Differences in the excitability of two populations of trigeminal primary afferent central terminals

The excitability of lingual and inferior dental nerve terminals in the trigeminal main sensory nucleus was increased following a conditioning stimulus delivered to the same nerves of the contralateral side. The lingual nerve primary afferent depolarization (PAD) began at a shorter CS-TS interval (CS, conditioning stimulus; TS, test stimulus), and reached a maximum level of depolarization sooner, than did the PAD evoked in the inferior dental nerve. This difference in the time course of the PAD was not dependent on the site of the CS;i.e., the same time course was observed for the lingual nerve terminals whether the CS was delivered to either the contralateral lingual, or inferior dental nerve.The effect of the contralateral CS was also tested on the ipsilateral lingual-digastric and inferior dental-digastric reflexes in order to determine if the PAD observed in the ipsilateral nerve terminals would be reflected in similar changes in reflexes mediated by those nerves. It was found that both digastric reflexes were inhibited by the CS. The time course of the inhibition showed similar characteristics to that of the previously discussed PAD;i.e., the onset of the lingual-digastric reflex inhibition began a shorter CS-TS interval and reached maximum effectiveness sooner than did the inhibition of the inferior dental-digastric reflex. The possible significance of the results in relation to the role of presynaptic inhibitory mechanisms in the reflex control of jaw movement is discussed.     

Persistence of PAD and presynaptic inhibition of muscle spindle afferents after peripheral nerve crush

Two to twelve weeks after crushing a muscle nerve, still before the damaged afferents reinnervate the muscle receptors, conditioning stimulation of group I fibers from flexor muscles depolarizes the damaged afferents [M. Enriquez, I. Jimenez, P. Rudomin, Changes in PAD patterns of group I muscle afferents after a peripheral nerve crush. Exp. Brain Res., 107 (1996), 405-420]. It is not known, however, if this primary afferent depolarization (PAD) is indeed related to presynaptic inhibition. We now show in the cat that 2-12 weeks after crushing the medial gastrocnemius nerve (MG), conditioning stimulation of group I fibers from flexors increases the excitability of the intraspinal terminals of both the intact lateral gastrocnemius plus soleus (LGS) and of the previously damaged MG fibers ending in the motor pool, because of PAD. The PAD is associated with the depression of the pre- and postsynaptic components of the extracellular field potentials (EFPs) evoked in the motor pool by stimulation of either the intact LGS or of the previously damaged MG nerves. These observations indicate, in contrast to what has been reported for crushed cutaneous afferents [K.W. Horch, J.W. Lisney, Changes in primary afferent depolarization of sensory neurones during peripheral nerve regeneration in the cat, J. Physiol., 313 (1981), 287-299], that shortly after damaging their peripheral axons, the synaptic efficacy of group I spindle afferents remains under central control. Presynaptic inhibitory mechanisms could be utilized to adjust the central actions of muscle afferents not fully recovered from peripheral lesions.     

Presynaptic inhibition of identified wind-sensitive afferents in the cercal system of the locust

The paired cerci located at the tip of the locust abdomen bear a large number of wind-sensitive filiform hairs, each of which sends an axon via the cercal nerve into the terminal ganglion of the CNS. The filiform afferents fire bursts of action potentials when their hairs are displaced by wind or mechanical stimuli. Filiform axon terminals in the CNS are depolarized concomitantly with the discharge of another type of unit (a primary afferent-depolarizing, or PAD, unit) recorded in the cercal nerve. The instantaneous spike frequency of PAD unit discharges matches the evoked depolarization very closely, and during such depolarizations spike amplitudes in the filiform afferent terminals are reduced by up to 55%. Depolarizing current pulses injected into the axonal terminals of an identified filiform afferent evoke spikes that are blocked by the PAD unit, probably via an intercalated interneuron. The PAD unit makes a monosynaptic connection with only one of the 4 giant interneurons (GIN 2) on each side of the terminal ganglion, and indirect connections with 2 others. Depolarizing current pulses injected into the neuropilar segments of GINs evoke fewer spikes when the PAD unit is active, consistent with the PAD unit's mediation of conductance changes in postsynaptic cells. Iontophoretic injection of Lucifer yellow shows the PAD unit to be an afferent with axon terminals overlapping those of filiform afferents and posteriorly directed branches of interneurons such as GIN 2 in the CNS. Passive movements of a cercus, monitored with a position transducer, show that the PAD unit fires discrete bursts during cercal displacement. The PAD unit most probably has its soma and dendrites in tissue spanning the cercal base. By responding to cercal movements sufficient to also activate filiform hairs, and by mediating conductance changes in both the presynaptic terminals of filiform afferents and the postsynaptic membranes of interneurons, the PAD unit desensitizes a pathway to movement-generated afferent input, and ensures that the locust remains sensitive to external wind stimuli.     

Porta-caval shunting changes neuronal sensitivity to ammonia

The relations between an effect of ammonia on postsynaptic inhibition, the amount of ammonium acetate i.v. to obtain this effect, and the tissue concentrations of NH4+ and glutamine were investigated in the cerebral cortex of cats without and with portacaval shunts. Normal cats required 2.43 mmol/kg ammonium acetate to affect postsynaptic inhibition. Cerebral NH4+ and glutamine increased from 0.21 mumol/g to 0.77 mumol/g and from 2.92 mumol/g to 5.54 mumol/g, respectively. In portacaval shunted cats, postsynaptic inhibition was normal in spite of increases of NH4+ and glutamine to 1.37 mumol/g and 14.28 mumol/g, respectively. Only 0.7 mmol/kg of ammonium acetate were sufficient to affect postsynaptic inhibition. This was associated with a statistically insignificant increase of NH4+ to 1.61 mumol/g and no change of glutamine. A chronic portasystemic shunt markedly increases the tolerance of postsynaptic inhibition to NH4+. However, postsynaptic inhibition becomes very sensitive to an acute systemic ammonia load and the associated increase of tissue NH4+ in the cerebral cortex. These observations help to understand the pathogenesis of the encephalopathy precipitated in patients with portasystemic shunts by an acute systemic ammonia load such as resulting from a gastrointestinal hemorrhage.     

Neurophysiology of pain-peripheral aspects. Speculation concerning the possibility of a unitary peripheral cutaneous input system for pressure, hot, cold and tissue damage.

The gate theory of pain is criticized at three levels: (1) at the dorsal horn "gate", where pre-synaptic inhibition in the primary afferent endings may go beyond mere reduction of synaptic power at the afferent endings and induce antidromic impulses (dorsal root reflexes) that may modulate peripherally by blocking; (2) central to the "gate", where postsynaptic neuronal repetitive (epileptiform) firing is believed to be an important underlying mechanism in clinical chronic pain syndromes; and, (3) in the periphery, where there is more to input coding than a balance between the ratio of large and smaller fiber inputs. Contrary to the belief of many sensory neurophysiologists, the present authors contend that pattern theory is viable; and that specificity, while important and not to be ignored, should be considered as only a partially evolved refinement superimposed on a basic underlying spatial and temporal patterning of input that probably requires central decoding, which begins in the dorsal horn.     

Presynaptic and long-lasting postsynaptic inhibition during penicillin-induced spinal seizures

In experiments on seven cats we tested the hypothesis that the epileptogenic effect of penicillin (PCN) on the spinal cord is mediated by a reduction of presynaptic inhibition. PCN-induced spinal hyperactivity was not associated with changes in either the presynaptic inhibition of extensor monosynaptic reflexes by conditioning volleys in flexor muscle nerves, or in evoked dorsal root potentials. Long-lasting inhibition of monosynaptic reflexes by repetitive cutaneous nerve volleys, shown by intracellular recording to be associated with prolonged inhibitory postsynaptic potentials (IPSPs), was also not changed by PCN. Antagonism of either pre- or postsynaptic spinal inhibition is not a necessary condition for induction of spinal seizures by PCN.     

The effects of naloxone, morphine and methionine enkephalinamide on Ia afferent terminations in the cat spinal cord

Naloxone, morphine, Met5-enkephalinamide (MENKA) and procaine were administered microelectrophoretically near extracellularly stimulated extensor muscle group Ia afferent fibres and terminations in the lumbar spinal cord of cats anaesthetized with pentobarbitone sodium. Observations were made of effects on the electrical threshold, on the depolarizing action of GABA or piperidine-4-sulphonate (P4S), and on bicuculline-sensitive primary afferent depolarization (PAD) generated by tetanic stimulation of flexor muscle low threshold afferents. All 4 agents reversibly elevated the threshold of Ia fibres in the dorsal column and Ia terminations in the ventral horn. The depolarizations of terminations by GABA or P4S were also reduced, an effect, which for all except MENKA, probably accounted for a concomitant reduction in PAD. In the absence of a consistent effect on either threshold or depolarization by GABAmimetics, MENKA reversibly diminished PAD, an action blocked by naloxone. Intravenously administered naloxone, in doses known to enhance spinal monosynaptic excitation in the cat, had no effect on GABAergic PAD and little or no effect on Ia termination threshold. The results are discussed in relation to a naloxone-sensitive effect of MENKA which reduces transmitter release from GABAergic axo-axonic synapses on Ia terminals, but which does not account for the enhancement of spinal reflexes by naloxone.     

The role of 5-HT, GABA and opioid peptides in presynaptic inhibition of tooth pulp input from the medial brainstem

In decerebrate or chloralose-anaesthetized cats electrical stimulation in the spinal trigeminal nucleus evoked antidromic responses in the mandibular canine tooth pulp. Conditioning stimulation in nucleus raphe magnus (NRM) and in the adjacent contralateral medullary reticular formation, nucleus reticularis gigantocellularis (NRGC) and nucleus reticularis magnocellularis (NRMC), produced a decrease in the threshold for the antidromic responses in a proportion of the tooth pulp inputs. This was interpreted as being due to depolarization of the tooth pulp afferent terminals, reflecting presynaptic inhibition. The primary afferent depolarization (PAD) of tooth pulp afferent terminals by NRM stimulation could be selectively blocked by bicuculline applied intravenously or by iontophoresis in the terminal region. Intravenous naloxone, cinanserin and methysergide had no effect on the PAD evoked from NRM, NRGC or NRMC. Thus NRM appears to exert presynaptic inhibitory control of A delta tooth pulp input to the spinal trigeminal nucleus via GABA-containing neurones.     

Efferent activity in the phrenic nerve during the startle reflex in chloralose-anesthetized cats

Reflex activity in the phrenic nerve was studied in chloralose anesthetized cats during development of somatic startle reflexes in limb and lower intercostal nerves. It was shown that the main component of this activity during low-threshold reflexes evoked by acoustic, tactile and low-threshold somatic afferent stimulation was depression of phrenic inspiratory activity. The following reflex discharges were prevalent components of phrenic responses to high-threshold afferent stimulation: early, propriospinal (intercostal-to-phrenic reflex) and late, suprasegmental ones. The latter were of two types: inspiratory (observed mainly during inspiration in about 75% of experiments) and expiratory (observed during expiration in 25% of experiments) which could be classified as "phrenic startle reflexes". Modulation of all responses during the respiratory cycle was described. Structural characteristics of reflex responses evoked in the phrenic nerve by stimulation of various respiratory and nonrespiratory bulbar sites as well as their respiratory modulation have been analyzed. Organization of possible neurophysiological mechanisms of phrenic responses during startle reflexes is discussed.     

Ammonia and methionine sulfoximine intoxication

Intoxication with ammonium acetate abolished the suppression of action potential generation by cortical postsynaptic inhibition, i.e. produced ‘disinhibition’, due to the inactivation of neuronal Cl⁻ extrusion. With the occurence of disinhibition cerebral ammonia increased to 445% of normal; glutamine increased to 170%.Methionine sulfoximine (MSO), an inhibitor of glutamine synthetase, produced disinhibition about 3 h after administration; at this time cerebral ammonia was increased to 290% of normal, glutamine was unchanged. Intoxication with MSO for less than 3 h significantly decreased the amount of ammonium acetate needed to produce disinhibition at cerebral ammonia concentrations of 340–430% of normal.MSO produces an endogenous ammonia intoxication which: (i) decreases the amount of exogenous ammonia required to affect cortical postsynaptic inhibitions; and (ii) eventually becomes sufficiently severe to disturb cortical inhibitory neuronal interactions by itself.     

Supraspinal regulation of spinal reflex discharge into cardiac sympathetic nerves

(1) In chloralose anaesthetized cats, reflex responses were recorded in inferior cardiac nerves following stimulation of intercostal nerves and hind limb afferent nerves. (2) In 80% of cats, a long latency reflex response alone was recorded, whereas, in the others, a short and long latency response was present to intercostal nerve stimulation. (3) In cats displaying only a long latency somatocardiac reflex response, damage to the ventral quadrant of the ipsilateral cervical spinal cord, through which runs a bulbospinal inhibitory pathway, resulted in the appearance of shorter latency reflexes to intercostal nerve stimulation. Lesions elsewhere in the cervical cord did not do this. (4) The characteristics of the early responses indicated that they were somatosympathetic reflexes and not dorsal root reflexes. (5) The early reflexes remained and the late reflex disappeared on subsequent complete transection of the spinal cord. The early reflexes were therefore spinal reflexes, and suppressed in the animal with cord intact. (6) Lesions at C4, which included a contralateral hemisection and a section of dorsal columns extending into the dorsal part of the lateral funiculus, abolished the inhibition of a sympathetic reflex that followed stimulation of some somatic afferent nerve fibres. These sections did not release the spinal reflex. Therefore, this reflex inhibition was not responsible for the suppression of the spinal somatosympathetic reflex. (7) The descending inhibitory influence on the segmental reflex pathway was not antagonized by strychnine, bicuculline or picrotoxin. (8) The possibility is discussed that the spinal reflex pathway into cardiac sympathetic nerves is tonically inhibited by a bulbospinal pathway originating from the classical depressor region of the ventromedial reticular formation.     

Flexor reflex decreases during sympathetic stimulation in chronic human spinal cord injury

A better understanding of autonomic influence on motor reflex pathways in spinal cord injury is important to the clinical management of autonomic dysreflexia and spasticity in spinal cord injured patients. The purpose of this study was to examine the modulation of flexor reflex windup during episodes of induced sympathetic activity in chronic human spinal cord injury (SCI). We simultaneously measured peripheral vascular conductance and the windup of the flexor reflex in response to conditioning stimuli of electrocutaneous stimulation to the opposite leg and bladder percussion. Flexor reflexes were quantified using torque measurements of the response to a noxious electrical stimulus applied to the skin of the medial arch of the foot. Both bladder percussion and skin conditioning stimuli produced a reduction (43–67%) in the ankle and hip flexor torques (p < 0.05) of the flexor reflex. This reduction was accompanied by a simultaneous reduction in vascular conductance, measured using venous plethysmography, with a time course that matched the flexor reflex depression. While there was an overall attenuation of the flexor reflex, windup of the flexor reflex to repeated stimuli was maintained during periods of increased sympathetic activity. This paradoxical depression of flexor reflexes and minimal effect on windup is consistent with inhibition of afferent feedback within the superficial dorsal horn. The results of this study bring attention to the possible interaction of motor and sympathetic reflexes in SCI above and below the T5 spinal level, and have implications for clinicians in spasticity management and for researchers investigating motor reflexes post SCI.     

Synaptic relationships between hair follicle afferents and neurones expressing GABA and glycine-like immunoreactivity in the spinal cord of the rat

gamma-Aminobutyric acid (GABA) and glycine have been implicated in the inhibition of sensory pathways in the dorsal horn of the spinal cord. The object of this study is to investigate the interactions between neurones immunoreactive for GABA and/or glycine and hair follicle afferent terminals labelled by intracellular injection with neurobiotin. GABA and glycine-like immunoreactivity in axons and dendrites in synaptic contact with the afferent terminals was demonstrated by using a postembedding immunogold method, and serial section reconstruction was used to show the distribution and nature of these interactions in lamina III of the dorsal horn. Most afferent boutons (94%) were postsynaptic at axo-axonic synapses: 67% of presynaptic boutons presynaptic to the afferent terminals were immunoreactive for GABA and glycine, 24% for GABA alone, and 7% for glycine alone. Only a small percentage of dendrites postsynaptic to afferent boutons appeared to belong to inhibitory interneurones: 3% were immunoreactive for GABA and glycine, 10% for glycine alone, but 87% were immunoreactive for neither antibody. Many afferent boutons were the central terminals of what appeared to be type IIb glomeruli and were involved triadic synaptic arrangements at which boutons presynaptic to an afferent terminal also made axodendritic contacts with dendrites postsynaptic to the afferent. Many of the presynaptic boutons involved in the triads were immunoreactive for GABA and glycine. Because afferent terminals do not themselves express glycine receptors (Mitchell et al. [1993] J. Neurosci. 13:2371-2381), glycine may therefore act on dendrites postsynaptic to hair follicle afferent terminals at these triads.     

Distribution and depression of the GABA(B) receptor in the spinal dorsal horn of adult rat.

gamma-Aminobutyric acid (GABA) is a principal inhibitory neurotransmitter in vertebrate nervous system. The metabotropic receptor for GABA, GABA(B) receptor, is characterized as a G protein-coupled receptor subtype. In the present study, GABA(B) receptor-like immunoreactivity (GABA(B)R-LI) in the rat spinal cord and dorsal root ganglion (DRG), as well as GABA(B) receptor-mediated depression in the spinal dorsal horn were examined by using immunohistochemistry and whole-cell voltage-clamp recording technique, respectively. Under light microscope, GABA(B)R-LI was densely found in laminae I and II of the dorsal horn. DRG cells of various diameters also showed GABA(B)R-LI. Electron microscopy further revealed that GABA(B)R-LI was also localized in terminals of myelinated, unmyelinated fibers as well as the somatodendritic sites of dorsal horn neurons. Bath application of a GABA(B) receptor agonist, baclofen (10 microM, 30 s), induced a slow outward (inhibitory) current in dorsal horn neurons. This slow current was depressed when the postsynaptic G protein-coupled receptor was inhibited, indicating the postsynaptic action of baclofen. Under the condition of postsynaptic GABA(B) receptor being inhibited, baclofen (10 microM, 60 s) depressed large (Abeta) and fine (C, Adelta) afferent fiber-evoked monosynaptic excitatory postsynaptic currents, indicating presynaptic inhibition of GABA(B) receptor on elicited neurotransmitter release. Taken together, the results suggest that baclofen-sensitive GABA(B) receptor is expressed pre- and postsynaptically on primary afferent fibers and neurons in the spinal dorsal horn; activation of GABA(B) receptor in the dorsal horn postsynaptically hyperpolarizes dorsal horn neurons and presynaptically inhibits primary afferents.     

Endocannabinoid-dependent plasticity at GABAergic and glutamatergic synapses in the striatum is regulated by synaptic activity

Long-term depression (LTD) at striatal synapses is mediated by postsynaptic endocannabinoid (eCB) release and presynaptic cannabinoid 1 receptor (CB₁R) activation. Previous studies have indicated that eCB mobilization at excitatory synapses might be regulated by afferent activation. To further address the role of neuronal activity in synaptic plasticity we examined changes in synaptic strength induced by the L-type calcium channel activator 2,5-dimethyl-4-[2-(phenylmethyl)benzoyl]-1H-pyrrole-3-carboxylic acid methyl ester (FPL 64176, FPL) at glutamatergic and γ-aminobutyric acid (GABA)ergic synapses in the striatum. We found that the basic mechanisms for FPL-mediated eCB signaling are the same at glutamatergic and GABAergic synapses. FPL-induced LTD (FPL-LTD) was blocked in slices treated with the CB₁R antagonist AM251 (2 μ m ), but established depression was not reversed by AM251. FPL-LTD was temperature dependent, blocked by protein translation inhibitors and prevented by intracellular loading of the anandamide transporter inhibitor VDM11 (10 μ m ) at both glutamatergic and GABAergic synapses. FPL-LTD at glutamatergic synapses required paired-pulse afferent stimulation, while FPL-LTD at GABAergic synapses could be induced even in the absence of explicit afferent activation. By evaluating tetrodotoxin-insensitive spontaneous inhibitory postsynaptic currents we found that neuronal firing is vital for eCB release and LTD induction at GABAergic synapses, but not for short-term depression induced by CB₁R agonist. The data presented here suggest that the level of neuronal firing regulates eCB signaling by modulating release from the postsynaptic cell, as well as interacting with presynaptic mechanisms to induce LTD at both glutamatergic and GABAergic synapses in the striatum.     

Quantitative characteristics of inhibition in the cuneate nucleus of the cat

Several properties of inhibition in the cuneate nucleus were investigated as an aid in deriving cuneate circuitry. Inhibition was examined by measuring changes in primary afferent terminal depolarization (PAD) and in the size of evoked medial lemniscal activity. Inhibition was produced by stimulation of several peripheral and central sites. Quantitative measurements were made of the inhibitory time course and degree of facilitation to conditioning trains of different lengths. The data suggest a dual organization of inhibition, dependent upon the conditioning site and characterized by the inhibitory time course. Additional information was derived from PAD measurements following simultaneous stimulation of two conditioning sites and from an investigation of a cortico-cuneate feedback loop. The proposed two inhibitory systems appear to converge for simultaneous activation did not produce simple summation of PAD. These results were substantiated when PAD was measured from single, identified cutaneous fibers. The time course of single fiber PAD was similar to that in a whole nerve preparation. Single fibers could be depolarized by conditioning several sites and with no apparent fiber class dependence. Several models of inhibitory circuitry are presented, and the features that must be taken into account are discussed.     

Long-term Depression in the Hippocampal CA1 Region is Associated with Equal Changes in AMPA and NMDA Receptor-mediated Synaptic Potentials

In the CA1 hippocampal region low-frequency (1-2 Hz) afferent activation leads to a long-term depression of excitatory synaptic potentials that is induced by calcium influx through postsynaptic N -methyl- d -aspartate receptor channels. In the present experiments using 2- to 3-week-old rats, long-term depressions of field excitatory postsynaptic potentials mediated by amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and by N -methyl- d -aspartate receptor channels were examined in parallel, using a perfusion solution containing low concentrations of an AMPA receptor antagonist and of magnesium (0.1 mM). These experiments revealed that long-term depression was associated with equal relative changes in the two components of the field potential, compatible with a presynaptic location of the expression mechanism for the long-term depression.     

Pre- and Post-synaptic Actions of 5-Hydroxytryptamine in the Rat Lumbar Dorsal Horn In Vitro: Implications for Somatosensory Transmission

Since the relative contribution of pre- versus post-synaptic actions of 5-hydroxytryptamine (5-HT) to modulation of somatosensory processing in the dorsal horn is not known, recordings fro m primary afferents and dorsal horn neurons from in vitro rat spinal cord were used to address this issue. 5-HT produced a depression of spontaneous dorsal root potentials and a slow primary afferent depolarization (PAD): the PAD versus 5-HT concentration-response curve was bell shaped (maximum at 5 μM; 250±C 41.5 μV). In 28/40 dorsal horn neurons, 5-HT elicited a slow depolarization not clearly associated with a specific input resistance change. Excitatory synaptic transmission from primary afferents to dorsal horn neurons was depressed by 5-HT in 40/45 neurons. 5-HT ≥ 5 μM significantly ( P ≤ 0.05) decreased the amplitude, shortened the total duration and half-decay time of the excitatory post-synaptic potential (EPSP). A dominant effect of 5-HT on longer latency EPSP components was evident. There was no direct relationship between the magnitude of PAD and the reduction of the EPSP by 5-HT. 5-Carboxamidotryptamine, an agonist for 5-HT¹ receptors, mimicked the depression of neurotransmission in the dorsal horn without producing PAD. A sample of dorsal horn neurons ( n = 8) was injected with biocytin and their morphology described. All had somata within laminae III-VI. In five of these neurons 5-HT depressed the EPSP but in one interneuron-like and one unclassed neuron the EPSP was potentiated. These data suggest that whilst depression of synaptic transmission is the predominant effect of 5-HT in the deep dorsal horn, this is not easily related to PAD or cellular actions of 5-HT on dorsal horn neurons.     

Cholinergic, noradrenergic, and serotonergic inhibition of fast synaptic transmission in spinal lumbar dorsal horn of rat

It is known that spinal nociceptive sensory transmission receives descending inhibitory and facilitatory modulation from supraspinal structures. Glutamate is the major fast excitatory transmitter between primary afferent fibers and spinal dorsal horn neurons. In whole-cell patch clamp recordings from dorsal horn neurons in spinal slices, we investigated synaptic mechanisms for inhibitory modulation at the lumbar level of the spinal cord. Application of the cholinergic receptor agonist carbachol produced a dose-dependent inhibition of glutamate-mediated excitatory postsynaptic currents (EPSCs) (IC(50) 13 microM). Postsynaptic injection of two different types of G-protein inhibitors, guanosine 5'-O-2-thiophosphate or guanosine 5'-O-3-thiotriphosphate, blocked the inhibition produced by carbachol. Clonidine, a selective alpha-adrenergic receptor agonist, also produced a dose-dependent inhibition of EPSCs (IC(50) 7 microM) that was reduced by postsynaptic inhibition of G-proteins. The inhibitory effect of serotonin was likewise mediated by postsynaptic G-proteins. Our results suggest that activation of postsynaptic neurotransmitter receptors plays a critical role in inhibition of glutamate mediated sensory responses by acetylcholine, norepinephrine, and serotonin. Our results support the hypothesis that descending sensory modulation may be mediated by multiple neurotransmitter receptors in the spinal cord.     

The orbicularis oculi response after hemispheral damage.

The corneal and blink reflexes were evaluated in 20 normal subjects and in 30 patients with motor deficits secondary to unilateral hemispheral lesions of vascular origin. In the normal population there were no differences between subjects below and subjects above 50 years of age. In the patients the reflex evoked by electrical stimulation of the cornea of the clinically affected side was depressed in 24 out of 30 cases. The depression mainly affected the afferent branch of the circuit, which triggers both homolateral and contralateral orbicularis oculi discharge (afferent abnormality). In three cases the depression was exerted concomitantly on the efferent branch (afferent and efferent abnormality) and only in one case was it limited to the efferent branch (efferent abnormality). The late R2 component of the blink reflex was depressed in 15 out of 30 patients. The early R1 component was slightly facilitated on the affected side. The changes of the corneal reflex and of the R2 component of blink reflex were similar, but the blink reflex had a greater safety factor. The patients with an abnormal corneal reflex had more extensive damage than had the patients with normal corneal response, as shown by computer tomography, but the site of the lesion was comparable in the two groups. Conduction through the brain stem circuits mediating the orbicularis oculi response is normally under pyramidal facilitatory influences while facial motoneurons are subjected to pyramidal inhibition. After pyramidal damage the transmission of impulses in the brain stem was slowed down, ultimately to a degree that abolished the reflex. Removal of pyramidal inhibition on facial motoneurons is probably the basis of the slight facilitation of the R1 component of the blink reflex.