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R A Davidoff

Publications and source records attributed to R A Davidoff.

At least 37 records · Page 2Linked to original sources
PubMed1991

Aspects of spinal cord structure and reflex function.

Current textbooks still feature overly simplistic approaches to spinal cord function. Medical training still emphasizes the notion of stereotyped spinal reflex responses fixed by rigid neuronal connections. These assumptions must be replaced by recognizing (1) that descending and sensory information converges on the same sets of interneurons, (2) that the effects of different classes of afferents from muscle, joints, and skin act together in different combinations as a result of convergence, (3) that the flexibility of reflex responses is determined in large measure by the excitability of interneurons, (4) that conventional and monoamine transmitters act and interact to adjust neuronal excitability and transmission in reflex pathways, and finally (5) that rhythmic movements are largely determined by intraspinal circuitry.

Animals↗
PubMed1990

Serotonin and GABA-induced depolarizations of frog primary afferent fibers.

The interaction of gamma-aminobutyric acid (GABA) and serotonin (5-HT) on primary afferent terminals of the isolated frog spinal cord was investigated by sucrose gap recordings from dorsal roots. Application of 5-HT (1.0-100 microM) to the Ringer's solution significantly reduced afferent terminal depolarizations elicited by concentrations of GABA ranging from 0.1 to 1.0 mM. The reductions of GABA-depolarizations which were produced by 1.0 microM 5-HT were mimicked by the 5-HT1A agonists 8-OH-DPAT (8-hydroxy-2-(n-dipropylamino)tetralin) and ipsapirone. The effects of ipsapirone were reversed by the 5-HT1A antagonist spiperone. The decreases of GABA-depolarizations produced by high doses of 5-HT were duplicated by application of alpha-methyl-5-HT, a 5-HT1C/2 agonist and reversed by superfusion of the cord with manserin, a 5-HT1C/2 antagonist. The presumptive 5-HT1A receptor-mediated effects of 1.0 microM 5-HT and 8-OH-DPAT appeared to result from a direct action on afferent terminals because the reduction of GABA responses was unchanged by addition of TTX to the Ringer's solution. In contrast, the putative 5-HT1C/2 receptor actions of 100 microM 5-HT and alpha-methyl-5-HT were substantially reduced by TTX and are presumably caused by activation of receptors located on interneurons. GABAB receptors did not appear to be affected by addition of 5-HT at low or high concentrations because baclofen-induced afferent terminal hyperpolarizations remained unchanged during exposure to 5-HT.(ABSTRACT TRUNCATED AT 250 WORDS)

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1990

An in vitro study of the effects of serotonin on frog primary afferent terminals.

The effects of serotonin on the membrane potential of primary afferent terminals of isolated hemisected frog spinal cords was investigated by sucrose gap recordings from dorsal root. Serotonin produced two distinctive changes in primary afferent terminal membrane potential: modest (about 0.5 mV) hyperpolarizations in low concentrations (0.01-1.0 microM) and larger (about 1.0 mV) slow depolarizations in higher concentrations (3.0-100 microM). The hyperpolarizations appeared related to a direct activation of 5-HT1A receptors on afferent terminals. The depolarizations were attributed to both direct and indirect actions and appeared to be generated by activation of 5-HT2 and/or 5-HT1C receptors. The results suggest that 5-HT released from terminals in the frog dorsal horn could exert a modulatory action on the afferent input of the spinal cord, but different effects generated by activation of different 5-HT receptor subtypes are dependent upon the concentration of the amine.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1990

Changes in membrane potential of frog motoneurons induced by activation of serotonin receptor subtypes.

Application of serotonin to the isolated, hemisected frog spinal cord resulted in two distinctive changes in motoneuron membrane potential: hyperpolarizations were produced by low concentrations (0.01-1.0 microM) and depolarizations by higher concentrations (3.0-100 microM). The hyperpolarizations appeared to be caused by a direct action of the amine upon motoneurons since exposure of spinal cord tetrodotoxin or magnesium ions in concentrations which blocked interneuronal firing and synaptic transmission, respectively did not reduce these responses. In contrast, depolarizations were significantly reduced by tetrodotoxin or magnesium indicating a large indirect component. The use of agonists and antagonists known to discriminate among different subtypes of serotonin receptors indicated that the hyperpolarizations were produced by activation of 5-HT1A receptors and the depolarizations were generated by activation of 5-HT2 and/or 5-HT1C receptors. Accordingly, the selective 5-HT1A agonists 8-hydroxy-2-(n-dipropylamino)tetralin and ipsapirone directly hyperpolarized motoneurons. The changes in potential produced by low concentrations of serotonin and by these agonists were blocked by the 5-HT1A receptor antagonists spiperone and spiroxatrine. In contrast, application of high concentrations of alpha-methyl-5-hydroxytryptamine, a serotonin analog which activates 5-HT1C and 5-HT2 receptor subtypes, depolarized motoneurons. These depolarizations, and those produced by high concentrations of serotonin, were blocked by the 5-HT1C/5-HT2 antagonists ketanserin, methysergide and mianserin. These observations indicate that serotonin can alter the membrane potential of motoneurons directly and indirectly by activation of both 5-HT1 and 5-HT2 receptor subtypes. Activation of different receptor subtypes depends upon the concentration of the amine.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1989

NMDA antagonists and potentiation of NMDA-induced motoneuron depolarizations in the isolated frog spinal cord.

The action of N-methyl-D-aspartate (NMDA) antagonists on motoneurons was studied in the isolated, hemisected frog spinal cord using sucrose gap techniques. NMDA-evoked motoneuron depolarizations were depressed by application of APV, APH, kynurenate, Mg2+ ions, ketamine, and MK-801. Upon returning to normal Ringer's solution after exposure to all antagonists (except MK-801). NMDA responses were significantly potentiated. Kainate- and quisqualate-induced depolarizations were unchanged. The facilitation appeared to result, at least in part, from a direct action on motoneuron membranes since it persisted in the presence of tetrodotoxin which eliminated interneuronal firing. However, indirect actions involving interneurons also contributed to the potentiation because NMDA-evoked changes in K+ release were increased following exposure to NMDA antagonists and return to normal medium. Reduction of temperature (7 degrees C) which should reduce amino acid uptake did not affect results with APV. In addition, desensitization of NMDA responses was not altered by application of APV. The results indicate that NMDA antagonists have complex and long-lasting effects on the function of the NMDA receptor complex.

2-Amino-5-phosphonovalerate↗
PubMed1989

Excitotoxicity, reflex responses, and evoked changes in extracellular potassium in the frog spinal cord.

1. The effects of the excitatory amino acid agonists kainate (KA), quisqualate (QUIS), and N-methyl-D-aspartate (NMDA) were studied in vitro on the hemisected frog spinal cord. 2. Prolonged (1.0 hr) application of excitatory amino acid agonists (KA, 50 or 300 microM; QUIS, 30 microM; NMDA, 300 microM) significantly reduced the ventral root potentials (VRPs) and [K+]0 evoked by a dorsal root tetanus (10 sec, 25 Hz), by brief (10 sec) applications of the same agonists (KA, 30 microM; QUIS, 30 microM; NMDA, 300 microM), and by GABA (10 sec, 1.0 mM). 3. The effect was essentially irreversible and persisted despite 2-4 hr of washing. 4. Excitatory amino acid antagonists (APV, 30 microM and kynurenate, 2 mM) blocked the neurotoxic effects of the excitatory agonists NMDA and KA respectively, an observation which indicates the observed effects of the agonists require the activation of specific excitatory receptors. 5. TTX did not alter the neurotoxic effects of KA suggesting that interneuronal firing does not contribute to the observed changes. 6. Addition of high K+ did not duplicate the effect of prolonged excitatory amino acid agonist exposure, an indication that elevation of K+ does not cause the decreased responses. 7. Light microscopy did not provide any evidence of gross tissue damage. 8. The parallel reduction of postsynaptic responses and delta [K+]0 support the idea that elevation of extracellular [K+] by afferent stimuli results from interneuronal activity.

Amino Acids↗
PubMed1988

Excitatory transmitters, ventral root potentials and [K+]o in the isolated frog leg-spinal cord preparation.

Motoneuron depolarizations and changes in [K+]o were studied in the isolated frog spinal cord in response to non-nociceptive (touch/pressure) and nociceptive (acetic acid, heat, pinch) stimulation of the skin of the leg. Kynurenate, APV (D(-)-2-amino-5-phosphonovalerate), and 1.0 mM Mg2+ blocked or substantially reduced responses produced by all types of stimuli. Spantide was minimally effective in reducing nociceptive responses and had insignificant effects on responses to innocuous stimuli. These observations are consistent with the notion that excitatory amino acids activating both N-methyl-D-aspartate (NMDA) and non-NMDA receptors participate in the reflex responses to cutaneous stimuli in the frog spinal cord.

2-Amino-5-phosphonovalerate↗
PubMed1988

Primary afferent activity, putative excitatory transmitters and extracellular potassium levels in frog spinal cord.

1. Changes in extracellular K+ activity were measured with ion-selective microelectrodes in the grey matter of the isolated hemisected frog spinal cord. The magnitude of the elevation of [K+]o (delta[K+]o) produced by repetitive stimulation (25 Hz, 10 s) of afferent fibres in the sciatic nerve was monotonically related to the strength of the electrical stimuli applied to the sciatic nerve. Repetitive stimulation of the largest diameter A alpha and A beta fibres, which were found histologically to comprise only 11% of the afferent axons in the dorsal root, elevated [K+]o to approximately 60% of the maximum level seen when all afferent fibres were stimulated. 2. Addition of Mg2+ (20 mM) to Ringer solution devoid of Mg2+ reduced delta[K+]o by over 85% suggesting that about 15% of delta[K+]o results from action potentials in presynaptic primary afferents. When 20 mM-Mg2+ was added to spinal cords bathed in Ringer solution containing a physiological (i.e. 1.0 mM) concentration of Mg2+, delta[K+]o was reduced by ca. 65-75% indicating that in spinal cords bathed in medium containing 'physiological' concentrations of Mg2+ about 25-35% of the K+ is released from primary afferent fibres. 3. Application of excitatory amino acids and agonists increased [K+]o with the following potency pattern: quisqualate greater than kainate greater than NMDA (N-methyl-D-aspartate) greater than glutamate greater than aspartate. 4. D(-)-2-Amino-5-phosphonovalerate (APV), an NMDA antagonist, reduced [K+]o by only about 50%, but kynurenate, an NMDA and non-NMDA antagonist, reduced [K+]o by approximately 85%; i.e. the same levels observed when synaptic transmission was blocked with 20 mM-Mg2+. These findings support the idea that synaptic release of excitatory amino acids such as L-glutamate and/or L-aspartate and subsequent activation of specific receptors by these putative transmitters are necessary for the postsynaptic component of delta[K+]o. 5. Addition of tachykinins elevated [K+]o but the effect appeared to require the participation of excitatory amino acids because it was blocked by APV and by kynurenate. 6. The finding that tetrodotoxin substantially reduced the ability of excitatory amino acid agonists and tachykinins to elevate [K+]o suggests that discharges in interneurones as a result of excitatory amino acid receptor activation are responsible for the postsynaptic component of delta[K+]o.

Action Potentials↗
PubMed1987

After-hyperpolarizations produced in frog motoneurons by excitatory amino acid analogues.

After-hyperpolarizations (AHPs) produced in frog motoneurons by applications of the excitatory amino acid analogues quisqualate (QUIS), N-methyl-D-aspartate (NMDA), and kainate (KA) were studied in the isolated hemisected frog spinal cord using sucrose gap techniques. AHPs were present following 98% of QUIS-induced depolarizations, but were seen in only 35% and 15% of NMDA- and KA-evoked responses respectively. AHPs produced by QUIS are produced both by direct effects of QUIS on motoneuron membranes and by indirect effects mediated through a synaptic process involving interneurons. Thus, application of Mg2+, Mn2+, or tetrodotoxin (TTX) in concentrations sufficient to block synaptic transmission and interneuronal firing, reduced, but did not abolish the AHPs produced by QUIS. In contrast, NMDA- and KA-AHPs appear to be entirely mediated by indirect means as block of synaptic transmission and interneuronal firing eliminated AHPs produced by these substances. Exposure of the cord to Mn2+ after addition of TTX did not affect the size of QUIS-AHPs. In the presence of TTX, QUIS-AHPs were reduced or completely blocked by addition of dinitrophenol (DNP) and sodium cyanide, by dihydro-ouabain, by removal of K+ from the superfusate, by cooling, and by replacement of 50% of the external Na+ with Li+. The results suggest that the QUIS-AHPs are largely the result of the direct effect of the excitatory amino acid agonist on motoneuron membranes and is caused by activation of an electrogenic Na+ pump. AHPs following depolarizations evoked by NMDA and KA are presumably the result of indirect actions of these latter analogues on interneurons.

2,4-Dinitrophenol↗
PubMed1987

Epinephrine and norepinephrine modulate neuronal responses to excitatory amino acids and agonists in frog spinal cord.

The interaction of the catecholamines epinephrine (E) and norepinephrine (NE) (1.0-100 microM) and excitatory amino acids on motoneurons of the isolated superfused frog spinal cord was investigated by sucrose gap recordings from ventral roots. Exposure of the cord to E or NE 30 sec prior to application of L-aspartate or L-glutamate reduced the motoneuron depolarizations produced by the amino acids. The reduction of responses to the mixed receptor agonists L-glutamate and L-aspartate may be the result of opposite actions of the catecholamines on the activation of specific excitatory receptors by the amino acids. Thus, E and NE facilitated depolarizations caused by application of N-methyl-D-aspartate (NMDA) and depressed those produced by quisqualate. The effect on NMDA responses appeared to be beta-adrenoceptor mediated because it was mimicked by the beta-agonist isoproterenol and blocked by propranolol. The effect on quisqualate depolarizations appeared to require activation of alpha 2-adrenoceptors; it was mimicked by the alpha 2-agonists clonidine and alpha-methylnorepinephrine and antagonized by yohimbine and piperoxan. These results are important in understanding the actions of catecholamines on reflex transmission in spinal pathways which use excitatory amino acids as transmitters.

Amino Acids↗
PubMed1986

Analysis of the responses of frog motoneurons to epinephrine and norepinephrine.

Epinephrine and norepinephrine were applied to the isolated superfused frog spinal cord hyperpolarized motoneurons. The hyperpolarization was related to both direct and indirect actions and the indirect effects were produced by activation of alpha 2-adrenoceptors. In about half of the spinal cords a slow depolarization caused by activation of beta-receptors was seen and was largely attributable to direct actions of the catecholamines on motoneuron membranes. In a small number of preparations an early alpha 1-mediated depolarization was noted. The results suggest that catecholamines released from terminals in the frog ventral horn could exert a modulatory action on the motoneuron output from the spinal cord.

Adrenergic Antagonists↗
PubMed1986

Effects of barium on isolated frog spinal cord.

The effects of Ba2+ were studied in vitro on the isolated frog spinal cord. Ba2+ (25 microM-5 mM) caused a concentration-dependent depolarization of ventral (VR) and dorsal (DR) roots. TTX and Mg2+ substantially reduced the depolarization suggesting that interneuronal effects were involved. Ba2+ (25-500 microM) markedly increased the frequency and duration of spontaneous VR and DR potentials and substantially enhanced the duration (and frequently the amplitude) of VR and DR potentials evoked by DR stimulation. Higher concentrations of Ba2+ (1-5 mM) reduced both spontaneous and evoked potentials. Ba2+ (25-500 microM) enhanced the amount of K+ released by a DR volley and by application of L-glutamate and L-aspartate. The cation reduced VR and DR root depolarizations produced by elevated [K+]0. VR potentials induced by L-glutamate, L-aspartate, GABA and glycine and DR depolarizations caused by GABA were reduced by Ba2+. These results show that Ba2+ has complex actions on reflex transmission, interneuronal activity, the postsynaptic actions of excitatory and inhibitory amino acids and the evoked release of K+.

Action Potentials↗
PubMed1985

Potential changes of frog afferent terminals in response to dopamine.

The actions of dopamine on the membrane potential of afferent fibers of the isolated hemisected frog spinal cord were studied by sucrose gap techniques. The most prominent effect seen after addition of dopamine to the superfusing Ringer's solution was a slow reversible hyperpolarization at concentrations as low as 0.01 microM; its amplitude and duration were dependent upon concentration and length of application. Biphasic responses with an initial dominant hyperpolarization and a much smaller, later depolarization were also noted and were particularly prominent when dopamine was applied at higher concentrations. Exposure of the cord to apomorphine, a non-selective agonist, to SKF 38393A, a D-1 selective agonist, or to LY-14186, a D-2 selective agonist, hyperpolarized the dorsal root in a manner similar to that of dopamine, but only when the former compounds were applied at higher concentrations (100 microM or greater). Apomorphine also elicited a late depolarization. The non-selective dopamine antagonists, fluphenazine and haloperidol, reversibly reduced dopamine's actions. Similar effects were produced by the selective D-2 antagonists, sulpiride and metoclopramide, which had no effect on hyperpolarizations evoked by norepinephrine. Dopamine did not appear to activate adrenergic or serotonergic receptors, for its effects were not affected by yohimbine, corynanthine, propranolol, or methysergide. The effect of dopamine appeared to result from an action of the amine on both afferent fibers and interneurons. This inference was drawn because the potential changes produced by dopamine were substantially reduced, but never eliminated, by superfusion of the cord with solutions containing Mn2+ ions, tetrodotoxin or mephenesin.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1985

Epinephrine- and norepinephrine-evoked potential changes of frog primary afferent terminals: pharmacological characterization of alpha and beta components.

The effects of superfused epinephrine (E) and norepinephrine (NE) on the membrane potential of primary afferent fibers of the isolated frog spinal cord were studied by sucrose gap recordings from the dorsal root. In all preparations both E and NE, applied in concentrations ranging from 0.1 microM to 1.0 mM, produced a hyperpolarization of afferent terminals. In many instances this was followed by a slow depolarization and, in a small number of cords, a small depolarization preceded the increase in membrane potential. E- and NE-induced hyperpolarizations were blocked by the selective alpha 2-antagonists yohimbine and piperoxan, but not by the selective alpha 1-antagonists prazosin and corynanthine or by the beta-blockers propranolol and sotalol. The alpha 2-agonists clonidine, alpha-methylnorepinephrine and guanabenz also hyperpolarized terminals, causing a change in potential that was reduced by yohimbine and piperoxan. Taken together, these results suggest that alpha 2-receptors mediate the hyperpolarizing effects of E and NE. The beta-agonist isoproterenol evoked a slow depolarization similar to that produced by E and NE. The isoproterenol-depolarization was antagonized by propranolol. Sometimes, application of E and NE after superfusion with yohimbine produced only a depolarization of the dorsal root and this depolarization was sensitive to propranolol. It would appear therefore that the late depolarization seen after the application of E and NE is produced by activation of beta-receptors. In contrast, the alpha 1-agonist phenylephrine elicited a short latency, short duration depolarization similar to those seen preceding approximately 10% of the E- and NE-hyperpolarizations. Such short-latency depolarizations were blocked by prazosin and corynanthine. The major component of the response to both E and NE is indirectly mediated through a synaptic process: application of Mn2+, Mg2+, procaine or tetrodotoxin in concentrations sufficient to block synaptic transmission substantially reduced, but never eliminated, the actions of the catecholamines. Interneurons are probably involved because mephenesin, which reduces interneuronal transmission, significantly decreased the E and NE effects. Furthermore, interneurons which secrete excitatory amino acids and/or GABA may mediate the indirect effects of the catecholamines on afferent terminals because (-)baclofen and D.L-alpha-aminoadipate decrease, and picrotoxin and bicuculline increase, the dorsal root (DR) effects of E and NE.(ABSTRACT TRUNCATED AT 400 WORDS)

Adrenergic Agonists↗
PubMed1985

Antispasticity drugs: mechanisms of action.

Several different drugs are now used, or are potentially useful, to treat patients with spasticity. Although these compounds vary in their actions on spinal neurons and reflex arcs, it is possible to formulate reasonable hypotheses regarding their modes of action. The benzodiazepines bind to specific benzodiazepine receptors linked to classic gamma-aminobutyric acid (GABA) receptors located on the terminals of primary afferent fibers. This binding results in an increased affinity of the GABA receptor for the amino acid, an augmented flux of chloride ions across the terminal membrane, and an increase in the amount of presynaptic inhibition. Baclofen activates GABAB receptors putatively located on the same terminals. Activation of these receptors retards the influx of calcium ions into the terminals, thereby reducing the evoked release of excitatory amino acids and possibly other transmitters. Progabide and its metabolites act on both classic and GABAB receptors. Glycine works on specific inhibitory receptors located on spinal interneurons and motoneurons. The phenothiazines act on the brainstem to alter the function of fusimotor fibers. Phenytoin and carbamazepine reduce the afferent output of muscle spindles. Dantrolene diminishes the activation of the contractile process in muscle fibers by reducing the release of calcium ions from the sarcoplasmic reticulum. This review summarizes the data supporting these concepts.

Adrenergic alpha-Antagonists↗