Excitation Of Afferent Fibers Research Articles

Modulation of sensory input to the spinal cord: Contribution of focal epidural polarization and of GABA released by interneurons and glial cells.

Modulation of input from primary afferent fibres has long been examined at the level of the first relays of these fibres. However, recent studies reveal that input to the spinal cord may also be modulated at the level of the very entry of afferent fibres to the spinal grey matter before action potentials in intraspinal collaterals of afferent fibres reach their target neurons. Such modulation greatly depends on the actions of GABA via extrasynaptic membrane receptors. In the reported study we hypothesized that the increase in excitability of afferent fibres following epidural polarization close to the site where collaterals of afferent fibres leave the dorsal columns is due to the release of GABA from two sources: not only GABAergic interneurons but also glial cells. We present evidence, primo, that GABA released from both these sources contributes to a long-lasting increase in the excitability and a shortening of the refractory period of epidurally stimulated afferent fibres and, secondo, that effects of epidural polarization on the release of GABA are more critical for these changes than direct effects of DC on the stimulated fibres. The experiments were carried out in deeply anaesthetized rats in which changes in compound action potentials evoked in hindlimb peripheral nerves by dorsal column stimulation were used as a measure of the excitability of afferent fibres. The study throws new light on the modulation of input to spinal networks but also on mechanisms underlying the restoration of spinal functions.

The plasticity of nerve fibers: the prolonged effects of polarization of afferent fibers.

The review surveys various aspects of the plasticity of nerve fibers, in particular the prolonged increase in their excitability evoked by polarization, focusing on a long-lasting increase in the excitability of myelinated afferent fibers traversing the dorsal columns of the spinal cord. We review the evidence that increased axonal excitability 1) follows epidurally applied direct current (DC) as well as relatively short (5 or 10 ms) current pulses and synaptically evoked intrinsic field potentials; 2) critically depends on the polarization of branching regions of afferent fibers at the sites where they bifurcate and give off axon collaterals entering the spinal gray matter in conjunction with actions of extrasynaptic GABAA membrane receptors; and 3) shares the feature of being activity-independent with the short-lasting effects of polarization of peripheral nerve fibers. A comparison between the polarization evoked sustained increase in the excitability of dorsal column fibers and spinal motoneurons (plateau potentials) indicates the possibility that they are mediated by partly similar membrane channels (including noninactivating type L Cav++ 1.3 but not Na+ channels) and partly different mechanisms. We finally consider under which conditions transspinally applied DC (tsDCS) might reproduce the effects of epidural polarization on dorsal column fibers and the possible advantages of increased excitability of afferent fibers for the rehabilitation of motor and sensory functions after spinal cord injuries.NEW & NOTEWORTHY This review supplements previous reviews of properties of nerve fibers by surveying recent experimental evidence for their long-term plasticity. It also extends recent descriptions of spinal effects of DC by reviewing effects of polarization of afferent nerve fibers within the dorsal columns, the mechanisms most likely underlying the long-lasting increase in their excitability and possible clinical implications.

Interactions Between Baclofen and DC-induced Plasticity of Afferent Fibers within the Spinal Cord

The aims of the study were to compare effects of baclofen, a GABAB receptor agonist commonly used as an antispastic drug, on direct current (DC) evoked long-lasting changes in the excitability of afferent fibers traversing the dorsal columns and their terminal branches in the spinal cord, and to examine whether baclofen interferes with the development and expression of these changes. The experiments were performed on deeply anesthetized rats by analyzing the effects of DC before, during and following baclofen administration. Muscle and skin afferent fibers within the dorsal columns were stimulated epidurally and changes in their excitability were investigated following epidural polarization by 1.0–1.1 μA subsequent to i.v. administration of baclofen. Epidural polarization increased the excitability of these fibers during post-polarization periods of at least 1 h. The facilitation was as potent as in preparations that were not pretreated with baclofen, indicating that the advantages of combining epidural polarization with epidural stimulation would not be endangered by pharmacological antispastic treatment with baclofen. In contrast, baclofen-reduced effects of intraspinal stimulation combined with intraspinal polarization (0.3 μA) of terminal axonal branches of the afferents within the dorsal horn or in motor nuclei, whether administered ionophoretically or intravenously. Effects of DC on monosynaptically evoked synaptic actions of these fibers (extracellular field potentials) were likewise reduced by baclofen. The study thus provides further evidence for differential effects of DC on afferent fibers in the dorsal columns and the preterminal branches of these fibers and their involvement in spinal plasticity.

Long-term effects of direct current are reproduced by intermittent depolarization of myelinated nerve fibers.

Direct current (DC) potently increases the excitability of myelinated afferent fibers in the dorsal columns, both during DC polarization of these fibers and during a considerable (>1 h) postpolarization period. The aim of the present study was to investigate whether similarly long-lasting changes in the excitability of myelinated nerve fibers in the dorsal columns may be evoked by field potentials following stimulation of peripheral afferents and by subthreshold epidurally applied current pulses. The experiments were performed in deeply anesthetized rats. The effects were monitored by changes in nerve volleys evoked in epidurally stimulated hindlimb afferents and in the synaptic actions of these afferents. Both were found to be facilitated during as well as following stimulation of a skin nerve and during as well as following epidurally applied current pulses of 5- to 10-ms duration. The facilitation occurring ≤2 min after skin nerve stimulation could be linked to both primary afferent depolarization and large dorsal horn field potentials, whereas the subsequent changes (up to 1 h) were attributable to effects of the field potentials. The findings lead to the conclusion that the modulation of spinal activity evoked by DC does not require long-lasting polarization and that relatively short current pulses and intrinsic field potentials may contribute to plasticity in spinal activity. These results suggest the possibility of enhancing the effects of epidural stimulation in human subjects by combining it with polarizing current pulses and peripheral afferent stimulation and not only with continuous DC. NEW & NOTEWORTHY The aim of this study was to define conditions under which a long-term increase is evoked in the excitability of myelinated nerve fibers. The results demonstrate that a potent and long-lasting increase in the excitability of afferent fibers traversing the dorsal columns may be induced by synaptically evoked intrinsic field as well as by epidurally applied intermittent current pulses. They thus provide a new means for the facilitation of the effects of epidural stimulation.

DC-Evoked Modulation of Excitability of Myelinated Nerve Fibers and Their Terminal Branches; Differences in Sustained Effects of DC

Direct current (DC) evokes long-lasting changes in neuronal networks both presynaptically and postsynaptically and different mechanisms were proposed to be involved in them. Different mechanisms were also suggested to account for the different dynamics of presynaptic DC actions on myelinated nerve fibers stimulated before they entered the spinal gray matter and on their terminal branches. The aim of the present study was to examine whether these different dynamics might be related to differences in the involvement of K+ channels. To this end, we compared effects of the K+ channel blocker 4-amino-pyridine (4-AP) on DC-evoked changes in the excitability of afferent fibers stimulated within the dorsal columns (epidurally) and within their projection areas in the dorsal horn and motor nuclei (intraspinally). 4-AP was applied systemically in deeply anesthetized rats. DC-evoked increases in the excitability of epidurally stimulated afferent nerve fibers, and increases in field potentials evoked by these fibers, were not affected by 4-AP. In contrast, sustained decreases rather than increases in the excitability of intraspinally stimulated terminal nerve branches were evoked by local application of DC in conjunction with 4-AP. The study leads to the conclusion that 4-AP-sensitive K+ channels contribute to the sustained DC-evoked post-polarization increases in the excitability at the level of terminal branches of nerve fibers but not of the nodes of Ranvier nor within the juxta-paranodal regions where other mechanisms would be involved in inducing the sustained DC-evoked changes.

Evidence that some long-lasting effects of direct current in the rat spinal cord are activity-independent.

The effects of trans-spinal direct current (DC) stimulation (tsDCS) on specific neuronal populations are difficult to elucidate, as it affects a variety of neuronal networks. However, facilitatory and depressive effects on neurons processing information from the skin and from muscles can be evaluated separately when weak (0.2-0.3μA) DC is applied within restricted areas of the rat spinal cord. The effects of such local DC application were recently demonstrated to persist for at least 1h, and to include changes in the excitability of afferent fibres and their synaptic actions. However, whether these effects require activation of afferent fibres in spinal neuronal pathways during DC application, i.e. whether they are activity-dependent or activity-independent, remained an open question. The aim of the present study was to address this question by analysing the effects of local DC application on monosynaptic actions of muscle and skin afferents (extracellular field potentials) and afferent fibre excitability. The results revealed that long-lasting post-polarization changes evoked without concomitant activation of afferent fibres replicate changes evoked by stimuli applied during, before and after polarization. The study leads to the conclusion that the reported effects are activity-independent. As this conclusion applies to the local effects of DC application in at least two spinal pathways and to the effects of both cathodal and anodal polarization, it indicates that some of the more widespread effects of trans-spinal and trans-cranial stimulation (both tsDCS and transcranial DC stimulation) may be activity-independent. The results may therefore contribute to the design of more specific DC applications in clinical practice.

Neural control of the bladder

Normal bladder function includes a storage phase and a voiding or micturition phase, which are controlled by neural circuits integrated at the level of the forebrain, brainstem, and spinal cord. Urine storage depends on lumbosacral spinal reflexes, whereas normal micturition involves a spino-bubo-spinal reflex mediated by the pontine micturition center (PMC). Behavioral and emotional influences affect the micturition reflex via integration of inputs from the frontal lobe and bladder afferents at the level of the periaqueductal gray (PAG). Experimental studies in animals and functional neuroimaging studies in humans have provided abundant information into the normal mechanisms of micturition, including the role of the bladder urothelium, plasticity of the spinal micturition reflexes, and behavioral control of micturition by cortical networks. This information has provided new insight into the pathophysiology of neurogenic bladder, including detrusor overactivity, in spinal cord and other neurologic disorders. There are recent excellent reviews by investigators who have contributed to the current understanding of bladder control mechanisms.1,–,5 Only few salient concepts will be emphasized here. ### Urothelium and mechanosensory transduction. The urothelium is the epithelial lining of the lower urinary tract and includes a superficial layer composed of large hexagonal cells, called “umbrella cells”; these cells are interconnected by tight junctions and covered by crystalline proteins called uroplakins.2,6 The urothelium has a major role in mechanosensory transduction via reciprocal interactions with afferent and efferent nerves (figure 1). During bladder filling, the umbrella cells release several chemical signals, including acetylcholine (ACh), nitric oxide (NO), and adenosine triphosphate (ATP), which alter the excitability of afferent fibers. For example, ATP, acting via P2X and P2Y receptors, excites C-fiber afferents by reducing threshold of activation of transient receptor potential vanilloid type 1 (TRPV1) channels. ATP also acts as an autocrine signal between urothelial cells and as a paracrine signal …

중주파 전류의 주파수가 감각 역치에 미치는 영향

Purpose : The purpose of this study was to examine the effects of different medium frequency currents on afferent fibers. Methods : Thirty healthy volunteers who had no known history of neurological disorders were equally assigned to one of three groups; 2500Hz, 4000Hz, and control and each group was applied to the left wrist in palmer cutaneous branch of radial nerve by different medium frequency currents for 15 min. We measured the changes of thresholds for tactile, two-point discrimination, and thresholds for pain. Results : The results showed that the medium frequency currents stimulation increased thresholds for tactile, two-point discrimination, and thresholds for pain. However, there is no statistically significant difference between group 2500Hz and group 4000Hz. Conclusion : This may explain thresholds for tactile, two-point discrimination, and thresholds for pain plain medium frequency currents stimulation inhibits the excitability of afferent fibers, but the effect of the frequency difference within medium frequency currents is not demonstrated.

Inflammation-induced plasticity of the afferent innervation of the airways.

The activation of primary afferent neurons that innervate the airways leads to homeostatic and defensive reflexes. The anatomic and physiologic characteristics of these afferent fibers do not appear to be static properties but rather appear to change rapidly in response to inflammation. The threshold for activation of airway afferent neurons to various stimuli, for example, is not fixed; these fibers can be become sensitized during inflammation. A subset of nociceptive-like (C-fibers) airway afferent neurons not only participates in centrally mediated reflexes but is also thought to release neuropeptides at their peripheral terminals, leading to neurogenic inflammation. An increase in the content of tachykinins is commonly seen in inflamed tissues, and there is accumulating evidence that irritation and inflammation of the airways is associated with the induction of tachykinin synthesis in non-nociceptive airway afferent fibers that under normal conditions do not contain neuropeptides. The release of neurokinins from the peripheral terminals in the airways and their central terminals in the brain stem may contribute to the symptoms of inflammatory airway diseases. Elevated release of neurokinins from peripheral terminals may promote local inflammatory responses, and the release of neurokinins in the brainstem, together with inflammation-induced increases in the excitability of afferent fibers, may culminate in altered visceral autonomic reflex activity, changes in breathing pattern, and cough.

The NMDA receptor antagonist CPP suppresses long-term potentiation in the rat hippocampal-accumbens pathway in vivo.

Excitation of afferent fibres originating in the ventral subiculum of the hippocampus through stimulation of the fimbria elicits field potentials in the nucleus accumbens. When recorded in the dorsomedial aspect of the nucleus accumbens, the evoked field responses consisted of an early, negative-going component (N1) with a peak latency of 8-10 ms, followed by a second negative-going peak (N2) with a latency of 22-24 ms. The N1 response reflects monosynaptic activation of nucleus accumbens neurons; the N2 component appears to be polysynaptic in origin. In control rats, high-frequency stimulation of the fimbria (three trains at 250 Hz, 250 ms, delivered at 50 min intervals) resulted in a long-lasting potentiation of both the N1 and N2 components. The magnitude of potentiation exhibited by the polysynaptic N2 response was typically greater than that of the monosynaptically evoked N1 response. Following delivery of the first train, the amplitude of the N1 and N2 components was increased by approximately 20 and 50% respectively. Administration of the competitive N-methyl-D-aspartate (NMDA) receptor antagonist 3-[(+-)-2-carboxypiperazin-4-yl]-propyl-1-phosphonic acid (CPP, 10 mg/kg i.p.) had no significant effects on the evoked nucleus accumbens responses. High-frequency stimulation failed to produce a significant increase in the amplitude of either the N1 or the N2 response when delivered 45-60 min after CPP administration. To test whether the suppressant effects of CPP were time-dependent, two further high-frequency trains were applied 90 and 180 min after administration of the drug.(ABSTRACT TRUNCATED AT 250 WORDS)

Knee joint input into the peripheral region of the ventral posterior lateral nucleus of cat thalamus.

1. Experiments were carried out in chloralose-anesthetized cats to study the responses of neurons in the lateral thalamus to excitation of afferent fibres from the knee joint. 2. Single- and multi-unit recordings were made with tungsten electrodes in dorsoventral penetrations through the ventral posterior lateral nucleus (VPL) during electrical stimulation of the medial articular nerve (MAN) of the cat's knee joint at an intensity sufficient to excite slowly conducting unmyelinated fibers. The locations of the recording sites were verified by recovering electrolytic lesion sites in histological sections (Nissl and cytochrome oxidase staining). 3. The average earliest latency for excitation of thalamic responses was 19.1 +/- 8.5 (SD) ms (n = 50). The threshold for excitation of most thalamic units was found to correspond to peripheral joint afferent fibers of the A-delta group. 4. The majority of neurons responding to MAN stimulation were found to be dorsal or ventral to the low-threshold cutaneous hindlimb region of the lateral division of the VPL (stereotaxic coordinates: AP 9.0-11.5; ML 7.0-9.5). In the ventral periphery of the VPL, most neurons responding to MAN stimulation (11/14) were wide dynamic range (WDR) with a discrete cutaneous receptive field on the hindpaw digits. Six WDR neurons were found dorsal to the hindlimb VPL with a convergent receptive field on the hindlimb (but not hindpaw digits). No nociceptive-specific knee joint units were found. 5. Other neurons were found dorsal to the hindlimb VPL with large receptive fields often encompassing the whole contralateral leg, including skin and deep hindlimb structures, possibly in a region described as the dorsal portion of the posterior complex (POd). Some neurons were found with no receptive field. 6. This study provides the first observations on the responses of lateral thalamic neurons to stimulation of the MAN of the cat knee joint. These results demonstrate a central pathway conveying impulses from specific deep joint afferents of the MAN to the peripheral region of the VPL and overlying region known as the POd, regions implicated in the transmission of nociceptive information.

Buspirone attenuates synaptic activation of hippocampal pyramidal cells

The actions of 5-hydroxytryptamine (5-HT) and buspirone, an anxiolytic agent that displays high and selective affinity for 5-HT1A receptor sites, on synaptic activation of hippocampal CA1 pyramidal cells were studied in vitro. Whereas 5-HT application leads to a rapid hyperpolarization and decreased input resistance in pyramidal cells, buspirone has no measurable effects on membrane potential and input resistance. However, unlike 5-HT, buspirone application leads to a gradual and reversible reduction in excitatory postsynaptic potentials (EPSPs) elicited by stimulation of afferents in the stratum radiatum. Concurrent with this attenuation of the EPSP, buspirone decreases the excitability of afferent fibers in the stratum radiatum as evidenced by conduction slowing, increased refractory period, and decreased ability to generate repetitive impulses. 5-HT has no measurable effect on the afferent fibers. The attenuation of the EPSPs and the decrease in afferent fiber excitability appear to be independent of 5-HT receptors as 5-HT neither shares nor antagonizes the effects of buspirone. Thus, both 5-HT and buspirone can contribute to reduced spike activity in pyramidal cells, but they do so via different mechanisms: 5-HT hyperpolarizes pyramidal cells whereas buspirone attenuates their synaptic activation, possibly via action on the presynaptic fibers in the stratum radiatum.

Effects of d-α-aminoadipate on excitation of afferent fibers in the lateral line of Xenopus laevis

The effects of d-α-aminoadipate (DαAA) on excitation of afferent nerve fibers in the Xenopus laevis lateral line were studied in vitro. DαAA reversibly suppressed spontaneous activity and excitation induced by water motion at concentrations as low as 0.25–0.5 mM. Higher concentrations (up to 10 mM) caused a greater suppression that was rapidly and fully reversible. l-α-Aminoadipate at 0.25–1.0 mM had no suppressive effects. Responses elicited by NMDA (1.0–2.0 mM) were the most sensitive to DαAA (0.25–0.5 mM), those elicited by l-aspartate and l-glutamate (1.0–2.0 mM) were less sensitive and similar, and those elicited by kainate (5–15 μM) were the least sensitive. The results provide evidence that the transmitter released by hair cells in the Xenopus lateral line interacts postsynaptically with NMDA-preferring receptors and that the transmitter is an excitatory amino acid, possibly l-glutamate of l-aspartate.

Effects of 4-aminopyridine on synaptic transmission in the cat spinal cord

An analysis was made of effects of 0.1–1.0 mg/kg 4-aminopyridine (4-AP) i.v. on excitatory and inhibitory spinal reflex pathways in lightly anaesthetized or decerebrated cats. The effects appeared within the first minutes of the injection, reached maximum after about 10–15 min and remained stable during at least several hours. 4-AP enhanced the following synaptic actions on motoneurones: monosynaptic excitation from Ia afferents and descending tracts, disynaptic and polysynaptic excitation from group Ib, group II, cutaneous and high threshold muscle afferents, disynaptic inhibition from Ia and Ib afferents and recurrent and polysynaptic inhibition from different afferents. 4-AP also increased primary afferent depolarization and excitation of ascending tract cells by peripheral stimuli. In the case of the disynaptic inhibitory pathways it has been shown that 4-AP may enhance the excitation of the interposed interneurones but it also increases the actionof these interneurones on the motoneurones; monosynaptic inhibition evoked in motoneurons by electrical stimulation of the axons of the inhibitory interneurones was used as a test response in these experiments. No indications were found of direct effects of 4-AP on excitability of afferent fibres or motoneurones to electrical stimuli. No systematic changes were either found in the membrane potential of motoneurones or in the duration of action potentials of these neurones or of primary afferents. It is therefore concluded that small doses of 4-AP enhance synaptic transmission in the spinal cord by an action at a presynaptic level.

Role of the subsequently activated receptors in electro-acupuncture of the rat.

Role of the subsequently excited receptors elicited by tetanic muscular contraction in electro-acupuncture analgesia was examined. Conditioning stimulation of the nerve (CPN) as well as electro-acupuncture induced a significant delay of the tail flick latencies of the rat with weak intensity of stimulus (1.0-1.5 x DFT), and this effect was abolished after section of the nerve at a point distal to the stimulating electrode. Electrophysiological data indicate that a small amplitude of the A large fiber group's potential was recorded with the intensity range of 1.0-1.5 x DFT. These facts suggest that the analgesic effect induced by weak stimulation is not the result of direct excitation of afferent fibers but the result of subsequent activation of receptors provoked by tetanic muscular contraction. The possible receptors are proposed and their participation in acupuncture analgesia also discussed. CPn = the common peroneal nerve; DFT = dorsal flexion threshold (1.0 x DFT = 1.15 x Ta).

Presynaptic inhibitory action of acetylcholine in area CA1 of the hippocampus

The effect of iontophoretically applied acetylcholin (ACh) was investigated in area CA1 of transverse hippocampal slices maintained in vitro. In synaptically activated regions of the dendritic field, ACh reduced the amplitude of the population spike recorded from the pyramidal layer. In dendritic regions which were not synaptically activated, ACh increased the amplitude of the population spike or it had no effect. The depressing effect of ACh was abolished in denervated dendritic regions. The intracellularly recorded excitatory postsynaptic potential (EPSP) decreased in amplitude when ACh was applied at the synaptic site. The resting membrane potential, the time course of the EPSP, and the membrane resistance were unaffected. ACh increased the excitability of afferent fibers and this was independent of synaptic transmission. We conclude that ACh in addition to its postsynaptic effects has a presynaptic site of action.

Excitation of afferent cardiac sympathetic nerve fibers induced by vagal stimulation.

The effect of vagal stimulation on activity of afferent sympathetic nerve fibers from the dog's left ventricle has been examined. During partial constriction of the coronary artery, a brief electrical stimulation of the cervical vagus nerves resulted in a decrease in blood flow of the constricted artery, systolic bulge of the left ventricle, elevation of the ST segment of electrocardiogram and excitation of the afferent nerve fibers, which continued for up to 15 min. These changes were not produced without coronary artery constriction. Intravenous injection of phentolamine eliminated the decrease in blood flow, and suppressed systolic bulge, elevation of the ST segment and excitation of afferent fibers. Propranolol could not eliminate the decrease in blood flow while suppressed the other changes. Atropine eliminated all of these changes. The results indicate participation of adrenergic alpha-receptors in sustained decrease of coronary blood flow and excitation of afferent cardiac sympathetic nerve fibers which can be produced by a brief vagal excitation.

Bradykinin-induced excitation of afferent cardiac sympathetic nerve fibers.

The effect of bradykinin on afferent cardiac sympathetic nerve fibers has been examined. Using anesthetized dogs, the action potentials of the fibers were derived from either the 2nd or 3rd thoracic communicating ramus of the left side. Excitation of the afferent fibers was observed following administration of bradykinin acetate dissolved in physiological saline on the left ventricular wall. The minimum concentration required for excitation was 50-100ng/ml. The fibers were excited rhythmically synchro-nous with myocardial contraction and/or relaxation. However, no significant augmentation of myocardial contraction was produced by the agent. Bradykinin-induced excitation of the fibers was significantly reduced by pretreatment with acetylsalicylic acid. The results suggest bradykinininduced sensitization of the receptor sites of the afferent fibers for normal modality of left ventricular motion.

The effects of respiratory acidosis on a sensory relay system.

The effects of hypercarbia on afferent inputs and synaptic transmission in the cuneate nucleus were studied in decerebrate cats. Stimulation with microelectrodes placed in the cuneate nucleus and/or dorsal column evoked antidromic potentials in the superficial radial nerve; stimulation of afferent fibres in the forelimb, dorsal column, or cuneate nucleus evoked orthodromic responses in the medial lemniscus. Small increases of inspired C02 ( ≦ 5% ) often increased synaptic transmission and the excitability of afferent fibres. Further increases of Pco2 depressed transmission and terminal excitability, while producing considerably smaller changes in postsynaptic excitability. CO2 had no obvious effect on the inhibition of orthodromic transmission produced by afferent nerve interaction, but markedly depressed the dorsal column reflexes. The efficiency of synaptic transmission, as estimated from the input-output relation of the cuneate, was maintained at individual active synapses. It is suggested that C02 does not depress release of transmitter at this synapse, and that the changes in transmission are effected mainly by presynaptic events, possibly by block of conduction in the intraspinal afferent fibres and/or their terminals.