experiments, dose-response curves were generated to examine the effect of CGP56433A (0.6, 1.0, or 1.8 mg/kg, i.p.) on cocaine (1.5 mg/kg per injection) and heroin (25 microg/kg per injection) self-administration reinforced under a fixed-ratio (FR1) or progressive ratio (PR) schedule. Separate sets of experiments then examined the effect of the co-administration of CGP56433A and baclofen on responding for cocaine or heroin under both schedules. RESULTS: Pretreatment with CGP56433A had no effect on cocaine or heroin self-administration, while baclofen dose dependently reduced responding for both cocaine and heroin under both the FR1 and PR schedule. CGP56433A (1.8 mg/kg) blocked the effect of baclofen on cocaine but not on heroin self-administration. CONCLUSION: The specific GABA(B) antagonist CGP56433A attenuated the effect of baclofen on cocaine self-administration, suggesting that GABA(B) receptors are critical in mediating the anti-cocaine effect of baclofen. In combination with other studies, the data demonstrate that the susceptibility of baclofen and other GABA(B) agonists to receptor blockade depends on the behavioral response being studied. Whether this indicates different receptor mechanisms are involved (e.g., pre- versus post-synaptic effects or differential receptor reserve) remains to be determined.

GABA-B receptor-mediated spinal inhibition.

The intravenous administration to pentobarbitone-anaesthetized cats of the GABA-B antagonists CGP 46381 and CGP 35348 blocks the longer duration component of the inhibition of lumbar extensor monosynaptic reflexes by tetanic stimulation of low threshold flexor primary afferent fibres. GABA-B receptors thus appear to be associated with this inhibitory process, in addition to bicuculline-sensitive GABA-A receptors associated with shorter duration 'presynaptic' inhibition of reflexes and the depolarization of the terminals of primary afferent fibres.