Spike train structure following application of nociceptive potassium chloride solutions to the cat saphenous nerve

The structure of the spike train coding the nociceptive signal was investigated by a cross-correlation method. The action of nociceptive solutions of potassium chloride (125–1000 mM) on the saphenous nerve caused excitation of both myelinated and nonmyelinated fibers. The density of the spike train increased during the action of the stimulus up to a threshold sufficient for the appearance of nociceptive reflexes. The maximum of these reflexes coincided with the appearance of synchronous pulsations of discharges in the group of unmyelinated fibers. The nociceptive signal evoked by direct action of highly concentrated potassium chloride solutions on the nerve is thus coded by a high density of the spike train generated by the nerve fibers. Synchronous pulsations may be present in the spike train under these circumstances.Research Institute of Applied Mathematics and Cybernetics, N. I. Lobachevski Gor'kii State University. Translated from Neirofiziologiya, Vol. 9, No. 6, pp. 598–605, November–December, 1977.     

Postnatal Temporal,Spatial and Modality Tuning of Nociceptive Cutaneous Flexion Reflexes in Human Infants

Cutaneous flexion reflexes are amongst the first behavioural responses to develop and are essential for the protection and survival of the newborn organism. Despite this, there has been no detailed, quantitative study of their maturation in human neonates. Here we use surface electromyographic (EMG) recording of biceps femoris activity in preterm (<37 weeks gestation, GA) and term (≥37 weeks GA) human infants, less than 14 days old, in response to tactile, punctate and clinically required skin-breaking lance stimulation of the heel. We show that all infants display a robust and long duration flexion reflex (>4 seconds) to a single noxious skin lance which decreases significantly with gestational age. This reflex is not restricted to the stimulated limb: heel lance evokes equal ipsilateral and contralateral reflexes in preterm and term infants. We further show that infant flexion withdrawal reflexes are not always nociceptive specific: in 29% of preterm infants, tactile stimulation evokes EMG activity that is indistinguishable from noxious stimulation. In 40% of term infants, tactile responses are also present but significantly smaller than nociceptive reflexes. Infant flexion reflexes are also evoked by application of calibrated punctate von Frey hairs (vFh), 0.8–17.2 g, to the heel. Von Frey hair thresholds increase significantly with gestational age and the magnitude of vFh evoked reflexes are significantly greater in preterm than term infants. Furthermore flexion reflexes in both groups are sensitized by repeated vFh stimulation. Thus human infant flexion reflexes differ in temporal, modality and spatial characteristics from those in adults. Reflex magnitude and tactile sensitivity decreases and nociceptive specificity and spatial organisation increases with gestational age. Strong, relatively non-specific, reflex sensitivity in early life may be important for driving postnatal activity dependent maturation of targeted spinal cord sensory circuits.     

Some characteristics of the afferent flow during noxious stimulation of the skin

Quantitative characteristics of the afferent impulse flow in a cat cutaneous nerve during stimulation of the skin with acid, needles, and pins were studied by a cross-correlation method. The appearance of a nociceptive response served as the test of noxious stimulation. Mechanical and chemical noxious stimuli, acting directly on the nerve fiber, activate the same peripheral channels as weak tactile stimuli exciting receptors. Spike trains under these circumstances differed in the absolute and relative numbers of active A and C fibers and the duration of activity in them. The nociceptive response is brought about through marked predominance of activity in C fibers compared with A fibers and through its long duration in both types of fibers but, in particular, in C fibers. An optical correlometer can be used to investigate activity of a whole nerve.Research Institute of Applied Mathematics and Cybernetics, N. I. Lobachevskii Gor'kii State University. Translated from Neirofiziologiya, Vol. 8, No. 2, pp. 168–176, March–April, 1976.     

Effect of nociceptive stimulation of signal transmission from low-threshold cutaneous afferents in the somatosensory system

In cats anesthetized with chloralose nociceptive heating of the skin of the foot to 44–60°C led to a two- to fourfold increase in amplitude of primary cortical responses to direct stimulation of neurons of the spinocervical tract receiving information from the heated area of skin, but did not affect primary responses evoked by stimulation of axons of these neurons in the dorsolateral funiculus, and actually inhibited the response to stimulation of the nerve innervating the heated area of skin. Inhibition was accompanied by depolarization of central terminal of low-threshold fibers of this nerve: During heating the amplitude of the antidromic discharges evoked in the nerve by stimulation of its presynaptic endings in the spinal cord was increased two- to threefold. After abolition of presynaptic depolarization with picrotoxin (0.2–0.7 mg/kg, intravenously) or as a result of asphyxia, nociceptive heating acquired the ability to facilitate primary responses arising as a result of stimulation of the nerve also. The amplitude of the responses was increased under these circumstances by 3–20 times. It is concluded that acute nociceptive stimulation causes such powerful presynaptic inhibition of impulse transmission from low-threshold fibers of the cutaneous nerve that it virtually abolishes the facilitating effect of nociceptive impulses on sensory neurons of the spinal cord. It is suggested that it is this inhibitory mechanism which prevents the development of hyperalgesia during acute nociceptive stimulation.Institute of General Pathology and Pathological Physiology, Academy of Medical Sciences of the USSR, Moscow. Translated from Neirofiziologiya, Vol. 13, No. 6, pp. 621–627, November–December, 1981.     

Effects of stimulating the periaqueductal gray matter on high- and low-threshold startle reflexes

The effects of stimulating the periaqueductal gray matter (PAG) on two types of startle reflex (spino-bulbo-spinal reflex produced by intensive stimulation of the peripheral nerves and low-threshold tactile spino-reticulo-spinal reflex) as well as high-threshold jaw-opening reflex arising in response to tooth pulp stimulation were investigated in cats anesthetized with chloralose. Simulating most PAG test sites led to pronounced inhibition of jaw-opening reflex, profound depression of spino-bulbo-spinal reflex, and moderate inhibition of tactile reflexes. The facilitatory effect of stimulating a number of PAG sites on the latter reflexes was demonstrated. Effects of PAG stimulation fell into two classes: brief, measurable in hundreds of msec and more prolonged, measured in minutes and seconds. Findings would indicate certain differences between the effects of PAG stimulation low-threshold (non-nociceptive) and high-threshold (nociceptive) startle reflexes, of which the possible mechanisms are discussed.A. A. Bogomolets Institute of Physiology, Academy of Sciences of the Ukrainian SSR, Kiev. Translated from Neirofiziologiya, Vol. 21, No. 1, pp. 71–78, January–February, 1989.     

Mechanisms underlying inhibition of nociceptive jaw-opening reflex produced by stimulating limbic structures

The comparative effectiveness of the inhibitory influence of tetanic (100 Hz) stimulation of the hypothalamus, amygdala, and limbic cortex on electromyograph (EMG) response in m. digastricus produced by electrical stimulation of tooth pulp afferents was investigated in cats anesthetized by a mixture of chloralose and Nembutal. It was found that the most pronounced inhibition of nociceptive EMG response was produced by stimulating the medial and lateral structures of the hypothalamus, a less intense response by stimulating central and medial amygdaloid nuclei, and the least reaction by stimulation of different areas of the limbic cortex. It was shown that mechanisms underlying inhibition of the jaw-opening reflex produced by hypothalamic tetanic stimulation is unconnected with the concomitant increase in blood pressure. The inhibitory action of hypothalamic tetanic stimulation following blood pressure stabilization persists; this would suggest a primary but not baroafferent mechanism underlying inhibition of activity in trigeminal nucleus nociceptive neurons. Pronounced and protracted depression of jaw-opening reflex takes place following long-term pressor response produced by injecting noradrenaline intravenously. The same pronounced and protracted pressor response occurs under the effects of angiotensin but without any noticeable change in the amplitude of nociceptive EMG response. Hypothalamic and noradrenergic mechanisms of pain sensitivity are discussed.L. A. Orbeli Institute of Physiology, Academy of Sciences of the Armenian SSR, Erevan. Translated from Neirofiziologiya, Vol. 19, No. 6, pp. 825–832, November–December, 1987.     

Contribution of serotonin to establishing a conditioned food aversion reflex in the snail

Combined presentation of food and noxious electrical stimulation produced no response in snails injected 6–16 days previously with 5,7-dihydrooxytryptamine, which produces degeneration of serotoninergic nerve terminals and reduced serotonin synthesis, although a defense (aversive) response was observed in the control group. Application of serotonin to a preparation of the snail central nervous system (contained in a bath) was used as reinforcement during neurophysiological experiments. The amplitude of synaptic response to nerve stimulation increased significantly in preparations in which stimulation was paired with serotonin application. After 3–7 sets of twin stimuli consisting of serotonin application and applying a drop of juice to the chemoreceptive surface area of the skin, a spike response to the latter stimulus was produced. No such effects were seen in response to unpaired stimuli. It was deduced that serotonin makes a major contribution to establishing conditioned aversive reactions in the snail.Institute of Higher Nervous Activity and Neurophysiology, Academy of Sciences of the USSR, Moscow. Translated from Neirofiziologiya, Vol. 18, No. 3, pp. 291–298, May–June, 1986.     

Effects of calcium channel blockers on spino-bulbo-spinal reflexes evoked by activation of the high-threshold and low-threshold somatic afferents

Effects of the calcium channel blockers nifedipine and verapamil on spino-bulbo-spinal (SBS) reflexes were studied in rats anesthetized with a mixture of urethane and chloralose; the reflexes evoked by activation of the high-threshold and low-threshold (tactile) somatic afferents were tested. The blockers were microinjected into then. reticularis gigantocellularis, the main structure where the SBS reflexes are relayed. Nifedipine (10^–4 M) evoked fast (with a latency of 1–2 min) and significant (20%–60%) suppression of both the high-threshold and low-threshold SBS reflexes. The reflexes recovered within 40 to 90 min. Lower concentrations of nifedipine (10^–5 M) either did not modify both types of the SBS reflexes (in 25% of experiments) or facilitated these reflexes by 16%–40% within 15–20 min. Microinjections of verapamil affected the SBS reflexes in a similar manner, but the effects were shorter. Possible ways by which the L-type calcium channels are involved in the transmission of afferent impulsation of different modalities (nociceptive and non-nociceptive) are discussed.Neirofiziologiya/Neurophysiology, Vol. 26, No. 4, pp. 270–275, July–August, 1994.     

Study of cutaneous nociception by means of chemical agents

The response was investigated of cutaneous C-fiber polymodal mechano-thermo-sensitive sensory units (SMT units) to injecting potassium, acetylcholine, and methacholine ions at noxious and subnoxious concentrations into the arteries of anesthetized cats. Subnoxious chemical stimulation induced low-frequency excitation in SMT units. The parameters of firing in these units, when subjected to excitation during noxious or subnoxious chemical stimulation, may be used to estimate the analgesic action of local anesthetics. Local anesthesia may be achieved by inhibiting exclusively high-frequency discharge in SMT units, without complete blockade of these sensors. We propose use-dependent neural excitation blockers for this purpose. SMT units were found to be inhibited in this way by mechanical stimulation under the action of lidocaine or n-propylaj-maline. Mathematical modeling of C-fibers showed that slow alterations in ionic permeability play a major part in determining firing rate produced by chemical stimulation.Experimental Cardiological Research Institute, All-Union Cardiological Research Center, Russian Academy of Medical Sciences, Moscow. Translated from Neirofiziologiya, Vol. 24, No. 5, pp. 517–529, September–October, 1992.     

Inhibitory effect of dopamine on the transmission of excitation in isolated rat spinal cord

The effects of dopamine on ventral root potential produced by a single supramaximal dorsal root stimulation of the dorsal root was investigated during experiments on isolated superfused spinal cord segments from 10–16-day old rats. A reciprocal dose-dependent inhibition of the mono- and polysynaptic components of reflex response was also observed. Minimum effective concentration was 1×10^–8 M dopamine. Extent of reflex response increased in step with dopamine concentration, so that the amplitude of the monosynaptic component of ventral root potential was decreased by 20% and 87% of baseline level by the action of 10^–4 and 10^–3 M dopamine respectively on the cord. The amplitude of the polysynaptic component was thereby decreased by an average of 18% and 87%. Findings indicate that dopaminergic brainstem-spinal pathways contribute to the governing of impulse transmission in the segmental reflex arcs. Inhibition of dopaminergic synaptic transmission probably underlies the increase in latency already described in the literature, as well as the increase observed in the threshold of reflex motor response to nociceptive action following either stimulation of the dopaminergic brainstem structures or intravenous administration of dopamine agonists.A. A. Bogomolets Institute of Physiology, Academy of Sciences of the Ukrainian SSR, Kiev. Translated from Neirofiziologiya, Vol. 18, No. 5, pp. 616–621, September–October, 1986.     

Responses of neurons of different hypothalamic structures to stimulation of tooth pulp and Aß afferents in the cat sciatic nerve

The response of neurons of different hypothalamic structures to stimulation of painful tooth pulp afferents and painless sciatic nerve Aß afferents was investigated during acute experiments on cats. It was found that 80.7%, 81.5%, and 71.4% of neurons of the posterior, tuberal, and anterior hypothalamus respectively, responded to stimulation of the tooth pulp. Shortest latency of response was recorded in the posterolateral hypothalamus. Latency of response was shorter in the lateral than in the medial structures throughout the hypothalamus. A distinct prevalence of excitatory response was found in neurons of the posterior area and an almost equal proportion of excitatory and inhibitory response in neurons of the tuberal and anterior hypothalamus. A high degree of convergence between noxious and nonnoxious somatic afferents were discovered in hypothalamic neurons: 85.8% of those studied responded to stimulation of the sciatic nerve Aß afferents. The comparable unidirectional response pattern of hypothalamic neurons to stimulation of tooth pump painful afferents and painless sciatic nerve Aß fibers point to the nonspecific nature of the response observed in the mainstream population of multisensory hypothalamic neurons. A small population of unimodal nociceptive neurons (14.2%) was found in the hypothalamus. Nociceptive responses of anterior hypothalamic neurons were distinguished by their long refractory phase, lasting 200–500 msec, and their low rate of reproduction during rhythmic stimulation of tooth pulp (1.5–2 Hz). Neuronal organization of the nociceptive hypothalamic afferent system is discussed together with the role of convergent and specific "nociceptive" neurons in the shaping of thalamic regulatory functions.L. A. Orbeli Institute of Physiology, Academy of Sciences of the Armenian SSR, Erevan. Translated from Neirofiziologiya, Vol. 18, No. 2, pp. 171–180, March–April, 1986.     

Activity of myelinated fibers under heat and burn influences on the skin

The dynamics of the activity of myelinated fibers of a cutaneous nerve under heat and burn influences on hair-covered skin was investigated in acute experiments on cats using the method of cross-correlation functions. Under heat influence on the skin the total activity of the nerve was reduced chiefly at the expense of the rapidly conducting myelinated fibers, whereas in the case of painful heating of the skin the A fibers were activated. The results obtained make it possible to solve the problem of the heat-information code from the standpoint of the flow "pattern" theory.S. M. Kirov Medical Institute, Ministry of Health of the Russian Federation, Nizhnii Novgorod. Translated from Neirofiziologiya, Vol. 24, No. 5, pp. 567–577, September–October, 1992.     

Intrathecal somatostatin produces effects dependent on the interval between catheter implantation and drug injection

Intrathecal (i.t.) injection of somatostatin has been reported to depress nociceptive reflexes as well as to cause severe disturbance of somatomotor performance. The present study was designed to assess the dependence of these effects on the dose and the interval between implantation of the catheter and i.t. injection of somatostatin in rats. The effects produced by i.t. injection of somatostatin consisted of an increase in the response latencies of nociceptive responses to noxious heat, impairment of motor performance and grooming behavior, convulsions, and death. Except for grooming behavior, these were related in incidence and degree to the dose and the interval, the potency of somatostatin being highest at short intervals. Sham operations also affected the effectiveness of somatostatin.     

Effect of peripheral heating and cooling on spinal reflex activity

The effects of heating and cooling the skin of the thigh and leg on the character of changes in monosynaptic and polysynaptic reflexes and of the first negative wave (N_`) of the dorsal cord potential was studied in acute experiments on lightly anesthetized cats. During cooling of the skin the amplitude of the monosynaptic reflex and N₁-wave was increased while the polysynaptic reflex was inhibited; during heating the amplitude of the monosynaptic reflex and N₁-wave was reduced while the polysynaptic reflex was increased. After de-efferentation the cooling effect was reduced, and after division of the spinal cord responses to cooling of the skin were considerably inhibited. The mechanism of the selective action of cooling and heating of the skin on monosynaptic and polysynaptic reflexes are discussed.Institute of Physiology, Academy of Sciences of the Kazakh SSR, Alma-Ata. Translated from Neirofiziologiya, Vol. 5, No. 2, pp. 181–185, March–April, 1973.     

The bradykinin B1 receptor antagonist B9858 inhibits a nociceptive spinal reflex in rabbits

There are two bradykinin receptor subtypes, designated B1 and B2. Whilst both have been implicated in nociception, it is believed that there is a low level of constitutive expression of B1 receptors and that their expression is induced by inflammation or tissue damage. The present study investigated the role of B1 receptors in spinal nociceptive processing using an in vivo electrophysiological assay in decerebrate, spinalized rabbits, a species that shares close B1 receptor homology with the human receptor. Inflammation was induced in the paw by an injection of complete Freund's adjuvant at least 1 h before recording single motor unit activity of the semitendinous/biceps femoris muscle in response to a noxious pinch of the foot. Control animals received an intraplantar injection of saline. The peptide B1 receptor antagonist B9858 was administered i.v. and caused dose-dependent and complete inhibition of the nociceptive spinal reflex (ID50 = 1 mg x kg(-1)). In control animals without paw inflammation, B9858 had no effect. These findings are consistent with other evidence that peptide B1 receptor antagonists inhibit spinal nociceptive reflexes only after induction of B1 receptors by inflammation and support the potential therapeutic utility of B1 receptor antagonists as analgesic and anti-inflammatory drugs.     

Action of ammonium acetate on central primary afferent depolarization

Experiments on anesthetized spinal cats showed that ammonium acetate, injected intravenously (2–4 mmoles/kg) inhibits the depolarization of the central endings of primary afferent fibers activated by stimulation of afferent nerves. Inhibition of primary afferent depolarization is transient in character and develops parallel with depression of postsynaptic inhibition of monosynaptic reflexes. The depression produced by the action of ammonium was not due to blocking of negative postsynaptic potentials of the dorsal surface of the spinal cord or blocking of reflex electrical discharges in the ventral spinal roots. It is suggested that depression of primary afferent depolarization is due to a decrease in the emf for synaptic ion currents producing depolarization.Allergologic Research Laboratory, Academy of Medical Sciences of the USSR, Moscow. Translated from Neirofiziologiya, Vol. 9, No. 1, pp. 52–60, January–February, 1977.     

Activation of pontine and bulbar reticulo-spinal neurons in the cat by somatosensory stimuli of different modalities

The response pattern of reticulo-spinal (RS) neurons in two reticulo-spinal structures (n. reticularus pontis caudalis and n. reticularis gigantocellularis) to both electrical (somatic) nerve stimulation and natural mechanical innocuous (tapping with varying force) and noxious (pinch and prick) stimulation were investigated in chloralose-anesthetized cats. Bulbar and pontine neurons were found to vary considerably in their sensory characteristics: of the former 43% were activated only by high-threshold electrical nerve stimulation and noxious stimuli, while the remainder responded to innocuous stimuli as well. In the case of pontine neurons 81% produced a response to stimulation of low-threshold nerve fibers, and to innocuous as well as noxious stimuli. A relationship was found between the sensory characteristics of reticulo-spinal neurons and their axon conductance velocities. Various aspects and the likely functional significance of specialization in brainstem neurons of the pontine and bulbar reticular formation come under discussion.A. A. Bogomolets Institute of Physiology, Academy of Sciences of the Ukrainian SSR, Kiev. Translated from Neirofiziologiya, Vol. 18, No. 4, pp. 461–469, July–August, 1986.     

Effect of phosphocreatine on reflex activity of the brain stem reticular formation

The effects of phosphocreatine (PCr) on startle reflexes, known to be relayed through the brain stem reticular formation (RF), were investigated on chloralose-anesthetized rats. PCr (10^–6 to 10^–3 M) was either applied superficially to the bottom of the fourth ventricle or microinjected into the reticular gigantocellular nucleus. The PCr effect was found to depend on its concentration. At low concentrations (10^–6 to 10^–5 M), PCr markedly facilitated the reflexes; sometimes its application gave rise to additional, later and longer, discharges following startle reflexes, whereas an inhibitory effect predominated at higher PCr concentration (10^–4 to 10^–3 M). Possible mechanisms of PCr action on the studied reflexes are discussed.Neirofiziologiya/Neurophysiology, Vol. 25, No. 3, pp. 272–278, 1993.     

Role of endogenous opiates and extracellular K+ accumulation in the inhibition of frog spinal reflexes by electrical skin stimulation

Electrical skin stimulation of the hind limb (10-100 Hz, 30 s-5 min) at the intensity which leads only to the excitation of low threshold afferents depressed (for 1-30 min) the flexor reflex evoked in spinal frogs by nociceptive stimuli. The inhibition, which lasted for longer than 5 min was blocked by naloxone. Short-term poststimulation effects were associated with an increase of extracellular K+ concentration (delta [K]e) and were not blocked by naloxone. Enkephalins or morphine applied to the spinal cord surface increased the threshold for flexor reflexes while naloxone decrease their threshold. The stimulation was followed by short-term hyperpolarization of primary afferents (PAH; 1-5 min) and by depression of dorsal root potentials (DPRs) which had a similar time course to the delta [K]e, and were not blocked by naloxone. This period was frequently followed by longlasting PAH and enhancement of DRPs (5-30 min), which were abolished by naloxone. Superfusion of the isolated spinal cord with opioids produced PAH and enhanced DRPs evoked by nociceptive stimuli, while naloxone or increase of [K] in Ringer solution depolarized primary afferents and depressed DRPs. It is suggested that the antinociceptive effects of electrical stimulation of low threshold cutaneous afferents in spinal frogs involves at least two mechanisms. The short-term effect may result from delta [K]e, especially at high stimulus strength and is equally effective against noxious and non-noxious stimuli. The longlasting effects selectively affecting nociceptive transmission appear to be produced by endogenous opioids.     

Constitutive formulation and numerical analysis of the heel pad region

The aim of this work is to provide a numerical approach for the investigation of the mechanical behaviour of the heel pad region. A visco-hyperelastic model is formulated with regard to fat pad tissue, while a fibre-reinforced hyperelastic model is considered for the heel skin tissue. Bone components are defined by means of an orthotropic linear elastic model. Particular attention is paid to the evaluation of constitutive parameters within different models adopted in consideration of experimental tests data. Preliminarily, indentation tests on a skinless cadaveric foot are considered with regard to fat pad tissue. Indentation tests on an intact heel pad of a cadaveric foot are subsequently adopted for the final identification of constitutive parameters of fat pad and skin tissues. A numerical model of the rear foot is defined and different loading conditions are assumed according to experimental data. A comparison between experimental and numerical data leads to the evaluation of the real capability of the procedure to interpret the actual response of the rear foot.