Nerve Impulse Propagation Research Articles

Molecular and Cellular Limits to Somatosensory Specificity

Animals detect environmental changes through sensory neural mechanisms that enable them to differentiate the quality, intensity and temporal characteristics of stimuli. The 'doctrine of specific nervous energies' postulates that the different sensory modalities experienced by humans result of the activation of specific nervous pathways. Identification of functional classes of sensory receptors provided scientific support to the concept that somatosensory modalities (touch, pain, temperature, kinesthesis) are subserved by separate populations of sensory receptor neurons specialized in detecting innocuous and injurious stimuli of different quality (mechanical forces, temperature, chemical compounds). The identification of receptor proteins activated by different physicochemical stimuli, in particular ion channels of the Transient Receptor Potential (TRP) superfamily, has put forward the concept that specificity of peripheral sensory receptor neurons is determined by their expression of a particular "molecular sensor" that confers to each functional type its selectivity to respond with a discharge of nerve impulses to stimuli of a given quality. Nonetheless, recent experimental data suggest that the various molecular sensors proposed as specific transducer molecules for stimuli of different quality are not as neatly associated with the distinct functional types of sensory receptors as originally proposed. First, many ion channel molecules initially associated to the transduction of only one particular form of energy are also activated by stimuli of different quality, implying a limited degree of specificity in their transducing capacities. Second, molecular sensors associated with a stimulus quality and hence to a sensory receptor type and ultimately to a sensory modality may be concomitantly expressed in sensory receptor neurons functionally defined as specific for another stimulus quality. Finally, activation of voltage gated channels involved primarily in nerve impulse generation can also influence the gating of transducing channels, dramatically modifying their activation profile. Thus, we propose that the capacity exhibited by the different functional types of somatosensory receptor neurons to preferentially detect and encode specific stimuli into a discharge of nerve impulses, appears to result of a characteristic combinatorial expression of different ion channels in each neuronal type that finally determines their transduction and impulse firing properties. Transduction channels don't operate in isolation and their cellular context should also be taken into consideration to fully understand their function. Moreover, the inhomogeneous distribution of transduction and voltage-gated channels at soma, axonal branches and peripheral endings of primary sensory neurons influences the characteristics of the propagated impulse discharge that encodes the properties of the stimulus. Alteration of this concerted operation of ion channels in pathological conditions may underlie the changes in excitability accompanying peripheral sensory neuron injuries.

Potassium Channel Blockers and Openers as CNS Neurologic Therapeutic Agents

Potassium (K+) channels are the most heterogeneous and widely distributed class of ion channels. K(+) channels are dynamic pore-forming transmembrane proteins known to play important roles in all cell types underlying both normal and pathophysiological functions. Essential for such diverse physiological processes as nerve impulse propagation, muscle contraction, cellular activation and the secretion of biologically active molecules, various K(+) channels are recognized as potential therapeutic targets in the treatment of multiple sclerosis, Alzheimer's disease, Parkinson's disease, epilepsy, stroke, brain tumors, brain/spinal cord ischemia, pain and schizophrenia, migraine, as well as cardiac arrhythmias, pulmonary hypertension, diabetes, cervical cancer, urological diseases and sepsis. In addition to their importance as therapeutic targets, certain K(+) channels are gaining attention for their beneficial roles in anesthesia, neuroprotection and cardioprotection. The K(+) channel gene families (subdividing into multiple subfamilies) include voltage-gated (K(v): K(v)1-K(v)12 or KCNA-KCND, KCNF-KCNH, KCNQ, KCNS), calcium-activated (K(Ca): K(Ca)1-K(Ca)5 or KCNM-KCNN), inwardly rectifying (K(ir): K(ir)1-K(ir)7 or KCNJ) and background/leak or tandem 2-pore (K(2P): K(2P)1-K(2P)7, K(2P)9-K(2P)10, K(2P)12-K(2P)13, K(2P)15-K(2P)18 or KCNK) K(+) channels. Worldwide, the pharmaceutical industry is actively developing better strategies for targeting ion channels, in general, and K(+) channels, in particular, already generating over $6 billion in sales per annum from drugs designed to block or modulate ion channel function. This review provides an overview of recent patents on emerging K(+) channel blockers and activators (openers) with potential for development as new and improved nervous system therapeutic agents.

Types of Bifurcations of FitzHugh–Nagumo Maps

The FitzHugh–Nagumo-like systems are of fundamental importance to the understanding of the qualitative nature of nerve impulse propagation. Our work provides a numerical investigation of bifurcations associated with a family of piecewise differentiable canonical maps for a planar FitzHugh–Nagumo system. We describe the bifurcation structure of the maps with the variation of the parameters.

The Role of Sodium Channels in Chronic Inflammatory and Neuropathic Pain

Clinical and experimental data indicate that changes in the expression of voltage-gated sodium channels play a key role in the pathogenesis of neuropathic pain and that drugs that block these channels are potentially therapeutic. Clinical and experimental data also suggest that changes in voltage-gated sodium channels may play a role in inflammatory pain, and here too sodium-channel blockers may have therapeutic potential. The sodium-channel blockers of interest include local anesthetics, used at doses far below those that block nerve impulse propagation, and tricyclic antidepressants, whose analgesic effects may at least partly be due to blockade of sodium channels. Recent data show that local anesthetics may have pain-relieving actions via targets other than sodium channels, including neuronal G protein–coupled receptors and binding sites on immune cells. Some of these actions occur with nanomolar drug concentrations, and some are detected only with relatively long-term drug exposure. There are 9 isoforms of the voltage-gated sodium channel α-subunit, and several of the isoforms that are implicated in neuropathic and inflammatory pain states are expressed by somatosensory primary afferent neurons but not by skeletal or cardiovascular muscle. This restricted expression raises the possibility that isoform-specific drugs might be analgesic and lacking the cardiotoxicity and neurotoxicity that limit the use of current sodium-channel blockers. Perspective Changes in the expression of neuronal voltage-gated sodium channels may play a key role in the pathogenesis of both chronic neuropathic and chronic inflammatory pain conditions. Drugs that block these channels may have therapeutic efficacy with doses that are far below those that impair nerve impulse propagation or cardiovascular function.

A note on the asymptotic reduction of the Hodgkin–Huxley equations for nerve impulses

The (standard) FitzHugh reduction of the Hodgkin–Huxley equations for the propagation of nerve impulses ignores the dynamics of the activation gates. This assumption is invalid and leads to an over-estimation of the wave speed by a factor of 5 and the wrong dependence of wave speed on sodium channel conductance. The error occurs because a non-dimensional parameter, which is assumed to be small in the FitzHugh reduction, is in fact large (≈18). We analyse the Hodgkin–Huxley equations for propagating nerve impulses in the limit that this non-dimensional parameter is large, and show that the analytical results are consistent with numerical simulations of the Hodgkin–Huxley equations.

Rate-dependent behavioral effects of stimulation of central motoric ?1-adrenoceptors: hypothesized relation to depolarization blockade

The purpose of this review is to clarify how central alpha(1)-adrenoceptors control behavioral activity under varying conditions of activity and stress. The literature is reviewed regarding the behavioral actions of alpha(1)-agonists and antagonists, and alpha(2)-agonists and antagonists under conditions of high and low baseline activity and stress. It was found that alpha(1)-receptor stimulation of active behavior has a number of similarities to rate dependency including: (1) a dependence on low-active, low-stress conditions or on the prior depletion of endogenous brain catecholamines; (2) a nonmonotonic dose-response relationship with high doses producing a fall-off or actual depression of activity; (3) a failure to be blocked at high agonist doses by alpha(1)-antagonists; and (4) a facilitation by alpha(2)-adrenoceptor agonists which produce an opposing hyperpolarization. To explain these findings, it is proposed that high levels of stimulation of central alpha(1)-receptors produce, in host neurons, a depolarization block that impedes nerve impulse generation and inhibits active behavior. This effect is assumed to be precluded or mitigated by low-active, low-stress conditions, depletion of brain catecholamines, and by hyperpolarizing alpha(2)-agonists, and to be reversed at high agonist doses by alpha(1)-antagonists. Because brain alpha(1)-receptors are not only involved in motor activity but also in the mechanism of action of antidepressant and stimulant drugs, arousal, anxiety, stress and psychosis, a depolarization block from intense stimulation of these receptors could have broad psychopharmacological consequences and underlie rate dependency to a variety of stimulant drugs.

Spectrum of cutaneous hyperalgesias/allodynias in neuropathic pain patients

The aim of this study was to discern the pathophysio-logical bases for neuropathic hyperalgesias. In this study, neurological and neurophysiological evaluation of 132 consecutive hyperalgesia patients using rigorous clinical and laboratory protocols were carried out. Two discrete semeiologic entities emerged: classic neurological vs atypical, fulfilling taxonomically complex regional pain syndrome (CRPS) II and I, respectively. The classic group (34.9%) exhibited sensorimotor patterns restricted to nerve distribution and documented nerve fiber dysfunction. Among them four (3.03%) had sensitization of C-nociceptors, seven (5.3%) had central release of nociceptive input, and 35 (26.52%) probable ectopic nerve impulse generation. The atypical group (65.1%) displayed weakness with interrupted effort; non-anatomical hypoesthesia and hyperalgesia; hypoesthesia or paresis reversed by placebo, or atypical abnormal movements, and physiological normality of motor and sensory pathways. Spatiotemporal features of neuropathic hyperalgesia constitute key criteria for differential diagnosis between CRPS II and I and, together with other behavioral sensorimotor features, signal psychogenic pseudoneurological dysfunction vs structural neuropathology. 'Neuropathic' hyperalgesias may reflect neuropathological or psychopathological disorders.

A proton pore in a potassium channel voltage sensor reveals a focused electric field.

Voltage-dependent potassium channels are essential for the generation of nerve impulses. Voltage sensitivity is conferred by charged residues located mainly in the fourth transmembrane segment (S4) of each of the four identical subunits that make up the channel. These charged segments relocate when the potential difference across the membrane changes, controlling the ability of the pore to conduct ions. In the crystal structure of the Aeropyrum pernix potassium channel KvAP, the S4 and part of the third (S3B) transmembrane alpha-helices are connected by a hairpin turn in an arrangement termed the 'voltage-sensor paddle'. This structure was proposed to move through the lipid bilayer during channel activation, transporting positive charges across a large fraction of the membrane. Here we show that replacing the first S4 arginine by histidine in the Shaker potassium channel creates a proton pore when the cell is hyperpolarized. Formation of this pore does not support the paddle model, as protons would not have access to a lipid-buried histidine. We conclude that, at hyperpolarized potentials, water and protons from the internal and external solutions must be separated by a narrow barrier in the channel protein that focuses the electric field to a small voltage-sensitive region.

Mania as a dysfunction of reentry: application of Edelman's and Tononi's hypothesis for consciousness in relation to a psychiatric disorder

The concept of reentry as the most important element in a hypothesis for consciousness proposed by Edelman and Tononi is reviewed. Reentry, is a process of ongoing parallel and recursive signalling between separate neuronal groups along parallel reciprocally fibers that link these groups anatomically. Reentry alters the activity of the target areas it interconnects until a synchronous activity across these areas is created, this may be the direct biological mechanism of consciousness. The repetitive process of reentry may explain how the millisecond time scale of neural signalling is turned into the time scale of seconds characterizing our impression of the duration of a given content of consciousness. It is suggested that reentry may be faster in mania, and specifically that the repetitive recursive signalling is faster in mania, hereby allowing reentry to produce a conscious state, faster than usual. Faster reentry may on a molecular level be caused by faster propagation of nerve impulses, which may be in accordance with a number of hypotheses where mania is seen as a disorder of ionic conductance, nerve cell excitability, action potential firing, membrane abnormalities, and cortical instability. Also the antiepileptic drugs used to treat mania may point to reentry as a factor in this disorder. On a more integrated level faster reentry processes may explain several of the core symptoms of the manic state. Also the drug induced switch from depression to mania in bipolar patients may be explained by the concept of reentry.

Multiple actions of systemic artemin in experimental neuropathy.

The clinical management of neuropathic pain is particularly challenging. Current therapies for neuropathic pain modulate nerve impulse propagation or synaptic transmission; these therapies are of limited benefit and have undesirable side effects. Injuries to peripheral nerves result in a host of pathophysiological changes associated with the sustained expression of abnormal pain. Here we show that systemic, intermittent administration of artemin produces dose- and time-related reversal of nerve injury-induced pain behavior, together with partial to complete normalization of multiple morphological and neurochemical features of the injury state. These effects of artemin were sustained for at least 28 days. Higher doses of artemin than those completely reversing experimental neuropathic pain did not elicit sensory or motor abnormalities. Our results indicate that the behavioral symptoms of neuropathic pain states can be treated successfully, and that partial to complete reversal of associated morphological and neurochemical changes is achievable with artemin.

Visualizing signals moving in cells.

Cells display a highly complex spatiotemporal organization, required to exert a wide variety of different functions, for example, detection, processing, and propagation of nerve impulses by neurons; contraction and relaxation by muscle cells; movement by leukocytes; and adsorption and secretion of nutrients and metabolites by epithelial cells lining the gut. Successful execution of these complex processes requires highly dynamic information transfer between different regions and compartments within cells. Through the development of fluorescent sensors for intracellular signaling molecules coupled with improved microscopic imaging techniques, it has now become possible to investigate signal propagation in cells with high spatial and temporal resolution.

Neural CAMS and their role in the development and organization of myelin sheaths.

Myelination of axons is a prerequisite for the rapid propagation of nerve impulses, and thus for the proper functioning of the nervous system. Phenotypic analysis of genetically engineered mice has provided evidence that cell adhesion molecules are critically involved in the interaction of myelin-forming glial cells with axons, the formation of regularly spaced myelin internodes along axons and the organisation of paranodes and the myelin-free gaps separating the internodes, the nodes of Ranvier. This review will focus on three members of the immunoglobulin-superfamily, the myelin-associated glycoprotein (MAG), the neural cell adhesion molecule (NCAM) and the neural adhesion molecule L1 and will discuss studies on transgenic mice that have analyzed the role of these cell adhesion molecules in the initiation of myelination, formation of structurally intact myelin sheaths and/or maintenance of myelin and axon integrity.

Role of female sex hormones in neuronal nitric oxide release and metabolism in rat mesenteric arteries.

This study examines the effects of female sex hormones on the vasoconstrictor response to electrical field stimulation (EFS), as well as the modulation of this response by neuronal NO. For this purpose, segments of denuded superior mesenteric artery from ovariectomized (OvX) female Sprague-Dawley rats and from control rats (in oestrus phase) were used. EFS induced frequency-dependent contractions, which were greater in segments from OvX rats than in those from control rats. The NO synthase inhibitor N(G)-nitro-l-arginine methyl ester strengthened EFS-elicited contractions to a greater extent in arteries from OvX rats than in those from control rats. Similar results were observed with the preferential neuronal NO synthase inhibitor 7-nitroindazole. The sensorial neurotoxin capsaicin did not modify EFS-induced contractions in segments from either group. In noradrenaline-precontracted segments, sodium nitroprusside (SNP) induced concentration-dependent relaxation, which was greater in segments from control rats than in those from OvX rats. 8-Bromo-cGMP induced similar concentration-dependent relaxation in noradrenaline-precontracted segments from both OvX and control rats. Diethyldithiocarbamate, a superoxide dismutase (SOD) inhibitor, reduced the relaxation induced by SNP in segments from both groups of rats. SOD, a superoxide anion scavenger, enhanced the relaxation induced by SNP in segments from OvX rats, but did not modify it in segments from control rats. EFS induced NO(-)(2) formation, which was greater in segments from OvX than in those from control rats, and pretreatment with tetrodotoxin, a blocker of nerve impulse propagation, abolished release in both cases. These results suggest that EFS induces greater neuronal NO release in mesenteric segments from OvX rats than in those from control rats and, although NO metabolism is also higher, the contribution of net neuronal NO in the vasomotor response to EFS is greater in segments from OvX rats than in those from control rats.

Invertebrates in neurotoxicology

Due to the relative simplicity of their nervous system, invertebrate animals were widely used in the past decades for studying the processes of excitability at membrane level, as well as the mechanisms of neuronal events and interneuronal communication. Parallel with investigating basic questions of neurobiology, lower animals have also been the object of toxicological studies, because simple invertebrate preparations with well-known physiological, biochemical and pharmacological characteristics proved to be excellent models for testing the action of natural and synthetic compounds important to human pharmaceutical research as well as in searching suitable chemicals for pest control. In the last ten-fifteen years with the growing interest towards environmental protection, a new field was opened for the application of invertebrates, namely, testing and monitoring the presence and harmful effects of anthropogenic toxic substances. Invertebrates are used today both as passive and as active biomonitors to detect and evaluate the level of pollution in a given ecosystem, and to study the effects and mechanisms of action of pollutants. Invertebrate nervous systems are suitable objects in clarifying the mechanisms of action of toxic chemicals at various levels of the neural regulation. Toxic influences can be reflected in behavioural alterations, by the modification of the function of different organs as well as the neural regulation, presented by examples on mussels and snails. In case of neurotoxicity, the targets of action are the elements of the nervous system. Alterations can occur in the permeability (ion channels) of the neuronal membrane influencing excitability, potential generation and propagation of nerve impulse, in the transmitter system (synthesis, release, elimination and binding to the receptors), in the interneuronal and neuroeffector connections responsible for co-ordinated and adequate responses to the internal and external challenges. For the future, it can be predicted that neurotoxicological research with new compounds cannot be effective without using invertebrate preparations, since, due to animal protection and restrictions in animal experimentation, the permission of the use of vertebrates is much more limited in most of the developed countries, and this trend is certainly to be expanded.

Octopamine modulates the sensitivity of silkmoth pheromone receptor neurons.

Effects of octopamine and its antagonist epinastine on electrophysiological responses of receptor neurons of Antheraea polyphemus specialised to the pheromone components (E,Z)-6,11-hexadecadienyl acetate and (E,Z)-6,11-hexadecadienal were investigated. Injections of octopamine and epinastine into the moths had no effect on the transepithelial potential of the antennal-branch preparation nor on the spontaneous nerve impulse frequency in either type of receptor neuron. However, in the presence of continuous low-intensity pheromone stimulation, octopamine significantly increased the nerve impulse frequency in the acetate receptor neuron, but not in the aldehyde receptor neuron. Octopamine and epinastine had no significant effect on the receptor potential amplitudes elicited in both receptor neuron types by pheromone stimulation. However, the peak nerve impulse frequency in the response of both receptor neuron types to pheromone was significantly affected: decreased by epinastine and increased by octopamine over a broad range of pheromone concentrations. In control experiments, injection of physiological saline did not significantly alter the peak nerve impulse frequency. The effect of octopamine was established within 1 h after injection and persisted for about 4 h. The possibility of a direct action of octopamine on the nerve impulse generation by the receptor neurons is discussed.

How many endobains are there?

Oxidative metabolism is very active in brain, where large amounts of chemical energy as ATP molecules are consumed, mostly required to maintain cellular Na+/K+ gradients through the participation of the sodium pump (Na+,K+-ATPase), whose activity is selectively and potently inhibited by the alkaloid ouabain. Na+/K+ gradients are involved in nerve impulse propagation, in neurotransmitter release and cation homeostasis in the nervous system. Likewise, enzyme activity modulation is crucial for maintaining normal blood pressure and cardiovascular contractility as well as renal sodium excretion. The present article reviews the progress in disclosing putative ouabain-like substances, examines their denomination according to different research teams, tissue or biological fluid sources, extraction and purification, assays, biological properties and chemical and biophysical features. When data is available, comparison with ouabain itself is mentioned. Likewise, their potential action in normal physiology as well as in experimental and human pathology is summarized.

A ferroelectric model for the generation and propagation of an action potential and its magnetic field stimulation

Action potential generation and propagation in axon membrances are discussed in the framework of the concept of a ferroelectric first-order phase transition. The model modifies Leuchtag's hypothesis of the ferroelectric origin of the gating mechanism in sodium ion channels. The propagation of the action potential represents the polarization kink-soliton describing the motion of the interphase boundary between closed and open gate states associated with different values of polarization. We show that the measured value of the action potential velocity in a squid axon and its temperature dependence can be obtained using typical values of protein relaxation times, channel densities and dielectric quantities as theory parameters. We discuss also the effect of magnetic field on stimulation and propagation of nerve impulse.

Oligodendrocyte-type-2 astrocyte (O-2A) progenitor cells express glutamine synthetase: developmental and cell type-specific regulation.

Glutamine synthetase (GS), the enzyme that catalyses glutamine synthesis from glutamate and ammonia, plays a central role in the detoxification of brain ammonia. In the central nervous system (CNS), GS also subserves additional important functions such as regulating glutamate, GABA and amino acid metabolism. Oligodendrocytes (OL) form the myelin sheath in the central nervous system (CNS) and are essential for efficient propagation of nerve impulses. In culture, OL arise from bipotential O-2A progenitor cells. These O-2A cells give rise to type-2 astrocytes in the presence of serum. GS is expressed in mature glial cells in vivo and in vitro, but it is unknown whether GS is present in glial progenitors. In addition, a comparison of the GS expression level among the various types of glial cells has never been done in vitro. The current study investigates in vitro GS expression levels in O-2A progenitors, astrocytes and OL. We demonstrate that the GS gene is expressed in O-2A progenitors and is expressed at different levels in each cultured glial cell type. GS also is stimulated during OL developmental maturation. Thus, the GS gene is expressed in O-2A cells and is regulated in a developmental and macroglial cell type-specific manner.

Electrical basis of peristalsis in the mammalian upper urinary tract.

1. Peristalsis in the mammalian upper urinary tract (UUT) is mostly myogenic in origin, originating predominately in the proximal pelvicalyceal regions of the renal pelvis, an area that is enriched with specialized smooth muscle cells termed 'atypical' smooth muscle cells. Propagating peristaltic contractions are little affected by blockers of either autonomic nerve function or nerve impulse propagation; however, blockers of sensory nerve function or prostaglandin synthesis reduce both the frequency and the strength of the spontaneous contractions underlying peristalsis. 2. The electrical drive for these peristaltic contractions has long been considered to involve mechanisms analogous to the heart, such that 'atypical' smooth muscle cells generate spontaneous 'pacemaker' action potentials. These pacemaker potentials trigger the firing of action potentials and contraction in the muscular regions of the renal pelvis, which propagate distally to the ureter, propelling urine towards the bladder. 3. Recent intracellular microelectrode and single cell/channel patch-clamp studies have revealed that the ionic conductances underlying the action potentials recorded in the UUT are likely to involve the opening and slow closure of voltage-activated 'L-type' Ca2+ channels, offset by the time-dependent opening and closure of both voltage- and Ca(2+)-activated K+ channels. 4. In the present review we summarize the current knowledge of the ionic mechanisms underlying action potential discharge in the UUT, as well as present our view on how this electrical activity supports the initiation and conduction of UUT peristalsis.

Chapter 18 Oligodendrocyte regeneration in the adult rodent CNS and the failure of this process in multiple sclerosis

Publisher Summary In the central nervous system (CNS), the processes of oligodendrocytes (OLs), one of the major classes of glial cells, enwrap axons to form the myelin sheaths. These sheaths act as insulators and increase the efficiency and velocity of the propagation of nerve impulses along axons. Damage to, and loss of myelin impairs conduction, and as a result, the functions mediated by the demyelinated fibres, even when the axons remain intact. In man, this process of demyelination is seen in a number of diseases of which the commonest is multiple sclerosis (MS). Although there is substantial evidence that replacement of OLs, reensheathment of axons— that is, remyelination, and restoration of conduction occurs in many experimental models of demyelinating disease, myelin repair in MS is often scant or absent, especially during chronic stages of the disease. Little is known about the underlying cause of the myelin destruction in MS and about why repair of MS lesions is not sustained. This chapter discusses the advances that have increased the understanding of both the cellular mechanisms and factors that control the generation of OLs in the normal and demyelinated adult rodent CNS and the reasons for the failure of myelin repair in MS, with particular emphasis on OL precursor cells. Finally, potential strategies to enhance remyelination in MS are discussed briefly.