Central analgesic effect of paracetamol manifested by depression of nociceptive activity in thalamic neurones of the rat

To study the question whether or not paracetamol produces a central analgesic effect, experiments were carried out on rats under urethane anaesthesia in which activity was elicited by supramaximal electrical stimulation of nociceptive afferents in the sural nerve and recorded from single neurones in the dorsomedial part of the ventral nucleus (VDM) of the thalamus. Paracetamol administered by intraperitoneal (i.p.) injection at doses of 50, 100 and 150 mg/kg reduced nociceptive evoked but not spontaneous activity. The amount of depression caused by the 3 doses and the time course of their effects was practically the same. suggesting that paracetamol is not capable to abolish nociceptive evoked activity in the thalamus but causes a maximum depression of the activity amounting to not more than about 60% of the controls. An intravenous (i.v.) injection of naloxone (1 mg/kg) did not diminish paracetamol-induced depression. The results present evidence for a central analgesic effect of paracetamol that is independent of endogenous opioids.     

Fluorescent double-labelling study of ascending and descending neurones in the feline lateral cervical nucleus

Summary The organization of ascending and descending neurones of the lateral cervical nucleus (LCN) was investigated in 10 adult cats after injections of the fluorescent tracers Fast Blue and Nuclear Yellow. Injections into the thalamus and tectum resulted in up to 3000 labelled cell profiles within the contralateral LCN. This corresponded to a calculated number of 4500 labelled LCN neurones. The greatest diameter of the labelled cell profiles was about 30 m. They were located throughout the nucleus, but were less numerous in its medial portion. Injections mainly into the dorsal horn of different pairs of cervical and lumbar segments of the spinal cord resulted in a calculated number of up to 305 labelled LCN cells. The diameter of these cell profiles was about 25 m and they were mainly situated in the rostro-ventral and medial parts of the LCN. Doublelabelled cells with ascending and descending projections were not encountered after injections into the thalamus-tectum and spinal segments C5-6. About 15% of the descending LCN cells were doublelabelled by pairs of spinal injections separated by intervals of one segment. It is concluded that the neurones descending down the spinal cord and ascending to the thalamus-tectum constitute different subpopulations of cells within the LCN and that a minor proportion of the descending cells seem to project to at least three adjacent segments of the spinal cord.     

Involvement of supraspinal and spinal segmental alpha-2-adrenergic mechanisms in the medetomidine-induced antinociception.

The effect of systemically administered medetomidine, a selective alpha-2-adrenoceptor agonist, was studied by electrophysiological recordings of the peripherally evoked responses of three different types of sensory neuronal populations in the rat: medial thalamic neurons exclusively responding to mechanical cutaneous stimuli at noxious intensities, spinothalamic tract neurons of the spinal cord responding exclusively or differentially to mechanical cutaneous stimuli at noxious intensities, and low-threshold mechanoreceptive spinal dorsal horn neurons with ascending projections. The neuronal effects were compared with the behavioral data obtained in mechanically and thermally induced nociceptive tail reflex tests in intact and spinal rats. A reversal of the antinociceptive effects was attempted by systemically (1.5 mg/kg, i.p.) or intrathecally (25 micrograms) administered atipamezole, a selective alpha-2-adrenoceptor antagonist. Systemically administered medetomidine produced an atipamezole-reversible, dose-dependent suppressive effect on the evoked responses of nociceptive medial thalamic and spinothalamic tract neurons. A lower dose of medetomidine was needed to suppress significantly (half-maximally) evoked responses of the nociceptive medial thalamic neurons (100 micrograms/kg) than those of the nociceptive spinothalamic tract neurons (300 micrograms/kg). The decrease of evoked responses of the nociceptive spinothalamic tract neurons was accompanied by a decrease in spontaneous activity. The responses of the low-threshold mechanoreceptive projection neurons of the spinal cord were not influenced by medetomidine (30-300 micrograms/kg). The reflex studies with a (anesthetic) medetomidine dose of 300 micrograms/kg indicated that in intact and otherwise drug-free rats, medetomidine produced a significant prolongation of the nociceptive reflex response latency to a tail-pinch and heat; these antinociceptive effects of systemic medetomidine were reversed by systemically and intrathecally applied atipamezole. In spinal rats systemically applied medetomidine (300 micrograms/kg) also produced a significant prolongation of the tail-flick latency, which was reversed by systemically applied atipamezole. The results suggest that a high anesthetic dose of systemically applied medetomidine (300 micrograms/kg) can suppress nociceptive sensory neuronal and reflex responses due to spinal segmental mechanisms through an action on alpha-2-adrenoceptors. This spinal effect is selective to responses of nociceptive neurons, and at least partly postsynaptic as indicated by the concomitant decrease in spontaneous activity. At a lower, subanesthetic (but sedative) dose (100 micrograms/kg) the antinociceptive effect of systemically applied medetomidine can be explained by supraspinal alpha-2-adrenergic mechanisms.     

The effect of morphine on the activity evoked in ventrolateral tract axons of the cat spinal cord

Summary The effect of morphine on the activity in ventrolateral tract axons was studied in intercollicularly decerebrate cats with and without spinal section. Activity was elicited by electrical stimulation of Aand C-fibres in the sural nerves. In spinal animals, morphine injected intravenously in a dose as low as 0.5 mg/kg reduced the post-stimulus discharge of impulses recorded in ventrolateral tract axons below the site of transection. The depression was not only abolished but reversed by levallorphan and naloxone. Pretreatment with reserpine did not diminish the effect of morphine. The effect of morphine was considerably weaker in decerebrate cats. Reversible block of the spinal cord produced by cold revealed that morphine reduced inhibition from the brain stem controlling the impulse transmission to ventrolateral tract axons.It is concluded that a spinal effect contributes to the analgesic action of morphine.This investigation was supported by the Sonderforschungsbereich 38 Membranen and the Stiftung Volkswagenwerk. The authors are indebted to Dr. Ferster of Endo Laboratories, Brussels, for the generous supply of naloxone.     

Descending control of spinal nociceptive transmission. Actions produced on spinal multireceptive neurones from the nuclei locus coeruleus (LC) and raphe magnus (NRM)

Summary The effects of electrical stimulation in the nuclei locus coeruleus (LC) and raphe magnus (NRM) were examined on the background and/or evoked discharge of neurones in the spinal dorsal horn of anaesthetized cats. These were qualitatively, and in most cases quantitatively similar, in their action on multireceptive neurones. In these neurones an inhibitory action on the discharge evoked by noxious cutaneous stimuli or by activation of A and C fibres was most prominent although in some neurones (22%) an initial excitation lasting up to 100 ms preceded the inhibition which could last up to 1 s. Excitation alone was observed in only 3% of multireceptive neurones. Electrical stimulation also produced an inhibitory action on the discharge of low threshold mechanoreceptive neurones (80%). In four of ten multireceptive neurones examined in detail, LC stimulation produced a selective inhibitory action on the discharge evoked by noxious cutaneous stimuli. In the remaining six multireceptive neurones it was partially selective against noxious as compared with non-noxious inputs. The inhibitory action was also more pronounced on the discharge evoked by activity in A and C fibres than fast conducting afferents. The inhibitory action evoked by electrical stimulation in LC on nociceptive transmission in the spinal cord is suggested to play a part in mediating analgesia from LC.Abbreviation for Structures 6 Abducens nucleus - BC Brachium Conjunctivum - BP Brachium Pontis Dorsal Nucleus of Raphe - DRM Medial division - TD Dorsal Tegmental nucleus - 7L Facial Nucleus lateral division - 7M Facial Nucleus medial Division - V4 Fourth ventricle - 7G Genu of the Facial Nerve - IC Inferior Colliculus - SOL, SOM Lateral, Medial Nucleus of Superior Olive - BCM Marginal Nucleus of the Brachium conjunctivum - 5ME Mesencephalic trigeminal nucleus - 5M Motor Trigeminal Nucleus - LC Nucleus locus coeruleus - PH Nucleus praepositus hypoglossi - NRM Nucleus Raphe Magnus - P Pyramidal tract - PPR Postpyramidal Nucleus of the Raphe - SC Subcoeruleus - CS Superior Central Nucleus - TB trapezoid body     

Bidirectional neurones in the cervical enlargement of the cat spinal cord with axons descending to sacral segments and ascending to the cerebellum and the lateral reticular nucleus

Neurones located in cervical segments (C6/C7) of the spinal cord were investigated electrophysiologically in cats deeply anaesthetized with alpha-chloralose. Extracellular recordings of antidromic action potentials were performed in order to establish whether long descending propriospinal neurones projecting to sacral segments could have collateral axonal branches ascending to supraspinal centres. The effects of stimulation of the lateral reticular nucleus (LRN) and the inferior cerebellar peduncle (restiform body, RB), as well as the thirteenth thoracic (Th13) and sacral (S1/S2) segments of the spinal cord were tested in 93 cells. Two main groups of cells were identified: 54 % of the total sample were classified as purely propriospinal and 46 % as bidirectional neurones. Various patterns of projections, as well as the ipsi-, contra- or bilateral courses of axons in the lateral funiculi of the spinal cord, enabled several types of neurones to be distinguished within the above groups. Comparison between particular types showed no significant difference with respect to location in the grey matter (predominantly Rexed's laminae VII-VIII) and the conduction velocities of descending axons. However, the mean axonal conduction velocities of branches ascending to LRN and/or RB were significantly lower in comparison to those measured for spinal collaterals. The hypothetical function of the neurones examined is discussed. Since the same information can be conveyed simultaneously by these branching neurones to lower spinal segments and supraspinal centres, an integrative role in the system of motor control is suggested.     

Anatomy of primary afferents and projection neurones in the rat spinal dorsal horn with particular emphasis on substance P and the neurokinin 1 receptor

The dorsal horn of the spinal cord plays an important role in transmitting information from nociceptive primary afferent neurones to the brain; however, our knowledge of its neuronal and synaptic organisation is still limited. Nociceptive afferents terminate mainly in laminae I and II and some of these contain substance P. Many projection neurones are located in lamina I and these send axons to various parts of the brain, including the caudal ventrolateral medulla (CVLM), parabrachial area, periaqueductal grey matter and thalamus. The neurokinin 1 (NK1) receptor on which substance P acts is expressed by certain neurones in the dorsal horn, including approximately 80 % of lamina I projection neurones. There is also a population of large NK1 receptor-immunoreactive neurones with cell bodies in laminae III and IV which project to the CVLM and parabrachial area. It has been shown that the lamina III/IV NK1 receptor-immunoreactive projection neurones are densely and selectively innervated by substance P-containing primary afferent neurones, and there is evidence that these afferents also target lamina I projection neurones with the receptor. Both types of neurone are innervated by descending serotoninergic axons from the medullary raphe nuclei. The lamina III/IV neurones also receive numerous synapses from axons of local inhibitory interneurones which contain GABA and neuropeptide Y, and again this input shows some specificity since post-synaptic dorsal column neurones which also have cell bodies in laminae III and IV receive few contacts from neuropeptide Y-containing axons. These observations indicate that there are specific patterns of synaptic connectivity within the spinal dorsal horn.     

Stimulation of pre- and postsynaptic elements in the red nucleus

Summary Stimulation of the red nucleus evokes a two-component descending discharge in the contralateral dorsal quadrant of the spinal cord; the first component is caused by direct and the second by synaptic activation of rubrospinal neurones projecting to the lumbosacral cord. Threshold maps for direct and synaptic activation are given. The low threshold focus for direct activation covers not only the hindlimb region of the red nucleus where the antidromic field potential is large but also the medial part of the nucleus where the axons leave. Direct activation can also be evoked from a region extending caudally from the medial part of the red nucleus. Synaptic activation of rubrospinal neurones, evoked at very low threshold from the ventro-medio-caudal border zone of the red nucleus, is due to stimulation of interposito-rubral efferents. The threshold, indicated by unitary EPSPs in rubral cells and antidromic activation of cells in interpositus, is about 1 A, which is 1/10 of the strength required for direct activation of rubrospinal neurones. There is neither evidence that rubral stimuli activate collaterals of corticospinal axons to the lumbosacral cord, nor that antidromic activation of interposito-rubral fibres evokes descending effect via their collaterals to the reticular formation.This work was supported by the Swedish Medical Research Council (Project No. 14X-94-07C).     

Responses of functionally identified neurones in the dorsal horn of the cat spinal cord to substance P, neurokinin A and physalaemin.

The mammalian tachykinins, substance P and neurokinin A, and the non-mammalian tachykinin, physalaemin, were tested on functionally identified dorsal horn neurones in vivo. The experiments were done on cats which were anaesthetized with sodium pentobarbital or were anaemically decerebrated. Extracellular single-unit recordings were made in the lumbar spinal cord and the tachykinins were applied by iontophoresis. Each neurone was classified functionally as wide dynamic range, non-nociceptive, nociceptive specific or proprioceptive. The response to tachykinin application was determined for each neurone. Application of each of the tachykinins evoked a characteristic excitatory response which was delayed in onset, slow in developing and prolonged: physalaemin excited 99/131 neurones tested, neurokinin A excited 45/63 neurones and substance P excited 32/49 neurones. With two neurones physalaemin evoked a depression of the rate of firing, which may have been caused indirectly by excitation of a neighbouring neurone. Such depression was not elicited by either substance P or by neurokinin A. Physalaemin had a preferential excitatory effect on nociceptive neurones evoking excitation of 76/94 nociceptive neurones compared with 12/23 non-nociceptive neurones (chi 2 = 7.9, 1 d.f., P = 0.005). Substance P also caused a preferential excitation, with 30/40 nociceptive neurones being excited while all of the non-nociceptive neurones (n = 7) were unaffected (chi 2 = 11.5, 1 d.f., P = 0.0007). In contrast, neurokinin A failed to have a preferential effect; 32/46 nociceptive and 9/10 non-nociceptive neurones were excited (chi 2 = 1.0, 1 d.f., P = 0.40). Comparing the proportions of nociceptive neurones excited by the different tachykinins indicated that this type of neurone was not differently sensitive to any of the three peptides (chi 2 = 3.2, 2 d.f., P = 0.20). On the other hand, non-nociceptive neurones were preferentially excited by neurokinin A and physalaemin compared with substance P (chi 2 = 13.4, 2 d.f., P = 0.001). With regard to the endogenous tachykinins the results of this study may be interpreted in the following ways. The differential excitatory effect of substance P on nociceptive neurones supports the proposed role for this peptide in the transmission specifically of nociceptive inputs at the first afferent synapse. On the other hand, as neurokinin A excited non-nociceptive as well as nociceptive neurones, there may be a functional role for neurokinin A distinct from that of substance P.     

Dorsal column inhibition of nociceptive thalamic cells mediated by gamma-aminobutyric acid mechanisms in the cat

Cells in posterior parts of the cat thalamus were investigated. Responses in single units excited by electrical stimulation in the lateral funiculus (LF), the dorsal column nucleus (DCN) or the canine tooth pulp (TP) were analysed. All cells had a spontaneous resting activity which could be increased by extracellular iontophoretic application of DL-homocysteic acid (DLH) and decreased by gamma-aminobutyric acid (GABA). No effect on the spontaneous firing rate was observed following iontophoresis of the selective GABA-antagonists, picrotoxin (GABA-A receptor antagonist) or saclofen (GABA-B receptor antagonist). However, the decreased firing following GABA application was partially blocked by picrotoxin but not by saclofen. A phasic inhibition induced by DCN stimulation in nociceptive thalamic cells is indicated since simultaneous administration of picrotoxin increased the evoked response. This type of inhibitory mechanism could not be detected following LF or TP stimulation. The extracellular activity evoked by electrical stimulation of LF or TP was significantly depressed by preceding electrical stimulation in the DCN. This inhibition was reversed by simultaneous administration of picrotoxin, indicating an involvement of GABA-A receptors. The reversal of the DCN-induced depression of the late responses following LF stimulation occurred after application of saclofen. It is suggested that this effect is partly mediated via GABA-B receptors. Results from the present study indicate an interaction in the thalamus between presumed low-threshold (DCN) and presumed nociceptive afferents (LF and TP) similar to that previously described in the spinal cord.     

Evidence for a role of protein kinase C in the sustained activation of rat dorsal horn neurons evoked by cutaneous mustard oil application

The intracellular mechanisms involved in the sensitisation of spinal dorsal horn neurons brought about by sustained or repeated nociceptive inputs are unknown. The present experiments addressed any role of protein kinase (PKC) in sustained nociceptive responses of rat dorsal horn neurons by: (i) ionophoretic administration of PKC inhibitors whilst recording activity evoked by repeated cutaneous application of mustard oil; and (ii) assessing subcellular translocation of PKC evoked in spinal cord by cutaneous application of mustard oil. Both marked attenuation of mustard oil-induced neuronal activity by PKC inhibitors and selective translocation of PKC in spinal cord tissue ipsilateral to mustard oil application strongly supported a critical role of PKC in sustained nociceptive responses to mustard oil.     

Structure-function relationships in identified afferent neurones

Summary The review deals with structure-function relationships in primary afferent and spinal cord neurones that were intracellularly injected with a marker substance (mostly HRP) after physiological identification. At the level of dorsal root ganglion (DRG) cells, there is a significant correlation between soma size and conduction velocity (or diameter) of the afferent fibre for most subpopulations of DRG cells, but the scatter of data is considerable, so that the size of a DRG cell soma cannot be predicted from the diameter of its axon or vice versa. The spinal terminations of primary afferent fibres are the best example of a relationship between structure and function, since most of the afferent units possess characteristic patterns of spinal arborization, e.g. the flame-shaped arbors of hair follicle afferents in lamina III of the dorsal horn, or the projection of nociceptive afferents onto lamina I. The morphological features of spinal cord neurones can be used only to a limited extent for functional identification. Thus, many SCT neurones can be recognized by their triangular dendritic tree and STT cells in lamina VII/VIII by their dendritic projection into the white matter. It is still not possible, however, to distinguish a nociceptive STT cell from a low-threshold mechanoreceptive one on the basis of morphological criteria.     

Spinal c-fos induction by sensory stimulation in neonatal rats

C-fos immunocytochemistry was used to investigate the functional connectivity between primary afferent nociceptive fibres and second-order neurons in the spinal cord of the anaesthetised neonatal rat. Subcutaneous injection of 50 mg/kg capsaicin potently induced c-fos in the spinal cord on the first postnatal day (P1), whilst plantar injection of dilute formalin was much less effective until P3. In contrast with the adult, there was no c-fos response of the neonatal rat spinal cord to cutaneous application of the C-fibre irritant, mustard oil. It is concluded that spinal c-fos expression induced by noxious sensory stimulation can occur before the development of mature functional synaptic contact with first-order neurones.     

Further study on pharmacological properties of the cerebellar-induced inhibition of Deiters neurones

Summary The pharmacological properties of Deiters neurones were studied in anaesthetized cats, together with their inhibition by cerebellar Purkinje cells. Purkinje cell inhibition, as detected by depression of antidromic field potentials of Deiters neurones, was blocked by relatively large doses of picrotoxin administered intravenously (5–10 mg/kg). The cerebellar inhibition was also detected as a depression of the discharge of Deiters neurones excited by electrophoretic administration of DL-homocysteic acid. This inhibition was abolished or reduced by picrotoxin, but was not altered by strychnine, administered either systemically or electrophoretically. -Aminobutyric acid (GABA), glycine, -alanine and imidazole acetic acid, when administered electrophoretically, also depressed the antidromic field potentials and the spike discharges of Deiters neurones. Picrotoxin antagonized the effect of GABA but not of glycine, while strychnine blocked only the action of glycine. Intracellular recording from Deiters neurones revealed that both GABA and glycine, ejected extracellularly, hyperpolarized the membrane and increased the membrane conductance. The reversal of the GABA-induced hyperpolarization was at the same potential level as that of the inhibitory postsynaptic potentials induced by cerebellar stimulation. These results are consistent with the hypothesis that the inhibitory transmitter released from Purkinje cell axons is GABA or a related substance.     

Do noradrenergic descending tract fibres contribute to the depression of transmission from group II muscle afferents following brainstem stimulation in the cat?

Two alpha 2 noradrenaline antagonists, idazoxan and yohimbine, were injected in midlumbar segments of the spinal cord to test whether they counteract depression of field potentials evoked by group II muscle afferents by conditioning stimuli applied in the brainstem. The tested field potentials were those evoked monosynaptically in the intermediate zone of midlumbar segments. Their depression reflected thus the depression of transmission between group II fibres and their first relay neurones. The conditioning stimuli were applied either within the ipsilateral locus coeruleus/subcoeruleus or outside these nuclei (in the raphe magnus, raphe obscurus, or cuneiform nuclei). The brainstem evoked depression of the tested field potentials (n = 12) was reduced following injection of idazoxan or yohimbine to about two thirds of that which was evoked originally but in three cases to about one half. The study leads thus to the conclusion that noradrenergic descending tract neurones contribute to the depression of transmission from group II afferents to spinal interneurones and that such noradrenergic neurones are activated by stimuli applied within as well as outside their nuclei. However, the relative contribution of monoaminergic and non-monoaminergic descending tract neurones to the control of transmission from group II afferents to these neurones remains to be established.     

The medullary dorsal reticular nucleus as a pronociceptive centre of the pain control system

The endogenous pain control system has long been considered as engaged in pain depression through the commitment of multiple descending actions that reduce the response capacity of spinal dorsal horn nociceptive neurones. Such a pure inhibitory antinociceptive nature was lately questioned by the observation of pronociceptive effects from areas classically regarded as antinociceptive. The thereby raised hypothesis of a more versatile functional arrangement that dynamically adjusts the pain modulatory effect to multiple conditions by balancing several excitatory and inhibitory actions found strong support on the recent discovery of a medullary area particularly dedicated to pain facilitation.Lesioning the medullary dorsal reticular nucleus (DRt) depresses nociceptive responses to acute and inflammatory pain, whereas stimulation produces the inverse effect. The decrease in formalin-induced pain behaviour following DRt lesioning is accompanied by a decrease of spinal noxious-evoked c-fos neuronal activation. DRt blocking by lidocaine results in a decrease of the nociceptive activity of spinal dorsal horn neurones, whereas stimulation by glutamate has the opposite effect. A reciprocal disynaptic putative excitatory circuit that links the DRt and the spinal dorsal horn and conveys nociceptive input through the ascending branch was described, indicating that the DRt pain facilitating action is mediated by a reverberating spino-DRt circuit that promotes the enhancement of the response capacity of spinal neurones to noxious stimulation.The demonstration of a primary pronociceptive centre in the endogenous pain control system brings new important data to the emerging concept of pain modulation as a dynamic and flexible process that integrates nociceptive processing by balancing multiple excitatory and inhibitory actions as the way of adapting to the various unsteady pain determinants.     

Diffuse noxious inhibitory controls (DNIC) in animals and in man.

Some neurones in the dorsal horn of the spinal cord are strongly inhibited when a nociceptive stimulus is applied to any part of the body, distinct from their excitatory receptive fields. This phenomenon was termed "Diffuse Noxious Inhibitory Controls" (DNIC). DNIC influence only convergent neurones: the other cell types which are found in the dorsal horn, including specific nociceptive neurones, are not affected by this type of control. In normal conditions, these inhibitions can be triggered only by conditioning stimuli which are nociceptive. The inhibitions are then extremely potent, affect all the activities of the convergent neurones and persist, sometimes for several minutes, after the removal of the conditioning stimulus. In fact, only activity of A delta- or A delta- and C-peripheral fibres can trigger DNIC. DNIC are sustained by a complex loop which involves supraspinal structures since, unlike segmental inhibitions, they can not be observed in animals in which the cord has previously been transsected at the cervical level. The ascending and descending limbs of this loop travel respectively through the ventro-lateral and dorso-lateral funiculi respectively. We proposed that DNIC result from the physiological activation of some brain structures putatively involved in descending inhibition. However, lesions of the following structures did not modify DNIC: Periaqueductal grey (PAG), Cuneiform nucleus, Parabrachial area, locus coeruleus/subcoeruleus, rostral ventromedial medulla (RVM) including Raphe Magnus, Gigantocellularis and Paragigantocellularis nuclei. By contrast, lesions of Subnucleus Reticularis Dorsalis (SPD) in the caudal medulla strongly reduced DNIC. Both electrophysiological and anatomical data support the involvement of SRD neurones in spin-bulbo-spinal loop(s). Indeed, they are unresponsive to visual, auditory or proprioceptive stimulation but are preferentially or exclusively activated by nociceptive stimuli with a "whole-body receptive field"; they encode precisely the intensity of cutaneous and visceral stimulation within the noxious range and are exclusively activated by cutaneous A delta- or A delta- and C-fibre peripheral volleys; they send descending projections through the dorsolateral funiculus that terminate in the dorsal horn at all levels of the spinal cord. In man, exactly analogous results have been obtained by means of combined psychophysical measurements and recordings of nociceptive reflexes. Electrical stimulation of the sural nerve at the ankle simultaneously induces a nociceptive reflex in a flexor muscle of the knee (the RIII reflex) and a painful sensation from the territory of the nerve. Painful heterotopic conditioning stimuli, no matter whether thermal, mechanical or chemical in nature, depress both the reflex and the associated painful sensation, with stronger effects being observed with more intense conditioning stimuli.(ABSTRACT TRUNCATED AT 400 WORDS)     

Ventrolateral and dorsolateral ascending spinal cord pathway influence on thalamic nociception in cat

1. In cat there are two portions of the spinothalamic tract (STT)--a ventral component, the ventral spinothalamic tract (VSTT) made up of axons of cells of spinal cord laminae IV-X, and a dorsolateral component, the dorsolateral spinothalamic tract (DSTT) made up of axons of cells in lamina I of the spinal cord dorsal horn. This study was designed to evaluate thalamic neuronal responses to cutaneous noxious thermal stimuli and to determine the functional importance of pathways ascending in the ventral and dorsolateral portions of the spinal cord, ipsilateral to the thalamic recording site and contralateral to the hindlimb stimulation region, for transmission of nociceptive information to the thalamus. 2. Extracellular single-unit recordings were made from 45 neurons in the ventrobasal complex (VBX) of cat thalamus. Thirty-five of these units responded either exclusively or preferentially to noxious cutaneous stimuli. Responses to noxious thermal stimuli applied to the unit's receptive fields were obtained, and then the effects on these responses of blocking conduction through the dorsolateral funiculus (DLF) and the ventrolateral quadrant (VQ) of the thoracic spinal cord ipsilateral to the thalamic recording site were determined. DLF and VQ conduction blocks were accomplished with the use of a cold probe technique and, at times, surgical lesions of the appropriate portion of the spinal cord. 3. The nociceptive units were located in the periphery of the ventral posterior lateral nucleus (VPL) of the thalamus. Their locations corresponded to the somatotopic organization of VPL. Nociceptive thermal responses were found in both high-threshold (HT) (10 cells) and wide-dynamic-range (WDR) (22 cells) units. The receptive fields of these units were generally small and were located on the hindlimb contralateral to the recording site. The thermoreceptive units had thresholds between 44 and 48 degrees C and were able to code for stimulus intensity. 4. Nine of the 35 nociceptive units demonstrated a decrease in response and two units an increase in response to noxious cutaneous stimulation during DLF block ipsilateral to the recording site and contralateral to the cutaneous stimulation site, whereas four units demonstrated a decrease in response and one unit an increase in response to noxious thermal cutaneous stimulation during VQ block ipsilateral to the recording site and contralateral to the cutaneous stimulation site.(ABSTRACT TRUNCATED AT 400 WORDS)     

Neurones in the cervical enlargement of the cat spinal cord antidromically activated from sacral segments and the inferior cerebellar peduncle

The electrophysiological investigation of neurones located in the cervical enlargement of the spinal cord was performed in eight-chloralose anaesthetized cats. Neurones were recorded intracellularly or extracellularly and identified by antidromic stimulation. The main purpose of the study was to test whether these neurones give off collateral branches ascending to the inferior cerebellar peduncle and descending to the sacral segments (S1/S2). Recordings were made from 78 neurones located in medial and central parts of Rexed's laminae VII and VIII of C6/C7 segments. Four subpopulations could be distinguished from their patterns of propriospinal or supraspinal projections: (a) ascending/descending neurones with axons ascending to RB and descending to S1/S2 (23%); (b) ascending/descending neurones projecting to RB and the level of Th13 (14%); (c) propriospinal neurones descending to Th13 (15%); (d) propriospinal neurones descending to S1/S2 (48%). Within these groups, ipsilateral, contralateral and bilateral descending projections were observed. The mean axonal conduction velocities for descending and ascending collaterals of bidirectional neurones were 59 and 39 m/s, respectively. Results suggest that parallel transmission of information to supraspinal and spinal centres plays an important role in the process of movement coordination.     

Thalamic neuronal activity in rats with mechanical allodynia following contusive spinal cord injury

Pain and allodynia following spinal cord injury are poorly understood and difficult to treat. Since there is evidence that supraspinal mechanisms are important in such pain, we have studied the role of the thalamus in an experimental model of spinal injury. Extracellular recordings were obtained from neurones of the thalamic nucleus ventralis postero-lateralis (VPL) in normal rats and those which had sustained a contusive spinal cord injury to the thoraco-lumbar junction 7 days previously. Behavioural testing with von Frey hairs established that 11 spinally injured rats showed exaggerated vocal responses to normally innocuous mechanical stimulation (allodynia) whereas eight were non-allodynic. Thalamic VPL neurones in spinally injured rats (both allodynic and non-allodynic) exhibited a dysrhythmia in that a significantly higher proportion fired spontaneously in an oscillatory mode when compared with neurones in uninjured rats. Thus this dysrhythmia was linked to spinal injury, not to allodynia. The evoked responses of VPL thalamic neurones to brushing the skin, however, were significantly elevated in allodynic rats when compared with those in uninjured rats and neuronal afterdischarges to these stimuli (which were absent in uninjured rats) were more common in allodynic than in non-allodynic rats. We have previously reported that a proportion of spinal neurones in allodynic spinally injured rats show increased evoked responses and afterdischarges following brushing the skin and hence the enhanced thalamic responses may reflect a greater spinal input. In view of the increasing evidence that thalamo-cortical rhythmical firing is linked to sensorimotor and cognitive brain functions, we propose that pain following brushing the skin results from an exaggerated spinal input being processed by a dysrhythmic thalamus. Thus both spinal and thalamic mechanisms may be important in the genesis of pain and allodynia following spinal cord injury.