Spinal fMRI Reveals Decreased Descending Inhibition during Secondary Mechanical Hyperalgesia

Mechanical hyperalgesia is one distressing symptom of neuropathic pain which is explained by central sensitization of the nociceptive system. This sensitization can be induced experimentally with the heat/capsaicin sensitization model. The aim was to investigate and compare spinal and supraspinal activation patterns of identical mechanical stimulation before and after sensitization using functional spinal magnetic resonance imaging (spinal fMRI). Sixteen healthy subjects (6 female, 10 male, mean age 27.2±4.0 years) were investigated with mechanical stimulation of the C6 dermatome of the right forearm during spinal fMRI. Testing was always performed in the area outside of capsaicin application (i.e. area of secondary mechanical hyperalgesia). During slightly noxious mechanical stimulation before sensitization, activity was observed in ipsilateral dorsolateral pontine tegmentum (DLPT) which correlated with activity in ipsilateral spinal cord dorsal gray matter (dGM) suggesting activation of descending nociceptive inhibition. During secondary mechanical hyperalgesia, decreased activity was observed in bilateral DLPT, ipsilateral/midline rostral ventromedial medulla (RVM), and contralateral subnucleus reticularis dorsalis, which correlated with activity in ipsilateral dGM. Comparison of voxel-based activation patterns during mechanical stimulation before/after sensitization showed deactivations in RVM and activations in superficial ipsilateral dGM. This study revealed increased spinal activity and decreased activity in supraspinal centers involved in pain modulation (SRD, RVM, DLPT) during secondary mechanical hyperalgesia suggesting facilitation of nociception via decreased endogenous inhibition. Results should help prioritize approaches for further in vivo studies on pain processing and modulation in humans.     

Pharmacology of descending control systems

In the cat there is no convincing evidence that a particular compound mediates a supraspinal control of spinal transmission of nociceptive information. There is good evidence that opioid peptides are released segmentally in response to nociceptive input to the spinal cord and that this acts to inhibit motoneurons and to reduce transmission of nociceptive information to supraspinal areas. In the cat there is no evidence that stimulation at supraspinal sites producing analgesia results in a spinal release of opioid peptides. In the rat evidence for the latter has been obtained but there are no data from other species. Tonically present supraspinal inhibition of spinal transmission of nociceptive information in the cat does not involve opioid peptides. Indirect evidence favours a role for 5-hydroxytryptamine and noradrenaline in supraspinal control of spinal processing of nociceptive transmission. Peripheral antagonists of 5-HT have reduced spinal inhibition from stimulation at supraspinal sites but the site of action is unknown. Progress with noradrenaline involvement has been hindered by lack of a suitable antagonist. Although the amino acids, glycine and GABA are involved in segmental inhibition of transmission of nociceptive information, no convincing evidence has indicated their involvement in supraspinal controls.     

Cortical Presynaptic Control of Dorsal Horn C–Afferents in the Rat

Lamina 5 sensorimotor cortex pyramidal neurons project to the spinal cord, participating in the modulation of several modalities of information transmission. A well-studied mechanism by which the corticospinal projection modulates sensory information is primary afferent depolarization, which has been characterized in fast muscular and cutaneous, but not in slow-conducting nociceptive skin afferents. Here we investigated whether the inhibition of nociceptive sensory information, produced by activation of the sensorimotor cortex, involves a direct presynaptic modulation of C primary afferents. In anaesthetized male Wistar rats, we analyzed the effects of sensorimotor cortex activation on post tetanic potentiation (PTP) and the paired pulse ratio (PPR) of dorsal horn field potentials evoked by C–fiber stimulation in the sural (SU) and sciatic (SC) nerves. We also explored the time course of the excitability changes in nociceptive afferents produced by cortical stimulation. We observed that the development of PTP was completely blocked when C-fiber tetanic stimulation was paired with cortex stimulation. In addition, sensorimotor cortex activation by topical administration of bicuculline (BIC) produced a reduction in the amplitude of C–fiber responses, as well as an increase in the PPR. Furthermore, increases in the intraspinal excitability of slow-conducting fiber terminals, produced by sensorimotor cortex stimulation, were indicative of primary afferent depolarization. Topical administration of BIC in the spinal cord blocked the inhibition of C–fiber neuronal responses produced by cortical stimulation. Dorsal horn neurons responding to sensorimotor cortex stimulation also exhibited a peripheral receptive field and responded to stimulation of fast cutaneous myelinated fibers. Our results suggest that corticospinal inhibition of nociceptive responses is due in part to a modulation of the excitability of primary C–fibers by means of GABAergic inhibitory interneurons.     

Tachykinins as modulators of the micturition reflex in the central and peripheral nervous system

In the normal urinary bladder, tachykinins (TKs) are expressed in a population of bladder nociceptors that is sensitive to the excitatory and desensitizing effects of capsaicin (i.e., capsaicin-sensitive primary afferent neurons (CSPANs)). Several endobiotics or xenobiotics excite CSPANs and release TKs and other mediators at both the peripheral and spinal cord level. The peripheral release of TKs determines a set of responses (known as neurogenic inflammation) that includes vasodilatation, plasma protein extravasation, smooth muscle contraction and stimulation of afferent nerves. Following chronic inflammation, both immune cells and capsaicin-resistant sensory neurons can de novo express TKs: whether these pools of TKs are releasable and contribute to inflammatory processes is presently unsettled. At the spinal cord level, the release of TKs contributes in determining an altered pattern of vesicourethral reflexes in response to nociceptive stimulation of the bladder by conveying: (a) the afferent transmission to supraspinal sites, and (b) descending or sensory inputs to the sacral parasympathetic nucleus (SPN). Recent evidence also attribute a synergetic role of TKs in the supraspinal modulation of the sensory arm of the micturition reflex.The overall available information suggests that TK receptor antagonists may affect bladder motility/reflexes which occur during different pathological states, while having little influence on the normal motor bladder function.     

Inhibition of spinal interneuronal activity by repeated cutaneous stimulation: a possible substrate of flexor reflex habituation

The responses of interneurones, situated in the lumbar region of the rat spinal cord, to repeated cutaneous stimulation, were studied. The main purpose of this investigation was to attempt to determine the extent to which habituation of the flexor reflex might be explained on the basis of a progressive development of inhibition. Spontaneously active interneurones, which were inhibited by cutaneous stimuli, were investigated in detail. In rats whose spinal cords were intact, the period of inhibition was shown to increase with successive stimuli. This increase in inhibition was directly related to the intensity and frequency of stimulation, occurred more rapidly during a second series of stimuli and was antagonized by strychnine. In spinal animals, an increase in the duration of the period of inhibition to repeated stimulation could not be demonstrated. In this preparation, a gradual decrease in inhibition occurred. It is tentatively concluded that inhibition of spinal interneurones, the development of which depends upon descending influences from supraspinal centres, may be partially responsible for habituation.     

Spinal and spino-bulbo-spinal neuronal mechanisms of transmission of somatomotor and visceromotor reflexes in the thoracic spinal cord

Early (spinal) and late (spino-bulbo-spinal) responses of interneurons in segments T9–10 to stimulation of the splanchnic and intercostal nerves and the dorso-lateral and ventral funiculi of the spinal cord (at the C3 level) were investigated in experiments on cats anesthetized with chloralose. The experiments showed that interneurons activated by spinal and spino-bulbo-spinal mechanisms differ in their distribution in the dorso-ventral plane of the spinal cord. Cells of layers I–V were excited by spinal pathways only, but those of layers VII and VIII by both spinal and spino-bulbo-spinal or only by the latter. Spino-bulbo-spinal effects were evoked in interneurons by both somatic and visceral afferent waves. A conditioning spino-bulbo-spinal wave evoked deep and prolonged inhibition of late activity induced by somatic or visceral afferent impulses. Early (spinal) activity was inhibited only partially under these circumstances. This inhibition was shown to take place with the participation of supraspinal structures. The possible types of spinal and supraspinal mechanisms of inhibition of early and late activity in spinal neurons are discussed.Institute of Normal and Pathological Physiology, Slovak Academy of Sciences, Bratislava, Czechoslovakia. A. A. Bogomolets Institute of Physiology, Academy of Sciences of the Ukrainian SSR, Kiev, USSR. Translated from Neirofiziologiya, Vol. 5, No. 4, pp. 392–400, July–August, 1973.     

Analgesia following electrostimulation of midbrain nuclei of rats with a pain syndrome of spinal origin]

The effect of electrostimulation of the mesencephalic grey matter and of the dorsal nucleus raphe on physiological pain produced by nociceptive stimulation (compression of the tail or the skin on the limb by a clamp) and on pathological pain (the pain syndrome of spinal origin) were studied in experiments on albino rats. Pathological pain was induced by creating a generator of pathologically enhanced excitation in the dorsal horn of the spinal cord by local disturbance of the inhibitory mechanisms with the aid of tetanus toxin. It was shown that electrostimulation of the indicated areas abolished both physiological and pathological pain. A conclusion was drawn that analgesia produced by electrostimulation of certain structure of the brain was connected not only with augmentation of the descending inhibition in the spinal cord as in the case of physiological pain caused by peripheral nociceptive stimulation (as shown by several authors), but also with the block of excitation at the supraspinal level. This mechanism should play a decisive role in analgesia realization in the pain syndrome of central origin, both under experimental and natural conditions.     

刺激大鼠下丘脑背内侧核对丘脑束旁核痛相关神经元放电的影响

本文在 79只清醒麻痹大鼠身上,用玻璃微电极记录丘脑束旁核痛兴奋(PfPE)和痛抑制(PfPI)单位的放电及其对刺激下丘脑背内侧核(DMH)的反应,并观察切割脊髓背外侧束的效应。主要结果如下:(1)刺激DMH使PfPE 单位的自发放电及痛放电有明显的抑制作用,而使PfPI 单位的自发放电增多,并解除伤害性刺激引起的抑制效应;(2)刺激DMH引起PfPE 单位的抑制效应,在切割脊髓背外侧束后仍然出现。上述结果提示:DMH 对丘脑束旁核在处理痛觉信息上具有调制作用,这种调制作用可能不通过脑干下行性抑制系统完成,而主要是通过脊髓上联系抑制丘脑束旁核神经元对痛传入的反应。     

Control of locomotion in vitro: I. Deafferentation

We previously described the ability to induce adult-like, coordinated airstepping following electrical stimulation of the brainstem in the hindlimb-attached, in vitro brainstem-spinal cord preparation. These findings suggest the presence at birth of supraspinal systems capable of activating and modulating spinal locomotor mechanisms, which presumably also are present at birth. The current study employed the hindlimb-attached in vitro brainstem-spinal cord preparation from 0- to 4-day-old rats maintained in oxygenated artificial cerebrospinal fluid. After the control threshold-frequency relationship for eliciting airstepping was established, the dorsal roots to the attached limbs were severed and the procedure was repeated. No changes in electrical threshold or major differences in the elicited locomotor pattern were observed after deafferentation, although the amplitude of the electromyograms decreased. The mean frequency of alternation at threshold before deafferentation was similar to that after deafferentation. However, the maximum mean frequency induced by suprathreshold stimulation was significantly higher after deafferentation than that before deafferentation. These results suggest that (1) the supraspinal modulation of spinal locomotor mechanisms is not entirely dependent on afferent input; (2) intrinsic spinal locomotor mechanisms are present in the spinal cord at birth; and (3) afferent input may limit the maximum frequency of alternation of the limbs early in development.     

Modulation of Short-Latency Afferent Inhibition Depends on Digit and Task-Relevance

Short-latency afferent inhibition (SAI) occurs when a single transcranial magnetic stimulation (TMS) pulse delivered over the primary motor cortex is preceded by peripheral electrical nerve stimulation at a short inter-stimulus interval (∼20–28 ms). SAI has been extensively examined at rest, but few studies have examined how this circuit functions in the context of performing a motor task and if this circuit may contribute to surround inhibition. The present study investigated SAI in a muscle involved versus uninvolved in a motor task and specifically during three pre-movement phases; two movement preparation phases between a “warning” and “go” cue and one movement initiation phase between a “go” cue and EMG onset. SAI was tested in the first dorsal interosseous (FDI) and abductor digiti minimi (ADM) muscles in twelve individuals. In a second experiment, the origin of SAI modulation was investigated by measuring H-reflex amplitudes from FDI and ADM during the motor task. The data indicate that changes in SAI occurred predominantly in the movement initiation phase during which SAI modulation depended on the specific digit involved. Specifically, the greatest reduction in SAI occurred when FDI was involved in the task. In contrast, these effects were not present in ADM. Changes in SAI were primarily mediated via supraspinal mechanisms during movement preparation, while both supraspinal and spinal mechanisms contributed to SAI reduction during movement initiation.     

Antidromic discharges of dorsal root afferents in the neonatal rat.

Presynaptic inhibition of primary afferents can be evoked from at least three sources in the adult animal: 1) by stimulation of several supraspinal structures; 2) by spinal reflex action from sensory inputs; or 3) by the activity of spinal locomotor networks. The depolarisation in the intraspinal afferent terminals which is due, at least partly, to the activation of GABA(A) receptors may be large enough to reach firing threshold and evoke action potentials that are antidromically conducted into peripheral nerves. Little is known about the development of presynaptic inhibition and its supraspinal control during ontogeny. This article, reviewing recent experiments performed on the in vitro brainstem/spinal cord preparation of the neonatal rat, demonstrates that a similar organisation is present, to some extent, in the new-born rat. A spontaneous activity consisting of antidromic discharges can be recorded from lumbar dorsal roots. The discharges are generated by the underlying afferent terminal depolarizations reaching firing threshold. The number of antidromic action potentials increases significantly in saline solution with chloride concentration reduced to 50% of control. Bath application of the GABA(A) receptor antagonist, bicuculline (5-10 microM) blocks the antidromic discharges almost completely. Dorsal root discharges are therefore triggered by chloride-dependent GABA(A) receptor-mediated mechanisms; 1) activation of descending pathways by stimulation delivered to the ventral funiculus (VF) of the spinal cord at the C1 level; 2) activation of sensory inputs by stimulation of a neighbouring dorsal root; or 3) pharmacological activation of the central pattern generators for locomotion evokes antidromic discharges in dorsal roots. VF stimulation also inhibited the response to dorsal root stimulation. The time course of this inhibition overlapped with that of the dorsal root discharge suggesting that part of the inhibition of the monosynaptic reflex may be exerted at a presynaptic level. The existence of GABA(A) receptor-independent mechanisms and the roles of the antidromic discharges in the neonatal rat are discussed.     

Nociceptive system response to repetitive painful stimuli during chronic psychoemotional stress in humans

Repeated nocigenic stimuli applied to the skin evoked a hyperalgesia in healthy subjects while in patients with neurasthenia which is a natural model of a chronic psychoemotional stress, they evoked a hyperalgesia accompanied by sensitization. The differences in the nociceptive system responses show particularities in reactivity (plasticity) of a wide dynamic range of the spinal neurons under chronic psychoemotional stress that is due to disorders in supraspinal descending modulation system of plasticity in the spinal nociceptive neurons.     

Sensorimotor regulation of movements: Novel strategies for the recovery of mobility

A series of observations have provided important insight into properties of the spinal as well as supraspinal circuitries that control posture and movement. We have demonstrated that spinal rats can regain full weight-bearing standing and stepping over a range of speeds and directions with the aid of electrically enabling motor control (eEmc), pharmacological modulation (fEmc), and training [1, 2]. Also, we have reported that voluntary control movements of individual joints and limbs can be regained after complete paralysis in humans [3, 4]. However, the ability to generate significant levels of voluntary weight-bearing stepping with or without epidural spinal cord stimulation remains limited. Herein we introduce a novel method of painless transcutaneous electrical enabling motor control (pcEmc) and sensory enabling motor control (sEmc) strategy to neuromodulate the physiological state of the spinal cord. We have found that a combination of a novel non-invasive transcutaneous spinal cord stimulation and sensory-motor stimulation of leg mechanoreceptors can modulate the spinal locomotor circuitry to state that enables voluntary rhythmic locomotor movements.     

The influence of learning on the "setting" of the spinal apparatus of reciprocal inhibition prior to voluntary motion]

The subjects performed daily for nine days from 200 to 250 single movements, namely a rapid dorsal flexion of the foot. Recording of the EMG of antagonist muscles and testing by the single and paired H-reflexes method has revealed three phenomena of learning: greater ratio of electrical activity (EA) of antagonist muscles owing to the enhanced agonist's EA; stronger reciprocal inhibition of the antagonist motoneurone nucleus at the beginning of the movement; enhanced supraspinal "tuning" of the spinal apparatus of the antagonist reciprocal inhibition before the beginning of the movement. It is suggested that the third phenomenon of learning underlies two phenomena.     

The effect of active pedaling combined with electrical stimulation on spinal reciprocal inhibition

ObjectivePedaling is widely used for rehabilitation of locomotion because it induces muscle activity very similar to locomotion. Afferent stimulation is important for the modulation of spinal reflexes. Furthermore, supraspinal modulation plays an important role in spinal plasticity induced by electrical stimulation. We, therefore, expected that active pedaling combined with electrical stimulation could induce strong after-effects on spinal reflexes.DesignTwelve healthy adults participated in this study. They were instructed to perform 7 min of pedaling. We applied electrical stimulation to the common peroneal nerve during the extension phase of the pedaling cycle. We assessed reciprocal inhibition using a soleus H-reflex conditioning-test paradigm. The magnitude of reciprocal inhibition was measured before, immediately after, 15 and 30 min after active pedaling alone, electrical stimulation alone and active pedaling combined with electrical stimulation (pedaling + ES).ResultsThe amount of reciprocal inhibition was significantly increased after pedaling + ES. The after-effect of pedaling + ES on reciprocal inhibition was more prominent and longer lasting compared with pedaling or electrical stimulation alone.ConclusionsPedaling + ES could induce stronger after-effects on spinal reciprocal inhibitory neurons compared with either intervention alone. Pedaling + ES might be used as a tool to improve locomotion and functional abnormalities in the patient with central nervous lesion.     

Spinal control of erection by glutamate in rats

The lumbosacral spinal network controlling penile erection is activated by information from peripheral and supraspinal origins. We tested the hypothesis that glutamate, released by sensory afferents from the genitals, activates this proerectile network. In anesthetized intact and T8 spinalized (i.e., freed from supraspinal inhibition) male rats, the parameters of electrical stimulation of the dorsal penile nerve (DPN) that elicited intracavernous pressure (ICP) rises were determined. In T8 spinalized rats, DPN stimulations were applied in the presence of d(-)-2-amino-5-phosphonopentanoic acid (d-AP5), a competitive NMDA receptor antagonist, or of 2,3-dioxo-6-nitro-1,2,3,4-tetrahydrobenzo[f]quinoxaline-7-sulphonamide (NBQX), an AMPA-kainate receptor antagonist, injected intrathecally at the lumbosacral level. Both antagonists, alone or in combination, dose dependently decreased the ICP rise and increased its latency. In conscious rats, reflexive erections were depressed by d-AP5 and NBQX, as revealed by an increased latency of the first erection and by decreases of the number of rats displaying erections, of the number of erection clusters and of the number of erections per cluster. In anesthetized ats, the combined administration of the glutamatergic agonists NMDA and AMPA elicited ICP rises in the absence of DPN stimulation. In contrast, both agonists moderately decreased the ICP rise elicited by DPN stimulation but did not affect its latency. These results support our hypothesis that glutamate, released on stimulation of the genitals and acting at AMPA and NMDA receptors, is a potent reactivator of the spinal proerectile network.     

Extrapyramidal descending influences on neurons of the spinal cord in a superreflexia state

The spinal superreflexia state was modeled in experiments on rats using preliminary transection of the spinal cord and injection (in the course of the acute experiment) of 4-aminopyridine. An extremely high (reaching 15–20 mV) amplitude of monosynaptic reflex discharges (MRs) evoked by stimulation of the dorsal root and recorded from the ventral root (VR) L ₄ and the presence of an additional component in the above discharges were phenomena indicative of the development of the above state. Under such conditions, the amplitudes of the discharges evoked in the VR by electrical stimulation of the round window of the labyrinth (vestibular stimulation) and of the discharges elicited by stimulation of the motor cortex under conditions of bilateral transection of the pyramids increased several times. Thresholds of the VR responses to vestibular and cortical stimulations demonstrated an about threefold drop; latencies of the mass responses and responses of single spinal moto-and interneurons decreased about twofold, on average. The pattern of vestibular conditioning effects on the VR MRs changed: in intact animals vestibular stimulation induced inhibition of the VR MRs, while in animals with superreflexia such stimulation led to facilitation of the MRs. Cortical stimulation under conditions of pyramidotomy in both intact animals and animals with superreflexia resulted in facilitation of the VR MRs of a nearly the same intensity. The levels of convergence of the segmental and supraspinal effects on interneurons and motoneurons of the rat spinal cord dramatically increased under superreflexia conditions. The possible mechanisms of augmentation of the descending influences on spinal neuronal systems under the above conditions are discussed. Neirofiziologiya/Neurophysiology, Vol. 38, No. 2, pp. 140–149, March–April, 2006.     

Locomotion induced by epidural stimulation in a decerebrated cat after spinal cord injury

The effect of partial and complete spinal cord transection (Th7–Th8) on locomotor activity evoked in decerebrated cats by electrical epidural stimulation (segment L5, 80–100 μA, 0.5 ms at 5 Hz) has been investigated. Transection of dorsal columns did not substantially influence the locomotion. Disruption of the ventral spinal quadrant resulted in deterioration and instability of the locomotor rhythm. Injury to lateral or medial descending motor systems led to redistribution of the tone in antagonist muscles. Locomotion could be evoked by epidural stimulation within 20 h after complete transection of the spinal cord. The restoration of polysynaptic components in EMG responses correlated with recovery of the stepping function. The data obtained confirm that initiation of locomotion under epidural stimulation is caused by direct action on intraspinal systems responsible for locomotor regulation. With intact or partially injured spinal cord, this effect is under the influence of supraspinal motor systems correcting and stabilizing the evoked locomotor pattern.     

Interactions of human cord dorsum potential.

The slow positive wave (P2 wave) of the evoked spinal electrogram was recorded from the posterior epidural space in wakeful man, and studied by applying several modes of peripheral nerve stimulation. With graded stimulation the P2 wave amplitude rapidly reached the maximum at weaker stimulation than that required for the initially positive spikes (P1) and the preceding negative (N1) wave. The "second" component of the P2 appeared during stronger stimulation or during excitemenpt of the subjects. With prolonged repetitive stimulation the P2 wave increased its duration with several summits on the decaying phase. Two interactions were observed between the P2 waves produced by conditioning and testing stimulations in the same or different nerves: inhibition or occlusion by strong stimulation and faciliation by weak stimulation. Thus, the characteristic of the P2 wave in man was similar in part to that of the positive wave observed in decerebrate animals, and differnt in other ways presumably due to influences from supraspinal structures or species differences.     

Control of the human and animal locomotor activity in the absence of supraspinal effects

In patients deprived of supraspinal effects, electrical epidural stimulation of the spinal cord's dorsal surface at the level of 2nd lumbar segment induces step-like movements accompanied by respective electromyographic activity of the leg's muscles. Triggering of the step-like movements occurs at certain parameters of the stimulation. The data obtained suggest that human spinal cord has networks of interneurons-generators of the step-like movements. A leading role of the spinal cord's propriospinal system in activation of spinal generators of stepping under epidural influences was shown in cats.