Dorsal column postsynaptic neurons in the cat are excited by myelinated nociceptors

Some (25-50%) dorsal column postsynaptic (DCPS) neurons respond only to innocuous mechanical stimuli; the remainder (50-75%) responds to both innocuous and noxious mechanical stimuli. Those that respond to noxious mechanical stimuli (pinch) are assumed to be excited by input from nociceptive primary afferents, but it is conceivable that their pinch-evoked responses are produced by the inadvertent activation of those low-threshold mechanoreceptive primary afferents that respond to stretching the skin. Because nociceptive primary afferents respond reliably to noxious heat and low-threshold mechanoreceptors do not, we tested DCPS neurons in the cat lumbar spinal cord with a series of noxious heat stimuli (48 degrees C or 50 degrees C-56 degrees C; 30 s duration). Seven of eight pinch-responsive neurons responded to noxious heat, but only after their receptive fields had been sensitized by prolonged or repeated heating. The results show that (1) many DCPS neurons in the cat are excited by nociceptive primary afferents and (2) these nociceptive afferents are probably myelinated high-threshold mechanoreceptors.     

Presynaptic excitability changes produced in brain stem endings of tooth pulp afferents by raphe and other central and peripheral influences

1. (1) In view of the association of tooth pulp stimulation with pain, and the possibility that nociceptive transmission may be presynaptically modulated by endogenous opiate-related mechanisms, we examined the presynaptic modulatory effects of peripheral and central conditioning stimuli on the excitability of brain stem endings of tooth pulp primary afferents in anesthetized or decerebrate cats. A presynaptic excitability effect was measured as a change in the amplitude of the antidromic compound action potential recorded from the pulp or as a change in the probability of antidromic activation of single pulp primary afferents recorded either in the trigeminal (V) ganglion or directly from the pulp.

2. (2) A total of 195 single tooth pulp afferents supplying the ipsilateral maxillary or mandibular canine teeth was recorded. The majority conducted in the A-delta range, although about 25 % had conduction velocities indicative of faster conducting axons. The excitability of the brain stem endings of the pulp afferents could be increased by conditioning stimuli delivered to the periaqueductal gray (PAG) and nucleus raphe magnus (NRM), as well as by noxious and non-noxious stimuli applied to oral-facial and more remote sites, and by stimulation of the cerebral cortex.

3. (3) The presynaptic effects induced in pulp endings in V subnucleus oralis by raphe stimulation do not rely on the integrity of V subnucleus caudalis which is considered the important brain stem relay site for oral-facial pain. This was shown by the inability of reversible cold block of synaptic transmission in caudalis to alter presynaptic excitability increases induced in oralis. Nonetheless, the cold block procedure did reveal that caudalis exerts a tonic presynaptic ascending facilitatory influence on the pulp afferent input to oralis neurons.

4. (4) Since tooth pulp afferents are predominantly, if not exclusively, related to pain, it is noteworthy that our studies with the opiate antagonist naloxone failed to provide any substantive evidence that the presynaptic modulatory effects on pulp afferent endings are opiate-related. Only in one of 25 pulp afferents tested did naloxone reduce the PAD effect induced by PAG, NRM or afferent conditioning. These findings do not support the view that the descending raphe influences operate through a presynaptic opiate-related mechanism on nociceptive transmission, at least as far as the tooth pulp afferent input to the brain stem is concerned.

     

Changes in mechanoreceptive field properties of trigeminal somatosensory brainstem neurons induced by stimulation of nucleus raphe magnus in cats

Experiments were carried out on adult anesthetized cats in which the effects of nucleus raphe magnus (NRM) conditioning stimulation (20 ms) were tested on the responses evoked by orofacial stimuli in single brainstem neurons of trigeminal (V) subnucleus oralis. The NRM stimulation induced inhibition of the responses of 57 of 77 low-threshold mechanoreceptive (LTM) neurons and the one wide-dynamic range (WDR) neuron tested. The duration of the neuronal inhibition ranged from 300-600 ms and the mean threshold for inhibition ranged from 47.8 +/- 4.8 to 102.7 +/- 15 microA depending on the orofacial stimulation site (skin or tooth pulp) and form (mechanical or electrical) of cutaneous stimuli used to evoke neuronal responses. In 20 LTM neurons showing NRM-induced inhibition that were specifically examined for the effects of NRM stimulation on the mechanoreceptive field, one population (n = 11) showed shrinkage (mean 55 +/- 4.4% from control area) of the mechanoreceptive field while the remaining neurons (n = 9) showed no change in mechanoreceptive field size during NRM stimulation. The former group of neurons were also distinguished from the latter neurons by their significantly larger mechanoreceptive field and the activation of the majority of them by electrical stimuli applied outside their mechanoreceptive field. The responses of these neurons evoked by low-threshold inputs from the edge of the mechanoreceptive field were more sensitive to NRM conditioning stimulation than responses evoked from the mechanoreceptive field center, as judged by threshold, magnitude and duration of the NRM-induced inhibition. These findings underscore the sensitivity of LTM neurons to NRM influences. They also reveal a particular population of oralis neurons which have a differential sensitivity of low-threshold inputs evoked from the edge compared to the center of the mechanoreceptive field.     

Excitation of mechanosensitive C-fiber sensory units of the skin in the cat by the intra-arterial administration of potassium ions

In anaesthetized cats the responses of low- and high-threshold mechanosensitive C-fiber sensory units (MSU) in n. saphenus to close-arterial injection of potassium ions in subnoxious and noxious concentrations (SC and NC) have been studied. Two groups of high-threshold MSU were found: 1) MSU excited by K+ in NC only and 2) MSU responded to K+ both in SC and NC. The data suggest the nociceptive role of high-threshold MSU in contrast to low-threshold MSU. The possibility is discussed of a differentiation between subnoxious and noxious stimuli by a portion of high-threshold MSU. The characteristics of firing of high-threshold MSU are given which correlate with their excitation by noxious and subnoxious chemical stimuli.     

Properties of nociceptive and non-nociceptive neurons in trigeminal subnucleus oralis of the rat

Recent studies have provided evidence suggesting the involvement of rostral components of the V brainstem complex such as trigeminal (V) subnucleus oralis in orofacial pain mechanisms. Since there has been no detailed investigation of the possible existence of nociceptive oralis neurons in the rat to substantiate this recent evidence, the present study was initiated to determine if neurons responsive to noxious orofacial stimuli were present in subnucleus oralis and to characterize their functional properties. In anesthetized rats, recordings were made of the extracellular activity of single neurons functionally characterized as low-threshold mechanoreceptive (LTM), wide dynamic range (WDR) or nociceptive-specific (NS) neurons. The 342 LTM neurons responded only to light mechanical stimulation of orofacial tissues. The mechanoreceptive field of the LTM neurons included the intraoral region in 28% and was localized to the adjacent perioral area in 65%. For 95% the field was localized within one V division. Responses evoked in LTM neurons by electrical stimulation of the orofacial mechanoreceptive field revealed A fiber afferent inputs but no activity that could be attributed to C fiber afferent inputs. The 72 nociceptive neurons included 52 WDR neurons which responded to light (e.g. tactile) as well as noxious (e.g. heavy pressure; pinch) mechanical stimulation of perioral cutaneous and intraoral structures, and 20 NS neurons which responded exclusively to noxious mechanical stimuli. They also differed from the LTM neurons in that 36% of the WDR and 20% of the NS neurons had a mechanoreceptive field involving more than one V division. However, in accordance with our findings for the LTM neurons, the majority of WDR and NS neurons had a mechanoreceptive field involving the intraoral and perioral representations of the mandibular and/or maxillary divisions; those neurons having a mandibular field which especially included intraoral structures predominated in the dorsomedial zone of subnucleus oralis whereas those with a perioral mechanoreceptive field which particularly involved the maxillary division were concentrated in the ventrolateral zone of oralis. In contrast to the LTM neurons, 57% of the WDR and 67% of the NS neurons showed evidence of electrically evoked C fiber as well as A fiber afferent inputs from their mechanoreceptive field. We also noted suppression of the electrically evoked responses by heating of the tail or pinching of the paw. This effect was considered to be a reflection of diffuse noxious inhibitory controls, and was seen in NS as well as WDR neurons; most, but not all, of these neurons received A fiber as well as C fiber orofacial afferent inputs.(ABSTRACT TRUNCATED AT 400 WORDS)     

Physilogy and morphology of substantia gelatinosa neurons intracellularly stained with horserdish peroxidase

Neurons in Rexed's layer II were physiologically characterized with natural and electrical stimuli applied to their cutaneous receptive field. The neurons were then intracellularly stained with horseradish peroxidase. Three general patterns of physiological responses were found Nociceptive specific neurons did not respond to gentle mechanical stimulation. Most responded exclusively to tissue-damaging stimuli. Some also responded to moderately heavy pressure, but these responded to noxious stimuli with an increased discharge frequency. Wide dynamic range neurons responded to both gentle mechanical stimulation and to tissue-damaging stimulation. Low-threshold mechanoreceptive neurons responded only to gentle mechanical stimulation. Some of the low-threshold mechanoreceptive neurons were innervated by primary afferents with unmyelinated axons. Excepting those low-threshold mechanoreceptive neurons with input form unmyelinated afferents, the patterns of primary afferent innervation of layer II neurons were similar to the patterns innervation that gave been found for neurons in layers I and IV-V. All nut 2 of the 22 neurons that we found were recognized as being of two general morphological types. Stalked cells had their perikarya situated along the superficial border of layer II. Most of their dendrites traveled ventrally while spreading out rostrocaudally. This gave their dendritic arbors a fan-like shape. Stalked cell axons arborized largely in layer I. Islet cell perikarya were found throughout layer II. Most of their dendrites traveled rostrocaudally. Their dendritic arbors were shaped like cylinders with their long axes parallel to the long axis of the spinal cord. Islet cell axons arborized in the immediate vicinity of their dendtritic territories, within layer II. Stalked cells and those islet cells whose dendritic arbors were largely contained within the superficial one-third of layer II (layer IIa) were either nociceptive specific or wide dynamic range neurons. The islet cells whose dendritic arbors were largely within the deeper two-thirds of layer II (layer IIb) were all low-threshold mechanoreceptive neurons. These observations suggest that layers IIa and IIb have different functional roles and that stalked cells and islet cells are separate and distinct components of the neural circuitry of the superficial dorsal horn.     

Dorsal raphe stimulation, 5-HT and morphine microiontophoresis effects on noxious and nonnoxious identified neurons in the medial thalamus of the rat

In single cell experiments, the characterization of the responses of medial thalamic neurons to noxious and nonnoxious stimulation was made to examine the effects of two substances involved in pain, morphine and 5-HT, and the action of one pain suppressor mechanism, dorsal raphe stimulation. Single cell activity was recorded in urethane anesthetized rats. Tail pinch and tail immersion in hot water were used as nociceptive stimuli. Skin strokes, air puffs and hair brushing were used as nonnociceptive stimuli. Morphine, 5-HT microiontophoresis and dorsal raphe stimulation were performed in all the recorded units. Fifty-eight percent from 61 medial thalamic recorded units responded both to noxious and nonnoxious stimulation; whereas only 18% and 24.6% of the units responded exclusively to noxious and nonnoxious stimulation, respectively. The noxious responding units were located in the most posterior portions of the medial thalamus. Dorsal raphe stimulation and 5-HT ejection prevented the excitation elicited by noxious input. Morphine ejection prevented both the noxious and nonnoxious input in medial thalamus, in a different population as compared to dorsal raphe stimulation or 5-HT ejection. These findings support the existence of a pain ascending mechanism mediated by an opioid-serotonergic interaction in the medial thalamus of the rat.     

Leukotriene B4 induced decrease in mechanical and thermal thresholds of C-fiber mechanonociceptors in rat hairy skin

We have recently shown that leukotriene B4 (LTB4), a product of the 5-lipoxygenase pathway of arachidonic acid metabolism, sensitizes nociceptors to mechanical stimuli. The present study examined whether LTB4 also induces a thermal sensitization of cutaneous C-fiber high-threshold mechanonociceptors (C-HTMs). C-HTMs were characterized according to their responsiveness to noxious mechanical, thermal and chemical stimuli, including glacial acetic acid, bradykinin and capsaicin. C-HTMs were found to be either heat responsive (heat C-HTMs) or heat and chemically responsive (polymodal C-HTMs). Ninety-four percent of polymodal C-HTMs and 60% of C-HTMs were sensitized to thermal and mechanical stimuli by LTB4 (75 ng). All sensitized C-HTMs showed decreases in both thermal and mechanical thresholds. LTB4 lowered in both subclasses of C-HTMs average thermal threshold from 45 to 35 degrees C and produced an average decrease in the mechanical threshold of approximately 82-86%. For both heat and polymodal C-HTMs, the magnitude of LTB4-evoked decreases in thermal and mechanical thresholds was similar to that produced by 75 ng of PGE2. The possibility was discussed that LTB4 may contribute to the component of hyperalgesia that is resistant to non-steroidal anti-inflammatory agents.     

Differential activation of the human trigeminal nuclear complex by noxious and non‐noxious orofacial stimulation

There is good evidence from animal studies for segregation in the processing of non‐nociceptive and nociceptive information within the trigeminal brainstem sensory nuclear complex. However, it remains unknown whether a similar segregation occurs in humans, and a recent tract tracing study suggests that this segregation may not exist. We used functional magnetic resonance imaging (fMRI) to define and compare activity patterns of the trigeminal brainstem nuclear complex during non‐noxious and noxious cutaneous and non‐noxious and noxious muscle orofacial stimulation in humans. We found that during cutaneous pain, signal intensity increased within the entire rostrocaudal extent of the spinal trigeminal nucleus (SpV), encompassing the ipsilateral oralis (SpVo), interpolaris (SpVi) and caudalis (SpVc) subdivisions. In contrast, muscle pain did not activate SpVi, but instead activated a discrete region of the ipsilateral SpVo and SpVc. Further, muscle noxious stimulation activated a region of the ipsilateral lateral pons in the region of the trigeminal principal sensory nucleus (Vp). Innocuous orofacial stimulation (lip brushing) also evoked a significant increase in signal intensity in the ipsilateral Vp; however, non‐noxious muscle stimulation showed no increase in signal in this area. The data reveal that orofacial cutaneous and muscle nociceptive information and innocuous cutaneous stimulation are differentially represented within the trigeminal nuclear complex. It is well established that cutaneous and muscle noxious stimuli evoke different perceptual, behavioural and cardiovascular changes. We speculate that the differential activation evoked by cutaneous and muscle noxious stimuli within the trigeminal sensory complex may contribute to the neural basis for these differences. Hum Brain Mapp, 2009. © 2009 Wiley‐Liss, Inc.     

Neural mechanisms and pathways in craniofacial pain

Many free nerve endings of small-diameter afferents (A-delta or C nerve fibres) respond to craniofacial noxious stimuli and a number of neurochemicals are involved in their activation or sensitization. The small-diameter nociceptive afferents project to the trigeminal (V) brainstem complex where they can excite nociceptive neurones that have been categorized as either nociceptive-specific (NS) or wide dynamic range (WDR). These neurones project to other brainstem regions or to the contralateral thalamus. The lateral and medial thalamus contain NS and WDR neurones which have properties and connections with the overlying cerebral cortex or other thalamic regions indicative of a role for most of them in the sensory-discriminative, affective or other dimensions of pain. Some of the V brainstem NS and WDR neurones respond exclusively to cutaneous sensory inputs and have features indicating their involvement in acute superficial craniofacial pain. Many of the neurones, however, receive convergent inputs from afferents supplying other craniofacial tissues (e.g. cerebrovascular, muscle) as well as skin, and are likely involved in deep pain, as well as spread and referral that is typically seen in headache and several craniofacial pain conditions involving deep tissues. Convergence may also be an important factor underlying the neuroplastic changes in V neuronal properties that may occur with peripheral injury or inflammation. These changes include a prolonged enhancement of the cutaneous as well as deep afferent inputs to most NS and WDR neurones and expansion of their cutaneous or deep mechanoreceptive field and increased EMG activity in the jaw musculature. They involve NMDA, non-NMDA and opioid neurochemical mechanisms within peripheral tissues as well as within the CNS. Such modulatory effects on brainstem neuronal properties reflect the functional plasticity of the central V system, and may be involved in the development of headache and other conditions that manifest craniofacial pain.     

Effect of stimulation of the central gray matter of the midbrain on responses of neurons of the ventroposteromedial nucleus of the thalamus in cats

Effect of the midbrain central gray matter (CGM) stimulation on neuronal responses of the thalamic ventro-postero-medial (VPM) nucleus evoked by stimulation of the tooth pulp, A-alpha, A-delta fibres of the infraorbital nerve and caudal nucleus of the spinal trigeminal tract have been studied in cats under thiopental-chloralose anesthesia. It is shown that the CGM stimulation by a short train of stimuli evoked excitatory responses with a latency of 30 ms in part of investigated neurons. The conditioning CGM stimulation suppressed responses in neurons of "low-threshold", "convergent" and "high-threshold" groups. Responses induced by stimulation of the tooth pulp and A-delta fibres of the infraorbital nerve in 40% of neurons and by stimulation of the A-alpha fibres of the infraorbital nerve in about 26% of investigated thalamic neurons were completely suppressed. The inhibitory influence of the CGM stimulation on neuronal responses evoked by stimulation of peripheral nerves and caudal nucleus of the spinal trigeminal tract shows that the CGM influences directly the activity of thalamic neurons.     

Inhibition of the human primary motor area by painful heat stimulation of the skin.

OBJECTIVE: To prove whether painful cutaneous stimuli can affect specifically the motor cortex excitability. METHODS: The electromyographic (EMG) responses, recorded from the first dorsal interosseous muscle after either transcranial magnetic or electric anodal stimulation of the primary motor (MI) cortex, was conditioned by both painful and non-painful CO2 laser stimuli delivered on the hand skin. RESULTS: Painful CO2 laser stimuli reduced the amplitude of the EMG responses evoked by the transcranial magnetic stimulation of both the contralateral and ipsilateral MI areas. This inhibitory effect followed the arrival of the nociceptive inputs to cerebral cortex. Instead, the EMG response amplitude was not significantly modified either when it was evoked by the motor cortex anodal stimulation or when non-painful CO2 laser pulses were used as conditioning stimuli. CONCLUSIONS: Since the magnetic stimulation leads to transynaptic activation of pyramidal neurons, while the anodal stimulation activates directly cortico-spinal axons, the differential effect of the noxious stimuli on the EMG responses evoked by the two motor cortex stimulation techniques suggests that the observed inhibitory effect has a cortical origin. The bilateral cortical representation of pain explains why the painful CO2 laser stimuli showed a conditioning effect on MI area of both hemispheres. Non-painful CO2 laser pulses did not produce any effect, thus suggesting that the reduction of the MI excitability was specifically due to the activation of nociceptive afferents.     

Modulation of upper extremity motor evoked potentials by cutaneous afferents in humans.

The excitability of motoneurons controlling upper limb muscles in humans may vary with cutaneous nerve stimulation. We investigated the effect of noxious and non-noxious conditioning stimuli applied to right and left digit II and right digit V on motor evoked potentials (MEPs) recorded from right thenar eminence, abductor digiti minimi, biceps and triceps brachii muscles in twelve healthy subjects. Transcranial magnetic stimulation (TMS) was applied at interstimulus intervals (ISI) ranging from 40 to 160 ms following conditioning distal digital stimulation. TMS and transcranial electrical stimulation (TES) were compared at ISI 80 ms. Painful digital stimulation caused differential MEP amplitude modulation with an early maximum inhibition in hand muscles and triceps brachii followed by a maximum facilitation in arm muscles. Stimulation of different digits elicited a similar pattern of MEP modulation, which largely paralleled the behavior of cutaneous silent periods in the same muscles. Contralateral digital stimulation was less effective. MEPs following TMS and TES did not differ in their response to noxious digital stimulation. MEP latencies were shortened by cutaneous stimuli. The observed effects were stimulus intensity dependent. We conclude that activation of A-alpha and A-delta fibers gives rise to complex modulatory effects on upper limb motoneuron pools. A-delta fibers initiate a spinal reflex resulting in MEP amplitude reduction in muscles involved in reaching and grasping, and MEP amplitude facilitation in muscles involved in withdrawal. These findings suggest a protective reflex mediated by A-delta fibers that protects the hand from harm. A-alpha fibers induce MEP latency shortening possibly via a transcortical excitatory loop.     

Differential labeling of the vestibular complex following unilateral injections of horseradish peroxidase into the cat and rat locus coeruleus

In anaesthetized cats, lumbar dorsal horn neurons were excited by brief noxious radiant heating of glabrous hindpaw skin. These nociceptive responses were inhibited by concomitant repetitive electrical stimulation of the ipsilateral deep radial nerve. Noxious heat responses were linearly correlated with skin temperature during heating. The slope of this stimulus-response function was decreased, and the response threshold increased, by deep radial nerve stimulation. Microinjection of lidocaine into the medullary raphe attenuated the inhibition induced by deep radial nerve stimulation. The results indicate that in the cat, ‘diffuse noxious inhibitory controls’ (DNIC) involve medial medullary regions.     

Psychophysiological and psychophysical responses to experimental pain induced by two types of cutaneous thermal stimuli

Evoked potentials (EPs) to noxious thermal stimulation of skin may provide information about integrity of the nociceptive afferent system and thus small afferent fiber integrity. Here we describe subjective report, EPs and response times to noxious contact thermal and laser stimuli in the same subjects. Pain quality to both forms of stimulation was consistently reported as a brief pricking or stinging sensation (first pain), occasionally followed, after a silent period, by a diffuse burning sensation (second pain). EPs to laser generated heat pulses consisted of bi- or triphasic waveforms with a large positive wave at approximately 300 ms following arm stimulation and 360 ms following stimulation of the leg. EPs to contact heat pulses consisted of a single, scalp positive wave occurring approximately 830 ms following arm stimulation and 890 ms following leg stimulation. Both forms of noxious stimulation activated afferents with a conduction velocity consistent with that of A-delta fibers ( approximately 10 m/s) and with the psychophysical attributes of first pain.     

Somatotopic organization of cutaneous afferent terminals and dorsal horn neuronal receptive fields in the superficial and deep laminae of the rat lumbar spinal cord

The somatotopic organization of A- and C-afferent fibre terminals in the dorsal horn of the rat lumbar spinal cord was compared with the spatial location of second-order dorsal horn neuronal mechanoreceptive fields. The central terminal fields of the sural, saphenous, and tibial nerve were mapped by labelling the nerves with horseradish peroxidase (HRP). A previous study used the transganglionic transport of wheat germ agglutinin conjugated to horseradish peroxidase (WGA-HRP) to produce a somatotopic map of high-threshold C-fibre terminal fields in lamina II (Swett and Woolf: J. Comp. Neurol. 231:66-77, '85). In the present study the terminal fields of low-threshold A beta afferents that terminate in laminae III and IV were mapped by using unconjugated HRP at prolonged survival times (72 hours). Unfixed tissue was used to increase the sensitivity of the tetramethylbenzidine reaction, thus allowing these afferent terminals to be clearly seen. The general spatial arrangement of the terminal fields in laminae III/IV closely resembled that found in lamina II in the mediolateral and rostrocaudal planes but because of a dorsoventral obliquity of the afferent terminals, the superficial and deeper fields are not in strict vertical register. The input to laminae II-IV of the dorsal horn may therefore be viewed as two horizontally arranged sheets of afferent terminals both accurately representing the skin surface, the more superficial sheet representing the high-threshold C-afferents and the deeper sheet, low-threshold A-beta afferents. The spatial organization of high-threshold A-delta afferents in laminae I and V appears to be quite different, with a transverse rather than a longitudinal orientation. To study dorsal horn cell receptive field organization two single units with mechanoreceptive fields were recorded extracellularly in each of 87 vertical tracks in the lumbar spinal cord, one unit in the superficial dorsal horn and the second in the deep dorsal horn. In general the somatotopic organization of the receptive fields of both sets of units followed that of the afferent terminal fields but there were cells with receptive fields that were anomalous relative to the recording site. No evidence of any vertical relation or columnar arrangement in receptive field size, threshold, or location on the body surface was found when comparing the two units in a pair. Furthermore, no laminar functional specialization was found, the majority of neurones having both low- and high-threshold inputs.(ABSTRACT TRUNCATED AT 400 WORDS)     

Postsynaptic inhibition of cat medullary dorsal horn neurons by stimulation of nucleus raphe magnus and other brain stem sites

Sensory responses of neurons in the medullary and spinal cord dorsal horn can be inhibited by stimulation of a number of brain stem regions. These regions include the nucleus raphe magnus (NRM), the nucleus reticularis gigantocellularis (NGC), the nucleus reticularis magnocellularis (NMC), the periaqueductal gray (PAG), and the nucleus cuneiformis (CU). The purpose of this study was to determine whether or not this inhibition is mediated by postsynaptic processes. Experiments were carried out on chloralose-anesthetized cats. The responses of 29 medullary dorsal horn (trigeminal subnucleus caudalis) cells were recorded with carbon-fiber microelectrodes. Included were cells which responded to noxious stimulation (nine cells) as well as cells which responded only to nonnoxious input. The presence of postsynaptic inhibition was tested by two indirect techniques. We studied the effects of conditioning stimulation of the five regions on the latency of antidromically activated cells and also on the firing rate of neurons excited by iontophoretically applied glutamate. Conditioning stimulation was associated with a block or increased latency of antidromic activation in 15 of 18 nociceptive and nonnociceptive neurons. These effects reflect membrane hyperpolarization, presumably resulting from postsynaptic inhibition. Furthermore, conditioning stimulation of these regions inhibited the glutamate-evoked firing of all 11 cells tested, also indicating a postsynaptic type of inhibition of medullary dorsal horn cells. Thus these results indicate that at least part of the inhibition induced by stimulation of the NRM, NGC, NMC, PAG, and the CU probably results from postsynaptic inhibitory mechanisms.     

Somatosensory cortex: A comparison of the response to noxious thermal,mechanical, and electrical stimuli using functional magnetic resonance imaging

In the present study, functional magnetic resonance imaging (fMRI) was used to examine pain perception in humans. Three types of noxious stimuli were presented: electric shock (20.8 mA, 2 Hz), heat (48°C), and mechanical, as well as a control tactile stimulus. The significance of activation at the level of the voxel was determined using correlation analysis. Significant region of interest (ROI) activation was determined by comparing the percentage of active voxels in each ROI to activation in a control ROI in the visual cortex. In response to tactile and shock stimuli, consistent activation was seen in the postcentral gyrus, parietal operculum, and ipsilateral cerebellar cortex. No significant cortical activation was detected in response to noxious heat or mechanical stimulation when compared to nonpainful intensity levels. The data did not indicate adaptation, although further study in this area is necessary. Stationary noxious thermal and mechanical stimulation are “pure” noxious stimuli, while electrical stimulation influenced nociceptive and nonnociceptive receptors. Lack of detectable activation in response to pure noxious stimuli supports the idea that nociceptive and nonnociceptive fibers are interspersed in the somatosensory cortex. Conflicting results from recent functional imaging studies of pain perception regarding cortical activation indicate that it is essential to consider both the tactile and nociceptive components of the stimuli used, the spatial extent of stimulation, and the possibility of adaptation to the response. Furthermore, these results suggest that subtractive or correlative methods may not be sufficiently sensitive to image the activity of nociceptive cells, which are sparsely distributed throughout the somatosensory cortex. Hum. Brain Mapping 6:150–159, 1998. © 1998 Wiley-Liss, Inc.     

Extra- and intracellular recordings from dorsal column postsynaptic spinomedullary neurons in the cat

Dorsal column postsynaptic (DCPS) spinomedullary neurons in the dorsal horn of spinal segments L6-S1 of adult cats anesthetized with sodium pentobarbital were identified by antidromic stimulation of cervical dorsal columns that were dissected free of, and electrically isolated from, the rest of the spinal cord. The neurons were categorized with respect to natural stimulation of their cutaneous receptive fields. An equal number of low-threshold mechanoreceptive and wide-dynamic-range neurons were found. No DCPS neurons could be classified as nociceptive-specific. All neurons received input from low-threshold mechanoreceptors with myelinated axons. There was no evidence that any neurons received monosynaptic input from unmyelinated, primary afferent fibers. The average conduction velocity of the antidromic responses was 45.7 m/s. Nearly half of the DCPS cells showed an antidromic spike followed by synaptically driven responses that were probably evoked by antidromic invasion into the intraspinal collaterals of A-beta primary afferent fibers that ascended the dorsal columns. Intracellularly recorded synaptic responses of DCPS neurons to dorsal column and receptive field stimulation usually consisted of an EPSP with overriding spike potentials followed by a prolonged IPSP whose amplitude decreased markedly as the stimulus frequency was increased in the range of 5 to 30 Hz. The results indicate that DCPS neurons constitute a projection system capable of signaling innocuous and tissue-damaging mechanical stimuli. The DCPS projection may play a role in the modulation of touch and pain perception.     

Recording of long-term potentiation in single dorsal horn neurons in vivo in the rat.

We have published several reports on long-term potentiation (LTP) in single spinal wide dynamic range (WDR) neurons (responding to both innocuous and noxious stimuli) in urethane-anaesthetised rats. The protocol presented here, with single unit recordings of dorsal horn neurons before and after a nociceptive conditioning stimulation, may be useful in many electrophysiological studies of plastic changes in the spinal cord, such as LTP. We invite others to use this protocol for the study of spinal plasticity. Findings using this technique may be relevant for the understanding of changes in nociceptive transmission, induction of central sensitisation and maybe even in mechanisms of pathological pain and chronic pain states. We describe modified and alternative protocols for the study of LTP mechanisms under different conditions in intact and in spinalised animals, and after natural noxious stimuli. We present a novel method minimising peripheral influence of afferent input induced by antidromic neurogenic inflammation or inflammatory changes following a natural noxious stimulation. This is made possible by dissection of the sciatic nerve at two separate locations and local anaesthetic block distal to the stimulation site.