[CHANGE OF CHARACTER OF INTERSYSTEMIC INTERACTIONS IN NEWBORN RAT PUPS UNDER CONDITIONS OF A DECREASE OF MOTOR ACTIVITY].

Interaction of slow-wave.rhythmic components of cardiac, respiratory.and motor activity was investigated in newborn rat pups on the first day after birth under normal conditions and after pharmacological depression of spontaneous periodic motor activity (SPMA) produced by injecting myocuran (myanesin) at low (100 mg/pg, i/p) and maximal (235 mg/pg, i/p) dosages. The data obtained allow to infer that in rat pups after birth the intersystemic interactions are realized mainly via slow-wave oscillations of about-one- and many-minute ranges whereas the rhythms of decasecond range do not play a significant role in integrative processes. Injection of miocuran at a dose causing no muscle relaxation and no inhibition of motor activity produces changes of the cardiac and respiratory rhythms as well as a transitory decrease of the magnitude of coordinate relations mediated by the rhythms of about-one- and many-minute ranges. The consequences of muscle relaxant injection were found to be more significant for intersystemic interactions with participation of the respiratory system. An increase of the dosage and, correspondingly, the total inhibition of SPMA is accompanied by reduction of the slow-wave components from the pattern of cardiac and respiratory rhythms. The cardiorespiratory interactions, more expressed in intact rat pups, are reduced in the about-one- and many-minute ranges of modulation whereas in the decasecond range of modulation they are slightly increased. Key words: early ontogenesis, intersystemic interactions, cardiac rhythm, respiration, motor activity, myocuran (myanesin).

Vestibular-mediated synaptic inputs and pathways to sympathetic preganglionic neurons in the neonatal mouse.

To assess when vestibulosympathetic projections become functional postnatally, and to establish a preparation in which vestibulosympathetic circuitry can be characterized more precisely, we used an optical approach to record VIIIth nerve-evoked synaptic inputs to thoracic sympathetic preganglionic neurons (SPNs) in newborn mice. Stimulation of the VIIIth nerve was performed in an isolated brainstem-spinal cord preparation after retrogradely labelling with the fluorescent calcium indicator Calcium Green 1-conjugated dextran amine, the SPNs and the somatic motoneurons (MNs) in the thoracic (T) segments T2, 4, 6, 8, 10 and 12. Synaptically mediated calcium responses could be visualized and recorded in individual SPNs and MNs, and analysed with respect to latency, temporal pattern, magnitude and synaptic pharmacology. VIIIth nerve stimulation evoked responses in all SPNs and MNs investigated. The SPN responses had onset latencies from 90 to 200 ms, compared with much shorter latencies in MNs, and were completely abolished by mephenesin, a drug that preferentially reduces polysynaptic over monosynaptic transmission. Bicuculline and picrotoxin, but not strychnine, increased the magnitudes of the SPN responses without changing the onset latencies, suggesting a convergence of concomitant excitatory and inhibitory synaptic inputs. Lesions strategically placed to test the involvement of direct vestibulospinal pathways versus indirect pathways within the brainstem showed that vestibulosympathetic inputs in the neonate are mediated predominantly, if not exclusively, by the latter. Thus, already at birth, synaptic connections in the vestibulosympathetic reflex are functional and require the involvement of the ventrolateral medulla as in adult mammals.

Organization of functional synaptic connections between medullary reticulospinal neurons and lumbar descending commissural interneurons in the neonatal mouse.

The medullary reticular formation (MRF) of the neonatal mouse is organized so that the medial and lateral MRF activate hindlimb and trunk motoneurons (MNs) with differential predominance. The goal of the present study was to investigate whether this activation is polysynaptic and mediated by commissural interneurons with descending axons (dCINs) in the lumbar spinal cord. To this end, we tested the polysynapticity of inputs from the MRF to MNs and tested for the presence of selective inputs from medial and lateral MRF to 574 individual dCINs in the L2 segment of the neonatal mouse. Reticulospinal-mediated postsynaptic Ca(2+) responses in MNs were reduced in the presence of mephenesin and after a midline lesion, suggesting the involvement of dCINs in mediating the responses. Consistent with this, stimulation of reticulospinal neurons in the medial or lateral MRF activated 51% and 57% of ipsilateral dCINs examined (255 and 352 dCINs, respectively) and 52% and 46% of contralateral dCINs examined (166 and 133 dCINs, respectively). The proportion of dCINs that responded specifically to stimulation of medial or lateral MRF was similar to the proportions of dCINs that responded to both MRF regions or to neither. The three responsive dCIN populations had largely overlapping spatial distributions. We demonstrate the existence of dCIN subpopulations sufficient to mediate responses in lumbar motoneurons from reticulospinal pathways originating from the medial and lateral MRF. Differential control of trunk and hindlimb muscles by the medullary reticulospinal system may therefore be mediated in part by identifiable dCIN populations.

Segmental patterns of vestibular-mediated synaptic inputs to axial and limb motoneurons in the neonatal mouse assessed by optical recording.

Proper control of movement and posture occurs partly via descending projections from the vestibular nuclei to spinal motor circuits. Days before birth in rodents, vestibulospinal neurons develop axonal projections that extend to the spinal cord. How functional these projections are just after birth is unknown. Our goal was to assess the overall functional organization of vestibulospinal inputs to spinal motoneurons in a brainstem-spinal cord preparation of the neonatal mouse (postnatal day (P) 0-5). Using calcium imaging, we recorded responses evoked by electrical stimulation of the VIIIth nerve, in many motoneurons simultaneously throughout the spinal cord (C2, C6, T7, L2 and L5 segments), in the medial and lateral motor columns. Selective lesions in the brainstem and/or spinal cord distinguished which tracts contributed to the responses: those in the cervical cord originated primarily from the medial vestibulospinal tracts but with a substantial contribution from the lateral vestibulospinal tract; those in the thoracolumbar cord originated exclusively from the lateral vestibulospinal tract. In the thoracolumbar but not the cervical cord, excitatory commissural connections mediated vestibular responses in contralateral motoneurons. Pharmacological blockade of GABA(A) receptors showed that responses involved a convergence of excitatory and inhibitory inputs which in combination produced temporal response patterns specific for different segmental levels. Our results show that by birth vestibulospinal projections in rodents have already established functional synapses and are organized to differentially regulate activity in neck and limb motoneurons in a tract- and segment-specific pattern similar to that in adult mammals. Thus, this particular set of descending projections develops several key features of connectivity appropriately at prenatal stages. We also present novel information about vestibulospinal inputs to axial motoneurons in mammals, providing a more comprehensive platform for future studies into the overall organization of vestibulospinal inputs and their role in regulating postural stability.

Spinal ventral root after-discharges as a pain index: involvement of NK-1 and NMDA receptors.

Nociceptive signals are transmitted to the spinal dorsal horn via primary afferent fibers, and the signals induce withdrawal reflexes by activating spinal motoneurons in the ventral horn. Therefore, nociceptive stimuli increase motoneuronal firing and ventral root discharges. This study was aimed to develop a method for the study of pain mechanisms and analgesics by recording ventral root discharges. Spinalized rats were laminectomized in the lumbo-sacral region. The fifth lumbar ventral root was sectioned and placed on a pair of wire electrodes. Multi unit efferent discharges from the ventral root were increased by mechanical stimulation using a von Frey hair applied to the plantar surface of the hindpaw. The low-intensity mechanical stimuli increased the discharges during stimulation (during-discharges) without increasing the discharges after cessation of stimulation (after-discharges), and the high-intensity mechanical stimuli increased both during- and after-discharges. Pretreatment with resiniferatoxin, an ultrapotent analogue of capsaicin, halved during-discharges and eliminated after-discharges, suggesting that after-discharges are generated by heat- and mechanosensitive polymodal nociceptors. Ezlopitant, a neurokinin-1 (NK-1) receptor antagonist, but not its inactive enantiomer, selectively reduced the after-discharges. Ketamine, an N-methyl-D-aspartate (NMDA) receptor antagonist, preferentially reduced the after-discharges, demonstrating that NK-1 and NMDA receptors mediate the after-discharges. Morphine reduced the after-discharges without affecting during-discharges. By contrast, mephenesin, a centrally acting muscle relaxant, reduced both during- and after-discharges. There results suggest that simultaneous recordings of during- and after-discharges are useful to study pain mechanisms and analgesics as well as to discriminate the analgesic effects from the side effects such as muscle relaxant effects.

Presynaptic GABAergic control of the locomotor drive in the isolated spinal cord of neonatal rats.

The in vitro newborn rat isolated brain stem/spinal cord preparation was used to study the involvement of presynaptic inhibition in the control of the synaptic locomotor drive. The recording chamber was partitioned with Vaseline walls to separate the L1-L2 locomotor network from the motoneurons in the lower segments. When locomotor like activity was induced by bath applying a mixture of N-methyl-D-L-aspartate and serotonin to the L1-L2 segments, intracellular recordings of L3-L5 motoneurons show an alternating pattern of monosynaptic excitatory glutamatergic and inhibitory glycinergic inputs known as the locomotor drive. Gamma-aminobutyric acid (GABA), baclofen and muscimol (respectively GABA(B) and GABA(A) agonists) superfused on the L3-L5 segments depressed the synaptic locomotor drive of motoneurons during the ongoing activity. On the contrary, the GABA(B) receptor antagonist CGP35348 enhanced the locomotor drive, which suggests that an endogenous release of GABA occurs during locomotor-like activity. Baclofen, unlike muscimol and GABA, did not affect the passive membrane properties and the firing discharge of synaptically isolated motoneurons. Baclofen and muscimol acted on the two phases (inhibitory and excitatory) of the synaptic drive. The effects of GABAergic agonists on the whole locomotor activity were tested. When superfused on the L3-L5 part of the cord, they affected only the L5 burst amplitude. When bath-applied to the L1-L2 network, GABA and muscimol decreased the amplitude of the L2 and L5 bursts and increased the locomotor period while baclofen had significant effects only on the period. It was concluded that GABA modulates the information conveyed by the L1-L2 network to its target motoneurons presynaptically via GABA(B) and possibly GABA(A) receptors and postsynaptically, via GABA(A) receptors.

Possible NMDA antagonist properties of drugs that affect high pressure neurological syndrome.

1. Previous studies have suggested that a series of drugs modelled on part of the strychnine molecule interfere with the development of high pressure neurological syndrome (HPNS) and it was presumed that this effect was via an action on inhibitory glycinergic transmission. We have now used the rat hippocampal slice preparation to examine the possibility that some of these drugs might instead have an action at the strychnine-insensitive (SI) glycine binding site associated with the NMDA receptor. 2. D-2-Amino-5-phosphonovalerate (AP5) and 7-chlorokynurenate (7CK) had no significant effect on the height of the population spike recorded from the CA1 region in 1 mM Mg2+ medium, but both blocked the multiple population spikes recorded in Mg(2+)-free medium. The effect of 7CK, but not AP5, was reversed by 200 microM D-serine which is consistent with the known antagonist action of 7CK at the SI-glycine site. 3. A derivative of benzimidazole, which shows the clearest structural similarities to known SI-glycine site antagonists and ameliorates HPNS, mirrored the effects of 7CK although it was considerably less potent. 4. Gramine, which exacerbates HPNS, significantly increased the number of population spikes evoked in Mg(2+)-free medium. 5. Mephenesin, which is the most potent known drug in ameliorating HPNS, had no significant effect on the response recorded in 1 mM Mg2+ and significantly reduced the number of population spikes recorded in Mg(2+)-free medium, but this effect was only partially reversed by the addition of D-serine. 6. The results are consistent with the benzimidazole derivative, but not gramine, being an antagonist at the SI-glycine receptor. The results with mephenesin are equivocal but leave open the possibility that some of the drugs which are effective against HPNS act via an effect on excitatory NMDA receptor mediated transmission, rather than on inhibitory glycine-mediated transmission.

The effects of centrally acting muscle relaxants on the intrathecal noradrenaline-induced facilitation of the flexor reflex mediated by group II afferent fibers in rats.

The effects of centrally acting muscle relaxants on the flexor reflex mediated by group II afferent fibers (group II flexor reflex) in anesthetized intact rats and on the intrathecal noradrenaline-HCl-induced facilitation of the group II flexor reflex in anesthetized spinal rats were investigated. In anesthetized intact rats, mephenesin, tolperisone-HCl, chlorpromazine-HCl and baclofen inhibited the group II flexor reflex dose-dependently, whereas the inhibitory effect of tizanidine-HCl was bell-shaped. The effect of diazepam tended to be saturated. In anesthetized spinal rats, mephenesin, tolperisone-HCl, chlorpromazine-HCl, diazepam and baclofen also depressed the group II flexor reflex, but tizanidine-HCl slightly increased it. The intrathecal noradrenaline-HCl-induced facilitation of the group II flexor reflex was not affected by mephenesin or diazepam, but was inhibited by tizanidine-HCl, tolperisone-HCl, chlorpromazine-HCl and baclofen. These results suggest that compounds with centrally acting muscle relaxant activity depress the group II flexor reflex in different manners, and the inhibition of descending noradrenergic tonic facilitation within the spinal cord participates in the depressant action of the group II flexor reflex produced by tolperisone-HCl, tizanidine-HCl, chlorpromazine-HCl and baclofen.

The flexor reflex mediated by group II afferent fibers: effects of morphine-HCl and mephenesin.

The effects of morphine-HCl and mephenesin on the flexor reflex mediated by group II afferent fibers were investigated. The flexor reflex was recorded by means of the electromyogram (EMG) evoked in the muscle tibialis anterior by stimulation of the ipsilateral tibial nerve in urethane-alpha-chloralose anesthetized rats. Afferent volleys corresponding to the phasic EMG component of the flexor reflex with 7.6-msec latency (flexor EMG: fEMG) were also recorded using the double volley technique. The threshold of the afferent volleys mediating the fEMG was approximately twice as high as that of the most excitable afferent volleys, which were considered the spikes of group I afferent fibers, and the conduction velocity of the afferent volleys was 39.9 +/- 3.2 m/sec. Morphine-HCl (5 mg/kg, i.v.) did not change the amplitude of the fEMG, but mephenesin (40 and 80 mg/kg, i.v.) depressed it dose-dependently. These results suggest that the fEMG is a flexor reflex mediated by group II afferent fibers, which is not affected by morphine-HCl but depressed by mephenesin.

Neuropsychopharmacological study of 2,4-dihydro[1,2,4]triazolo[3,4-c][1,4]benzothiazine-1-one (IDPH-791).

The neuropsychopharmacological profile of a new centrally acting skeletal muscle relaxant, 2,4-dihydro[1,2,4]triazolo[3,4-c][1,4]benzothiazine-1-one (IDPH-791), an analogue of triazolobenzothiazine, has been described and compared to mephenesin, a well known centrally-acting muscle relaxant. IDPH-791 was found to be safer and of longer duration of action than mephenesin in all the tests conducted in this study. Both IDPH-791 and mephenesin caused ataxia, decrease in spontaneous activity and inhibition of pinnal reflex. IDPH-791 was 1.5 to 2.0 times more potent in exhibiting motor inco-ordination and anticonvulsant activity than mephenesin in mice and rats. IDPH-791 was twice as active in inhibiting various spinal polysynaptic reflexes, crossed extensor, flexor, and linguomandibular reflexes; however, both did not affect the typical monosynaptic reflex, patellar reflex. IDPH-791 and mephenesin did not have sedative activity. Although mephenesin exhibited haemolytic activity, IDPH-791 was devoid of this activity. It is concluded that IDPH-791 is a safe and effective centrally-acting muscle relaxant having a longer duration of action than mephenesin. IDPH-791 is also devoid of sedative and haemolytic activity.

Specificity and potency of N-methyl-D-aspartate glycine site antagonists and of mephenesin on the rat spinal cord in vitro.

The potency, specificity and reversibility of various presumed glycine site N-methyl-D-aspartate (NMDA) antagonists was studied on neonatal rat spinal cord using the grease gap technique. 5,7-Dichlorokynurenate was the most potent and specific glycine site antagonist among the compounds tested. On the other hand mephenesin was a weak non-specific excitatory amino acid (EAA) antagonist; reduction of the response to NMDA was not reversed by D-serine. The EAA antagonist properties of mephenesin could explain its mode of action at the cellular level. The lack of effect of D-serine alone suggests that in our experimental conditions glycine sites on spinal neurones are occupied by an endogenous ligand.

[Pharmacology of neural mechanisms of the motor system].

In reviewing recent progress concerning the motor system and drug action, the following subjects will be discussed on the basis of our data: 1) the mechanisms of action of mephenesin and baclofen, 2) baclofen and gamma-aminobutyric acid B (GABAB) receptor, 3) GABA-, benzodiazepine receptors, 4) control of spinal motor system by descending noradrenergic neuron, 5) pharmacology of the muscle spindle, and 6) pharmaco-metrics of centrally acting muscle relaxants.

NMDA receptor complex antagonists have potential anxiolytic effects as measured with separation-induced ultrasonic vocalizations.

Pre-weaning rat pups emit ultrasonic vocalizations when removed from the litter. These 'separation-induced vocalizations' (SIV) are suppressed by classical benzodiazepine anxiolytics and by non-benzodiazepine anxiolytics which lack muscle relaxant and sedative properties. The present study used the SIV model to assess potential anxiolytic properties of compounds which target different sites associated with the NMDA receptor complex. Comparison was made to drugs which affect benzodiazepine or serotonin (5-HT) receptors. Muscle relaxant potential was assessed using 'TIP' (time on an inclined plane), the amount of time a pup was able to retain its position on a steeply inclined surface. Mephenesin, a centrally acting muscle relaxant, significantly suppressed TIP but not SIV. The benzodiazepine agonist diazepam suppressed both SIV and TIP, whereas the 5-HT1A partial agonists, buspirone and MDL 73,005EF, suppressed SIV without affecting TIP. The 5-HT2 antagonist MDL 11,939 suppressed TIP but not SIV, whereas neither measure was affected by the 5-HT3 antagonist MDL 73,147EF. SIV was suppressed by NMDA antagonists including those acting at the glutamate recognition site (D,L-amino-phosphonovaleric acid (AP5) and MDL 100,453) or at the ion channel (MK-801), or by the strychnine-insensitive glycine antagonist 5,7-dichlorokynurenic acid (5,7-DCKA). TIP was suppressed even more potently by AP5, MDL 100,453 and MK-801, whereas 5,7-DCKA was inactive on this measure. Thus, antagonists acting at different sites present on the glutamate recognition site exhibit potential anxiolytic activity, but the glycine antagonist was unusual in its lack of prominent muscle relaxant side effects.

[The effect of flupirtine, various analgesics and muscle relaxants on skeletal muscle tone in the conscious rat]. / Einfluss von Flupirtin, verschiedener Analgetika und Muskelrelaxantien auf den Skelettmuskeltonus wacher Ratten.

The influence of the skeletal muscle tone by flupirtine (D-9998, Katadolon; CAS 56995-20-1), some selected analgesics and muscle relaxants was investigated in conscious rats after intraperitoneal administration. Benzodiazepines (diazepam and tetrazepam), baclofen, dantrolene and mephenesine reduced the tone of the skeletal muscle. Opiate analgesics, such as morphine, codeine and tramadol, enhanced the muscle tone. Flupirtine reduced the skeletal muscle tone at doses comparable with its antinociceptive effective doses. In this dose range no sedative side effects as ataxia or decrease of spontaneous motor activity could be observed. The mode of this muscle relaxing effect of flupirtine is not known in all details. It is, however, likely that flupirtine is able to inhibit the mono- and/or polysynaptic reflexes at the spinal level.

[Centrally acting muscle relaxant effect of phthalides (ligustilide, cnidilide and senkyunolide) obtained from Cnidium officinale Makino].

The present study was carried out to elucidate a centrally acting muscle relaxant effect of chloroform soluble fraction and its component, namely, ligustilide, cnidilide and senkyunolide obtained from the rhizome of Cnidium officinale Makino. These three compounds were isolated from the chloroform soluble fraction by column chromatography on silica gel. The centrally acting muscle relaxant effect was investigated on the crossed extensor reflex in anesthetized rats and these samples were suspended in 0.5% carboxymethyl cellulose solution and administered i.p. These three compounds as well as the chloroform soluble fraction depressed the reflex response. The depressive potencies among them were almost the same and their potencies were also the same or somewhat weaker as that of mephenesin. As a curare-like action was not observed, a muscle relaxation induced by these phthalide compounds is considered to be due to central origin.

An evaluation of the structure-activity relationships of a series of analogues of mephenesin and strychnine on the response to pressure in mice.

1. A range of compounds structurally related to the centrally acting muscle relaxant mephenesin and to the chemical convulsant strychnine were synthesized and tested for their ability to alter the threshold pressures for the onset of high pressure convulsions in mice. 2. The ability of both groups of compounds to alter the threshold pressure for convulsions was found to be dependent on the nature of a simple molecular skeleton. Thus, compounds that possessed a negatively polarized group located both in the same plane as and some 4.5 A from an aromatic nucleus increased the thresholds whereas compounds with a positively polarized group at the same location reduced the thresholds. 3. These findings support the suggestion that pressure elicits convulsions via a selection action on a receptor protein complex rather than via some general perturbation of the lipid regions of cellular membranes.

Effects of some centrally acting muscle relaxants on spinal root potentials: a comparative study.

The effects of intravenously administered mephenesin, tolperisone, baclofen, diazepam and midazolam on reflex activity were studied in unanesthetized spinal cats. Monosynaptic, as well as polysynaptic ventral root reflexes, the dorsal root potential and the dorsal root reflex were recorded simultaneously from L6-S1 segments. An analogue integrating method was developed for quantitative monitoring and recording ipsilateral spinal root potentials evoked by stimulation of the tibial nerve. Mephenesin (12.5-50 mg/kg) caused a significant and dose-dependent reduction in the polysynaptic and the dorsal root reflexes, slightly decreased the dorsal root potential but minimally affected the monosynaptic ventral root reflex. Tolperisone (2.5-10 mg/kg) dose-dependently inhibited both ventral root reflexes and the dorsal root reflex. It slightly prolonged the dorsal root potential without affecting the amplitude. Baclofen (0.5 mg/kg) abolished the monosynaptic reflex, partially inhibited the polysynaptic reflex, while dorsal root responses were less attenuated. Both benzodiazepines exerted similar actions, both qualitatively as well as quantitatively: the polysynaptic reflex was partially reduced while the monosynaptic reflex was not modified by diazepam or midazolam. Dorsal root responses were enhanced and the half-time of decay of the dorsal root potential was prolonged. Different patterns of action of muscle relaxants studied here are discussed in terms of their possible mechanisms of action. Profound depressant effects of mephenesin and tolperisone on the dorsal root reflex are in contrast to the small effect of both drugs on the dorsal root potential and might reflect their inhibition of spike-generating mechanisms. For a yet unknown reason, various spinal pathways are affected differentially by baclofen. In spinal cats, the reduction by benzodiazepines of the polysynaptic reflex may be related to the potentiation of some unidentified GABA-ergic inhibitory processes. The use of water-soluble midazolam, as a model compound instead of diazepam, is suggested because the usual organic solvents for diazepam may affect its action.

Effects of centrally acting muscle relaxants on post-rotatory nystagmus in the rabbit.

1. The effects of some centrally acting muscle relaxants on the post-rotatory nystagmus induced by rotatory stimulation were investigated in the rabbit, to examine the action of the drugs on vestibular function. 2. Tolperisone-HCl (5-10 mg/kg, i.v.) and baclofen (1-3 mg/kg, i.v.) decreased the number of post-rotatory nystagmus beats dose-dependently, whereas mephenesin (40-80 mg/kg, i.v.) and diazepam (0.5-1.0 mg/kg, i.v.) prolonged it dose-dependently. 3. The inhibitory effects of tolperisone-HCl and baclofen may provide some suggestions as to the mechanisms and sites of actions of centrally acting muscle relaxants, while the significance of the prolonging action of mephenesin remains unclear. 4. The prolonging action of diazepam is discussed with reference to GABAergic mechanisms.

Comparative study in mice of tetrazepam and other centrally active skeletal muscle relaxants.

Tetrazepam is a 1,4 benzodiazepine (BZD) clinically used in France and Germany as a muscle relaxant. The activity of tetrazepam was compared to that of diazepam, baclofen, mephenesin and chlormezanone in mice, in pharmacological models which are predictive of muscle relaxant and sedative properties. Tetrazepam was active in all the 6 tests of muscle relaxation (traction, chimney, inclined screen, grip force, horizontal grid and morphine-induced Straub tail). The overall muscle relaxant potency of tetrazepam was inferior to that of diazepam, but was clearly superior to that of chlormezanone and mephenesin. Baclofen was less active than tetrazepam in 3 tests (traction, horizontal grid, and grip strength), but more active in the other 3 tests. The administration of the benzodiazepine receptor antagonist Ro 15-1788 blocked the effects of tetrazepam and diazepam in 2 representative tests, morphine-induced Straub tail and the rotarod test, but did not modify the activities of the other centrally acting muscle relaxants in these same models. The selectivity ratio (ED50 rotarod or ED50 locomotor activity/ED50 in each muscle relaxant test) for tetrazepam was superior to that of diazepam and all the other muscle relaxant drugs examined. It is concluded that tetrazepam exerts its muscle relaxant activity by stimulating central BZD receptors, and presents the advantage of a wide dissociation between muscle relaxant and sedative potencies.

Investigations into the origin of the high pressure neurological syndrome: the interaction between pressure, strychnine and 1,2-propandiols in the mouse.

1. The effects of a variety of structural isomers of the centrally acting muscle relaxant mephenesin on the high pressure neurological syndrome have been investigated. Threshold pressures for the onset of the behavioural signs, tremors and convulsions, were established. The effects of these compounds on the response to pressure were also compared with their ability to antagonize the convulsive action of strychnine. 2. The dose-response relationships for strychnine and picrotoxin were investigated at fixed pressures. Additionally, the dose-response relationship of strychnine, in the presence of mephenesin, at pressure was investigated. 3. All the isomers of mephenesin protected against the effects of both pressure and strychnine. The relative potency was found to be identical with respect to both. Mephenesin was clearly the most effective; it raised the threshold pressure for tremors by 2.5 times, that for convulsions elicited by pressure by 1.5 and the ED50 for strychnine convulsions by 1.6 times. Strychnine was found to be strictly additive with pressure whereas picrotoxin exhibited gross deviations from additivity. Mephenesin ameliorated the combined effects of pressure and strychnine equally. 4. The marked dependence on structure of the anticonvulsant activity of the mephenesin isomers can be interpreted as evidence that pressure acts not by some general perturbation of the membranes of excitable cells but rather via some specific interaction. The finding that strychnine and pressure are strictly additive supports the idea of specificity and also indicates that they may share a common mechanism in the production of convulsions. By analogy with the established mechanism of action of strychnine, it is suggested that the hyperexcitability associated with pressure might arise from an action on glycine-mediated inhibitory processes.