Review of childhood pain highlights the role of negative stress.

AIM: Recurrent pain of unknown origin is a major problem in children. The aim of the present review was to examine the hypothesis of negative stress as an aetiology of recurrent pain from different aspects. METHODS AND RESULTS: Epidemiological studies, clinical experience and hormonal data give support for such a hypothesis. Negative stress as a tentative aetiology for recurrent pain is reviewed. Stress, muscular tension, the startle reaction and its tentative relation to pain is illuminated. Deviations of hormonal secretion supporting a stress aetiology are mentioned. The role of central sensitisation for recurrent pain is discussed. Possible aetiological implications of recurrent pain as a local symptom or a general disorder are presented. Brain changes due to stress are shortly reviewed. Stress and pain in the clinic are highlighted. The importance of biological, psychological and social factors, as well as genetic elements, is discussed. CONCLUSION: Stress elicits neurobiological mechanisms. They may lead to many neurophysiological deviances. Increase of muscle tension and neuromuscular excitability and enhanced startle reaction may be of importance for recurring pain. The identification of stress as a primary cause of recurrent pain can have huge implications for understanding signs and treatment in clinical practice.

Children with chronic stress-induced recurrent muscle pain have enhanced startle reaction.

BACKGROUND: Children with recurrent pain of negative chronic stress origin from different locations have a characteristic pattern of tender points in the temporal, trapezoid, great pectoral and abdominal muscles. We tested the hypothesis that the startle reaction is activated in these children and that some of the startle-activated muscles are related to the tender point pattern and the recurrent pain. METHODS: In children/adolescents, aged 10-17 years, 19 with recurrent psychosomatic pain (PAIN) and 23 controls (CON) we measured and analysed resting activity and acoustic startle response with electromyography (EMG) for the muscles involved in the pattern of tender points and also the lumbar erector spinae. RESULTS: The PAIN group showed higher resting activity and higher acoustic startle response values than the CON group for all six muscles together regarding the mean amplitude in the initial 200 ms, and during the burst of activity, and longer burst duration and shorter burst latency. For PAIN versus CON, all separate muscles showed generally higher values of EMG amplitudes and burst durations, and shorter latencies for the burst onset in all measures; with significance or strong trends for several parameters and muscles. CONCLUSION: For the first time in children with recurrent psychosomatic pain, increased resting activity and potentiated startle response were demonstrated in the muscles involved in the stress tender point pattern. SIGNIFICANCE: This study demonstrates in adolescents how recurrent pain of negative stress origin from the head, stomach, back and chest is related to increased startle reaction and increased muscular tension in these regions. This study contributes to the understanding of the mechanisms underlying the global burden of recurrent pain.

A bioinspired autonomous swimming robot as a tool for studying goal-directed locomotion.

The bioinspired approach has been key in combining the disciplines of robotics with neuroscience in an effective and promising fashion. Indeed, certain aspects in the field of neuroscience, such as goal-directed locomotion and behaviour selection, can be validated through robotic artefacts. In particular, swimming is a functionally important behaviour where neuromuscular structures, neural control architecture and operation can be replicated artificially following models from biology and neuroscience. In this article, we present a biomimetic system inspired by the lamprey, an early vertebrate that locomotes using anguilliform swimming. The artefact possesses extra- and proprioceptive sensory receptors, muscle-like actuation, distributed embedded control and a vision system. Experiments on optimised swimming and on goal-directed locomotion are reported, as well as the assessment of the performance of the system, which shows high energy efficiency and adaptive behaviour. While the focus is on providing a robotic platform for testing biological models, the reported system can also be of major relevance for the development of engineering system applications.

A novel autonomous, bioinspired swimming robot developed by neuroscientists and bioengineers.

This paper describes the development of a new biorobotic platform inspired by the lamprey. Design, fabrication and implemented control are all based on biomechanical and neuroscientific findings on this eel-like fish. The lamprey model has been extensively studied and characterized in recent years because it possesses all basic functions and control mechanisms of higher vertebrates, while at the same time having fewer neurons and simplified neural structures. The untethered robot has a flexible body driven by compliant actuators with proprioceptive feedback. It also has binocular vision for vision-based navigation. The platform has been successfully and extensively experimentally tested in aquatic environments, has high energy efficiency and is ready to be used as investigation tool for high level motor tasks.

The hemisegmental locomotor network revisited.

The organization of the minimal neuronal substrate capable of generating locomotor rhythmicity in vertebrates is investigated in several species, with an emphasis on identifying evolutionary-conserved features. In lamprey, an eel-like lower vertebrate that swims by undulatory movements of the body, the network has been identified as a recurrent network of excitatory interneurons localized in each spinal hemisegment. This conclusion rested upon the observation that each side of the spinal cord is able to express rhythmic locomotor-related bursting after being surgically separated along the midline, even in the absence of inhibition. An important caveat, however, is that this rhythmicity must be an intrinsic capability of the hemisegmental networks and not a newly acquired property as a result of a plastic remodeling of the network occurring after the lesion. Here we examine this issue by recording the motor output expressed by the electrically activated hemicord in the first minutes after hemisection. We observed clear rhythmic bursting in the frequency range previously linked to the operation of the central pattern generator for swimming. Moreover, we recorded the output of the unilateral networks in the intact spinal cord (i.e. no midline section performed) by activating them with asymmetrical stimulation. We thus conclude that the lamprey hemicord does possess the intrinsic capability of generating the basic rhythmic drive of locomotion. The wider significance of these data stems from the lamprey being a model of axial locomotion, and from the many lesion studies previously performed in other animals.

Changes in spinal reflex and locomotor activity after a complete spinal cord injury: a common mechanism?

Locomotor activity and spinal reflexes (SRs) show common features in different mammals, including humans. Here we report the time-course of the development of locomotor activity and SRs after a complete spinal cord injury in humans. SRs evoked by tibial nerve stimulation were studied, as was the leg muscle electromyography activity evoked by mechanically assisted locomotion (Lokomat) in biceps femoris, rectus femoris, tibialis anterior and gastrocenmius medialis. Around 8 weeks after the injury, an early SR component (latency 60-120 ms) appeared, as in healthy subjects, and a well-organized leg muscle activity was present during assisted locomotion. At around 6 months after injury an additional, late reflex component (latency 120-450 ms) appeared, which remained even 15 years after the spinal cord injury. In contrast, the early component had markedly decreased at 18 months after injury. These changes in SR were associated with a loss of electromyography activity and a successively stronger electromyography exhaustion (i.e. decline of electromyography amplitude), when comparing the level of electromyography activity at 2 and 10 min, respectively, during assisted locomotion. These changes in electromyography activity affected mainly the biceps femoris, gastrocenmius medialis and tibialis anterior but less so the rectus femoris. When the amplitude relationship of the early to late SR component was calculated, there was a temporal relationship between the decrease of the early component and an increase of the late component and the degree of exhaustion of locomotor activity. In chronic, severely affected but sensori-motor incomplete spinal cord injury subjects a late SR component, associated with an electromyography exhaustion, was present in subjects who did not regularly perform stepping movements. Our data are consistent with the proposal of a common mechanism underlying the changes in SR activity and locomotor activity after spinal cord injury. These findings should be taken into consideration in the development of novel rehabilitation schemes and programs to facilitate regeneration-inducing therapies in spinal cord injury subjects.

Effect of intrathecal administration of serotoninergic and noradrenergic drugs on postural performance in rabbits with spinal cord lesions.

Our previous studies have shown that extensive spinal lesions at T12 in the rabbit [ventral hemisection (VHS) or 3/4-section that spares one ventral quadrant (VQ)] severely damaged the postural system. When tested on the platform periodically tilted in the frontal plane, VHS and VQ animals typically were not able to perform postural corrective movements by their hindlimbs, although EMG responses (correctly or incorrectly phased) could be observed. We attempted to restore postural control in VHS and VQ rabbits by applying serotoninergic and noradrenergic drugs to the spinal cord below the lesion through the intrathecal cannula. It was found that serotonin and quipazine (5-HT1,2,3 agonist) did not re-establish postural corrective movements. However, when applied during a 10-day period after lesion, these drugs produced a twofold increase of the proportion of correct EMG responses to tilts. It was also found that methoxamine (alpha1 noradrenergic agonist), as well as the mixture of methoxamine and quipazine, did not re-establish postural corrective movements and did not increase the proportion of correct EMG responses. Serotonin (at later stages) and methoxamine induced periodical bursting in EMGs, suggesting activation of spinal rhythm-generating networks. Appearance of bursting seems to perturb normal operation of postural mechanisms, as suggested by methoxamine-induced abolishment of postural effects of quipazine. When applied in an intact animal, none of the tested drugs affected the value of postural corrections or evoked periodical bursting. We conclude that activation of the serotoninergic system (but not the noradrenergic one) causes selective enhancement of spinal postural reflexes during the earlier postlesion period.

Forebrain dopamine depletion impairs motor behavior in lamprey.

The structure of the basal ganglia appears to be conserved throughout vertebrate evolution, with characteristic cellular and transmitter components in each area, and the same types of afferent input. As described in rodents and primates, depletion of the striatal dopamine results in characteristic motor deficits. To explore if this role of the basal ganglia in modulating motor function was present early in vertebrate evolution, we investigated here the effects of striatal dopamine depletion in the lamprey, a cyclostome, which diverged from the main vertebrate line around 560 million years ago. The lamprey striatum contains the same cellular elements as found in mammals, and receives the same types of input, including a prominent dopamine innervation. We show here that MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine; 100 mg/kg i.p.), a neurotoxin, depletes forebrain and striatal dopamine levels in lamprey to 15% of control values, and has profound effects on motor performance. Twenty-four and 48 h after MPTP injection, lampreys demonstrated marked reductions in spontaneous swimming and the duration of each swimming episode. Impairments in the ability to initiate movements were shown by a decreased rate of initiation. Furthermore, the initiation and maintenance of locomotion induced by olfactory mucosa stimulation was severely impaired, as was the coordination of different motor tasks. These deficits were ameliorated by the dopamine agonist apomorphine. The motor deficits arising after striatal dopamine depletion are thus qualitatively similar in cyclostomes and mammals. The role of the dopamine innervation of the striatum thus appears to be conserved throughout vertebrate evolution.

A hemicord locomotor network of excitatory interneurons: a simulation study.

Locomotor burst generation is simulated using a full-scale network model of the unilateral excitatory interneuronal population. Earlier small-scale models predicted that a population of excitatory neurons would be sufficient to produce burst activity, and this has recently been experimentally confirmed. Here we simulate the hemicord activity induced under various experimental conditions, including pharmacological activation by NMDA and AMPA as well as electrical stimulation. The model network comprises a realistic number of cells and synaptic connectivity patterns. Using similar distributions of cellular and synaptic parameters, as have been estimated experimentally, a large variation in dynamic characteristics like firing rates, burst, and cycle durations were seen in single cells. On the network level an overall rhythm was generated because the synaptic interactions cause partial synchronization within the population. This network rhythm not only emerged despite the distributed cellular parameters but relied on this variability, in particular, in reproducing variations of the activity during the cycle and showing recruitment in interneuronal populations. A slow rhythm (0.4-2 Hz) can be induced by tonic activation of NMDA-sensitive channels, which are voltage dependent and generate depolarizing plateaus. The rhythm emerges through a synchronization of bursts of the individual neurons. A fast rhythm (4-12 Hz), induced by AMPA, relies on spike synchronization within the population, and each burst is composed of single spikes produced by different neurons. The dynamic range of the fast rhythm is limited by the ability of the network to synchronize oscillations and depends on the strength of synaptic connections and the duration of the slow after hyperpolarization. The model network also produces prolonged bouts of rhythmic activity in response to brief electrical activations, as seen experimentally. The mutual excitation can sustain long-lasting activity for a realistic set of synaptic parameters. The bout duration depends on the strength of excitatory synaptic connections, the level of persistent depolarization, and the influx of Ca(2+) ions and activation of Ca(2+)-dependent K(+) current.

Impairment and recovery of postural control in rabbits with spinal cord lesions.

The aim of this study was to characterize impairment and subsequent recovery of postural control after spinal cord injuries. Experiments were carried out on rabbits with three types of lesion--a dorsal (D), lateral (L), or ventral (V) hemisection (HS) at T(12) level. The animals were maintaining equilibrium on a platform periodically tilted in the frontal plane. We assessed the postural limb/trunk configuration from video recordings and postural reflexes in the hindquarters from kinematical and electromyographic (EMG) recordings. We found that for a few days after DHS or LHS, the animals were not able to maintain the dorsal-side-up position of their hindquarters. This ability was then gradually restored, and the dynamic postural reflexes reached the prelesion value within 2-3 wk. By contrast, a VHS almost completely abolished postural reflexes, and they did not recover for > or =7 wk. The DHS, LHS, and VHS caused immediate and slowly compensated changes in the postural limb/trunk configuration as well as gradually developing changes. After DHS, both hind limbs were placed in an abnormal rostral and medial position. After LHS, the limb on the undamaged side was turned inward and occurred at the abnormal medial position; LHS also caused a gradually developing twisting of the caudal trunk. VHS caused gradually developing extension of the ankle and knee joints. These findings show that ventral spinal pathways are of crucial importance for postural control. When a part of these pathways is spared, postural reflexes can be restored rapidly, but not the postural limb/trunk configuration. Spinal and supraspinal mechanisms responsible for postural deficits and their compensation are discussed.

Postural control in the rabbit maintaining balance on the tilting platform.

A deviation from the dorsal-side-up body posture in quadrupeds activates the mechanisms for postural corrections. Operation of these mechanisms was studied in the rabbit maintaining balance on a platform periodically tilted in the frontal plane. First, we characterized the kinematics and electromyographic (EMG) patterns of postural responses to tilts. It was found that a reaction to tilt includes an extension of the limbs on the side moving down and flexion on the opposite side. These limb movements are primarily due to a modulation of the activity of extensor muscles. Second, it was found that rabbits can effectively maintain the dorsal-side-up body posture when complex postural stimuli are applied, i.e., asynchronous tilts of the platforms supporting the anterior and posterior parts of the body. These data suggest that the nervous mechanisms controlling positions of these parts of the body can operate independently of each other. Third, we found that normally the somatosensory input plays a predominant role for the generation of postural responses. However, when the postural response appears insufficient to maintain balance, the vestibular input contributes considerably to activation of postural mechanisms. We also found that an asymmetry in the tonic vestibular input, caused by galvanic stimulation of the labyrinths, can affect the stabilized body orientation while the magnitude of postural responses to tilts remains unchanged. Fourth, we found that the mechanisms for postural corrections respond only to tilts that exceed a certain (threshold) value.

Comparison of the motor effects of individual vestibulo- and reticulospinal neurons on dorsal and ventral myotomes in lamprey.

In the lamprey (a lower vertebrate), motor commands from the brain to the spinal cord are transmitted through the reticulospinal (RS) and vestibulospinal (VS) pathways. The axons of larger RS neurons reach the most caudal of approximately 100 spinal segments, whereas the VS pathway does not descend below the 15th segment. This study was carried out to compare functional projections of RS and VS neurons in the rostral spinal segments that the neurons innervate together. To reveal these projections, individual RS or VS neurons were stimulated, and the responses of different groups of spinal motoneurons were recorded in ventral root branches to dorsal and ventral parts of myotomes. The responses were detected using a spike-triggered averaging technique on the background of ongoing motoneuronal activity. Individual RS and VS neurons exerted uniform effects on segmental motor output within this rostral part of the spinal cord. The effects of VS neurons on different groups of motoneurons were weaker and less diverse than those of RS neurons. The results indicate that VS neurons are able to elicit a flexion of the rostral part of the body and to turn the head in different planes without affecting more caudal parts. By contrast, larger RS neurons can elicit head movement only together with movement of a considerable part of the body and thus seem to be responsible for formation of gross motor synergies.

Lateral turns in the Lamprey. II. Activity of reticulospinal neurons during the generation of fictive turns.

We studied the neural correlates of turning movements during fictive locomotion in a lamprey in vitro brain-spinal cord preparation. Electrical stimulation of the skin on one side of the head was used to evoke fictive turns. Intracellular recordings were performed from reticulospinal cells in the middle (MRRN) and posterior (PRRN) rhombencephalic reticular nuclei, and from Mauthner cells, to characterize the pattern of activity in these cell groups, and their possible functional role for the generation of turns. All recorded reticulospinal neurons modified their activity during turns. Many cells in both the rostral and the caudal MRRN, and Mauthner cells, were strongly excited during turning. The level of activity of cells in rostral PRRN was lower, while the lowest degree of activation was found in cells in caudal PRRN, suggesting that MRRN may play a more important role for the generation of turning behavior. The sign of the response (i.e., excitation or inhibition) to skin stimulation of a neuron during turns toward (ipsilateral), or away from (contralateral) the side of the cell body was always the same. The cells could thus be divided into four types: 1) cells that were excited during ipsilateral turns and inhibited during contralateral turns; these cells provide an asymmetric excitatory bias to spinal networks and presumably play an important role for the generation of turns; these cells were common (n = 35; 52%) in both MRRN and PRRN; 2) cells that were excited during turns in either direction; these cells were common (n = 19; 28%), in particular in MRRN; they could be involved in a general activation of the locomotor system after skin stimulation; some of the cells were also more activated during turns in one direction and could contribute to an asymmetric turn command; 3) one cell that was inhibited during ipsilateral turns and excited during contralateral turns; and 4) cells (n = 12; 18%) that were inhibited during turns in either direction. In summary, our results show that, in the lamprey, the large majority of reticulospinal cells have responses during lateral turns that are indicative of a causal role for these cells in turn generation. This also suggests a considerable overlap between the command system for lateral turns evoked by skin stimulation, which was studied here, and other reticulospinal command systems, e.g., for lateral turns evoked by other types of stimuli, initiation of locomotion, and turns in the vertical planes.

Modeling of substance P and 5-HT induced synaptic plasticity in the lamprey spinal CPG: consequences for network pattern generation.

Consequences of synaptic plasticity in the lamprey spinal CPG are analyzed by means of simulations. This is motivated by the effects substance P (a tachykinin) and serotonin (5-hydroxytryptamin; 5-HT) have on synaptic transmission in the locomotor network. Activity-dependent synaptic depression and potentiation have recently been shown experimentally using paired intracellular recordings. Although normally activity-dependent plasticity presumably does not contribute to the patterning of network activity, this changes in the presence of the neuromodulators substance P and 5-HT, which evoke significant plasticity. Substance P can induce a faster and larger depression of inhibitory connections but potentiation of excitatory inputs, whereas 5-HT induces facilitation of both inhibitory and excitatory inputs. Changes in the amplitude of the first postsynaptic potential are also seen. These changes could thus be a potential mechanism underlying the modulatory role these substances have on the rhythmic network activity. The aim of the present study has been to implement the activity dependent synaptic depression and facilitation induced by substance P and 5-HT into two alternative models of the lamprey spinal locomotor network, one relying on reciprocal inhibition for bursting and one in which each hemicord is capable of oscillations. The consequences of the plasticity of inhibitory and excitatory connections are then explored on the network level. In the intact spinal cord, tachykinins and 5-HT, which can be endogenously released, increase and decrease the frequency of the alternating left-right burst pattern, respectively. The frequency decreasing effect of 5-HT has previously been explained based on its conductance decreasing effect on K(Ca) underlying the postspike afterhyperpolarization (AHP). The present simulations show that short-term synaptic plasticity may have strong effects on frequency regulation in the lamprey spinal CPG. In the network model relying on reciprocal inhibition, the observed effects substance P and 5-HT have on network behavior (i.e., a frequency increase and decrease respectively) can to a substantial part be explained by their effects on the total extent and time dynamics of synaptic depression and facilitation. The cellular effects of these substances will in the 5-HT case further contribute to its network effect.

Heterogeneity of the population of command neurons in the lamprey.

The effects of signals transmitted from the brain to the spinal locomotor networks by a population of command neurons are determined by specific functional projections of each individual neuron. To reveal these projections, we used a simple vertebrate model, the lamprey, in which responses of the spinal networks to spikes in single reticulospinal axons were detected by using the spike-triggered averaging of the motoneuronal activity. We found that individual neurons exert a uniform effect on the segmental motor output along the whole extent of their axons. Twenty different patterns of effect, that is, combinations of influences on the segmental motoneuron pools, were found. The widespread projections and heterogeneity of the population of command neurons present a basis for formation of different gross motor synergies.

Gating and braking of short- and long-term modulatory effects by interactions between colocalized neuromodulators.

Spinal locomotor networks in the lamprey are modulated by tachykinin neuropeptides. A single 10 min application of the tachykinin substance P evokes a short-term ( approximately 1 hr) presynaptic facilitation of glutamate release and the postsynaptic potentiation of NMDA responses. The latter effect induces a long-term (>24 hr) protein synthesis-dependent increase in the frequency of network activity. Tachykinins are contained in a ventromedial spinal plexus into which the medial dendrites of network neurons project. Neurons in this plexus also contain colocalized dopamine and 5-HT. Here, dynamic plasticity evoked by modulator interactions has been examined by investigating the effects of 5-HT and dopamine on specific cellular, synaptic, and network effects of substance P. Preapplied 5-HT blocked the substance P-mediated increase in the network burst frequency and the potentiation of NMDA-evoked cellular responses that underlies its induction. 5-HT also blocked the presynaptic facilitation of glutamatergic synaptic transmission by substance P. The presynaptic, but not postsynaptic, effect of 5-HT was reduced by the protein phosphatase 2B inhibitor cypermethrin. Dopamine did not directly modulate the effects of substance P. However, it reduced the presynaptic interactive effect of 5-HT and thus gated the presynaptic potentiation of glutamatergic inputs by substance P. However, the substance P-mediated potentiation of NMDA responses was not gated by dopamine, and thus the long-term network modulation was not induced. Neuromodulator effects and their interactions can thus be modulated. By selecting components from the modulatory repertoire of substance P, these interactions evoke dynamic changes in short- and long-term synaptic and network plasticity.

Ion channels of importance for the locomotor pattern generation in the lamprey brainstem-spinal cord.

The intrinsic function of the spinal network that generates locomotion can be studied in the isolated brainstem-spinal cord of the lamprey, a lower vertebrate. The motor pattern underlying locomotion can be elicited in the isolated spinal cord. The network consists of excitatory glutamatergic and inhibitory glycinergic interneurones with known connectivity. The current review addresses the different subtypes of ion channels that are present in the cell types that constitute the network. In particular the roles of the different subtypes of Ca2+ channels and potassium channels that regulate integrated neuronal functions, like frequency regulation, spike frequency adaptation and properties that are important for generating features of the motor pattern (e.g. burst termination), are reviewed. By knowing the role of an ion channel at the cellular level, we also, based on previous knowledge of network connectivity, can understand which effect a given ion channel may exert at the different levels from molecule and cell to network and behaviour.

Modeling postural control in the lamprey.

A phenomenological model of the mechanism of stabilization of the body orientation during locomotion (dorsal side up) in the lamprey is presented. The mathematical modeling is based on experimental results obtained during investigations of postural control in lampreys using a combined in vivo and robotics approach. The dynamics of the model agree qualitatively with the experimental data. It is shown by computer simulations that postural correction commands from reticulospinal neurons provide information sufficient to stabilize body orientation in the lamprey. The model is based on differences between the effects exerted by the vestibular apparatus on the left and the right side.

Slow dorsal-ventral rhythm generator in the lamprey spinal cord.

In the isolated lamprey spinal cord, a very slow rhythm (0.03-0.11 Hz), superimposed on fast N-methyl-D-aspartate (NMDA)-induced locomotor activity (0.26-2.98 Hz), could be induced by a blockade of GABA(A) or glycine receptors or by administration of (1 s, 3 s)-l-aminocyclopentane-1,3-dicarboxylic acid a metabotropic glutamate receptor agonist. Ventral root branches supplying dorsal and ventral myotomes were exposed bilaterally to study the motor pattern in detail. The slow rhythm was expressed in two main forms: 1) a dorsal-ventral reciprocal pattern was the most common (18 of 24 preparations), in which bilateral dorsal branches were synchronous and alternated with the ventral branches, in two additional cases a diagonal dorsal-ventral reciprocal pattern with alternation between the left (or right) dorsal and the right (or left) ventral branches was observed; 2) synchronous bursting in all branches was encountered in four cases. In contrast, the fast locomotor rhythm occurred always in a left-right reciprocal pattern. Thus when the slow rhythm appeared in a dorsal-ventral reciprocal pattern, fast rhythms would simultaneously display left-right alternation. A longitudinal midline section of the spinal cord during ongoing slow bursting abolished the reciprocal pattern between ipsilateral dorsal and ventral branches but a synchronous burst activity could still remain. The fast swimming rhythm did not recover after the midline section. These results suggest that in addition to the network generating the swimming rhythm in the lamprey spinal cord, there is also a network providing slow reciprocal alternation between dorsal and ventral parts of the myotome. During steering, a selective activation of dorsal and ventral myotomes is required and the neural network generating the slow rhythm may represent activity in the spinal machinery used for steering.

Roles of high-voltage-activated calcium channel subtypes in a vertebrate spinal locomotor network.

Lamprey spinal cord neurons possess N-, L-, and P/Q-type high-voltage-activated (HVA) calcium channels. We have analyzed the role of the different HVA calcium channels subtypes in the overall functioning of the spinal locomotor network by monitoring the influence of their specific agonists and antagonists on synaptic transmission and on N-methyl-D-aspartate (NMDA)-elicited fictive locomotion. The N-type calcium channel blocker omega-conotoxin GVIA (omega-CgTx) depressed synaptic transmission from excitatory and inhibitory interneurons. Blocking L-type and P/Q-type calcium channels with nimodipine and omega-agatoxin, respectively, did not affect synaptic transmission. Application of omega-CgTx initially decreased the frequency of the locomotor rhythm, increased the burst duration, and subsequently increased the coefficient of variation and disrupted the motor pattern. These effects were accompanied by a depression of the synaptic drive between neurons in the locomotor network. Blockade of L-type channels by nimodipine also decreased the frequency and increased the duration of the locomotor bursts. Conversely, potentiation of L-type channels increased the frequency of the locomotor activity and decreased the duration of the ventral root bursts. In contrast to blockade of N-type channels, blockade or potentiation of L-type calcium channels had no effect on the stability of the locomotor pattern. The P/Q-type calcium channel blocker omega-agatoxin IVA had little effect on the locomotor frequency or burst duration. The results indicate that rhythm generation in the spinal locomotor network of the lamprey relies on calcium influx through L-type and N-type calcium channels.