Effects of a distant noxious stimulation on A and C fibre-evoked flexion reflexes and neuronal activity in the dorsal horn of the rat

In the halothane-anaesthetized rat, the responses of 49 neurons in the lumbo-sacral cord and the reflex discharge in the common peroneal nerve following electrical stimulation of the sural nerve were recorded in order to study possible relations between neuronal events and reflex nerve discharges. A distant noxious stimulus (to activate Diffuse Noxious Inhibitory Controls (DNIC) of Le Bars et al.) was used as a conditioning stimulus. Only the responses of neurons receiving an input from both A and C fibres were studied. The neurons were classified as class 1 (low threshold mechanoreceptive input only, n = 2), class 2 (nonnoxious and noxious inputs, n = 34) or class 3 (responding to noxious stimuli only, n = 13). During conditioning stimulation the C fibre evoked discharge was inhibited in 32 out of 34 class 2 neurons. The A fibre-evoked discharge was simultaneously inhibited in 29 of these neurons. The main effect of the distant noxious stimulation on the C fibre evoked neuronal discharge was to decrease the discharge by a constant number of spikes, independent of the level of evoked activity. Only one class 3 neuron was inhibited during conditioning stimulation and none of the class 1 cells were influenced by DNIC. During conditioning stimulation the late and prolonged C fibre evoked reflex nerve discharge (latency 160-200 ms, duration up to several hundred ms) was strongly depressed. Concomitantly, a short-lasting reflex nerve discharge appeared over the interval 115-160 ms. This released reflex nerve discharge (RR) had a constant latency. There was no simultaneous change of the A beta evoked reflex nerve discharge. After the end of the distant noxious stimulation the late C fibre evoked reflex nerve discharge (latency 160-200 ms) recovered. Concomitantly, the RR disappeared. The possibility that the class 2 neurons and the class 3 neurons are intercalated in different reflex pathways is discussed.     

The effects of a distant noxious stimulation on A and C fibre-evoked flexion reflexes and neuronal activity in the dorsal horn of the rat

In the halothane-anaesthetized rat, the responses of 49 neurons in the lumbo-sacral cord and the reflex discharge in the common peroneal nerve following electrical stimulation of the sural nerve were recorded in order to study possible relations between neuronal events and reflex nerve discharges. A distant noxious stimulus (to activate Diffuse Noxious Inhibitory Controls (DNIC) of Le Bars et al.¹⁹) was used as a conditioning stimulus. Only the responses of neurons receiving an input from both A and C fibres were studied. The neurons were classified as class 1 (low threshold mechanoreceptive input only, n = 2), class 2 (nonnoxious and noxious inputs, n =34) or class 3 (responding to noxious stimuli only, n = 13). During conditioning stimulation the C fibre evoked discharge was inhibited in 32 out of 34 class 2 neurons. The A fibre-evoked discharge was simultaneously inhibited in 29 of these neurons. The main effect of the distant noxious stimulation on the C fibre evoked neuronal discharge was to decrease the discharge by a constant number of spikes, independent of the level of evoked activity. Only one class 3 neuron was inhibited during conditioning stimulation and none of the class 1 cells were influenced by DNIC. During conditioning stimulation the late and prolonged C fibre evoked reflex nerve discharge (latency 160–200 ms, duration up to several hundred ms) was strongly depressed. Concomitantly, a short-lasting reflex nerve discharge appeared over the interval 115–160 ms. This released reflex nerve discharge (RR) had a constant latency. There was no simultaneous change of the Aβ evoked reflex nerve discharge. After the end of the distant noxious stimulation the late C fibre evoked reflex nerve discharge (latency 160–200 ms) recovered. Concomitantly, the RR disappeared. The possibility that the class 2 neurons and the class 3 neurons are intercalated in different reflex pathways is discussed.     

Intense peripheral electrical stimulation differentially inhibits tail vs. limb withdrawal reflexes in the rat

In an on-going study on mechanisms by which activation of sensory afferents regulates nociception, high-intensity, low-frequency electrical stimulation was applied to previously defined meridian and non-meridian points of the hindlimb or forelimb, and the effects measured on the withdrawal reflex of the tail or limb in the lightly anesthetized rat. Withdrawal was evoked by application of noxious radiant heat to the tip of the tail or to the plantar surface of a hindpaw or forepaw. Parameters of conditioning electrical stimulation were 2 ms pulses at 4 Hz for 20 min at 20 × threshold (20–30 mA) where threshold was the minimum intensity which evoked muscle twitch. In experiments on tail withdrawal, stimulation applied to meridian points fengshi (GB-31), femur-futu (ST-32) and zusanli (ST-36) of the hindlimb or to wai-kuan (TH-5) and hoku (LI-4) of the forelimb increased the latency of the withdrawal reflex to 70–100% of the maximum possible inhibition (MPI) during the stimulation. Inhibition persisted for more than 1 h after the end of stimulation. Bilateral stimulation of hindlimb meridian points evoked a greater inhibition during the stimulation ( > 95% of the MPI); the inhibition persisted for 40 min. Stimulation of non-meridian sites in hindlimb or forelimb inhibited the withdrawal reflexes by 45–50% of the MPI during the stimulation only. Thus, the evoked inhibition has two components, a brief effect elicited by non-meridian point stimulation and a persistent post-stimulation effect produced only upon stimulation of meridian points. Stimulation produced little effect on nociceptive limb withdrawal reflexes. The results suggest that high-intensity, low-frequency electrical stimulation of meridian points produced a long-lasting, extrasegmental inhibition of the tail withdrawal but not of limb withdrawal reflexes. This differential inhibition may be due to differences in neuronal circuitry and CNS modulatory control mechanisms. The persistent inhibition appears to be dependent on the site of stimulation because it is not evoked by stimulation of sites outside of meridian points.     

Developmental tuning in a spinal nociceptive system: effects of neonatal spinalization.

Recent studies indicate a modular organization of the nociceptive withdrawal reflex system. Each module has a characteristic receptive field, closely matching the withdrawal movement caused by its effector muscle. In the rat, the strength of the sensory input to each module is tuned during the first postnatal weeks, i.e., erroneous spinal connections are depressed, and adequate connections are strengthened. To clarify if this tuning is dependent on supraspinal structures, the effect of a complete neonatal spinal cord transection on the postnatal tuning of withdrawal reflexes was studied. The nociceptive receptive fields of single hindlimb muscles and compound withdrawal reflexes were examined in decerebrate unanesthetized and awake rats, respectively. Noxious thermal CO(2) laser stimulation was used to evoke reflex responses. Neonatal spinal cord transection resulted in a disrupted reflex organization in the adult rat, resembling that previously found in neonatal rats. The receptive fields of single hindlimb muscles exhibited abnormal distribution of sensitivity not matching the withdrawal action of the effector muscles. Likewise, the composite nocifensive movements, as documented in the awake rat, often resulted in erroneous movements toward the stimulus. It is concluded that withdrawal reflexes do not become functionally adapted in rats spinalized at birth. These findings suggest a critical role for supraspinal systems in the postnatal tuning of spinal nociceptive systems.     

Sensorimotor transformation in cat nociceptive withdrawal reflex system

The withdrawal reflex system of higher vertebrates has been extensively used as a model for spinal sensorimotor integration, nociceptive processing and plasticity. In the rat, the nociceptive withdrawal reflex system appears to have a modular organization. Each reflex module controls a single muscle or a few synergistic muscles, and its cutaneous receptive field corresponds to the skin area withdrawn upon contraction of the effector muscle(s) when the limb is in the standing position. This organization principle is at odds with the 'flexion reflex' concept postulated from cat studies. To assess the generality of the modular organization principle we have therefore re-examined the cutaneous input to the withdrawal reflex system of the cat. The cutaneous receptive fields of hindlimb and forelimb muscles were mapped using calibrated noxious pinch stimulation and electromyographic recording technique in barbiturate anaesthetized animals. The investigated muscles had specific cutaneous receptive fields that appeared to correspond to the area of the skin withdrawn upon contraction of the muscle when the limb is in the standing position. The spatial organization of receptive fields in the cat was similar to that in the rat. However, differences in gain properties of reflexes to some anatomically equivalent muscles in the two species were observed, possibly reflecting adaptations to the biomechanics characteristic of the digitigrade and plantigrade stance in cats and rats, respectively. Implications of the findings for the generality of the modular organization of the withdrawal reflex system and for its adaptive properties are discussed.     

Modulation of jaw reflexes induced by noxious stimulation to the muscle in anesthetized rats

Previous studies have shown that jaw reflexes and activity patterns of the jaw muscles were modulated in the presence of jaw muscle pain. However, there is no study comparing the modulatory effects on the jaw reflexes induced by noxious stimulation to the jaw muscle. To clarify this, effects of the application of mustard oil (MO), an inflammatory irritant, into the temporalis (jaw-closing) muscle on (1) jaw-opening reflex evoked by tooth pulp stimulation (TP-evoked JOR) as a nociceptive reflex, (2) jaw-opening reflex evoked by inferior alveolar nerve stimulation as a non-nociceptive reflex and (3) jaw-closing reflex evoked by trigeminal mesencephalic nucleus stimulation as a proprioceptive reflex were investigated in anesthetized rats. The MO application induced suppression of all reflexes, and the effect on the TP-evoked JOR was more prominent than on the other reflexes. To elucidate the involvement of endogenous opioid system for the suppressive effect, a systemic administration of naloxone following the MO application was conducted. The MO-induced suppressive effect on the TP-evoked JOR was reversed by the naloxone administration. The results suggest that noxious stimulation to the jaw muscle modulate jaw reflexes particularly for the nociceptive jaw-opening reflex, and the modulatory effect includes both facilitatory and inhibitory aspects. The results also suggest that pain modulatory systems such as the endogenous opioid system play a crucial role in the suppression of the nociceptive transmissions related to nociceptive reflexes, and in some pathological states, defense reflexes may not be evoked properly.     

Functional organization of long ascending propriospinal pathways linking lumbo-sacral and cervical segments in the cat

In high spinal cats propriospinal pathways ascending from lumbo-sacral levels of the spinal cord can mediate strong excitatory and inhibitory changes in reflexes to different groups of motoneurones supplying muscles of the forelimb. Discharges evoked by electrical stimulation of hindlimb nerves could be evoked in 41% of experiments in the motoneurones of pectoralis major and minor. The latency of the discharge (8–18 msec) could be shortened by increasing the repetition frequency of the stimulus, the greatest reduction occurring in the range 1–4 Hz. Contralateral hindlimb nerves were less effective and the discharge generally occurred at a latency 1–2 msec longer than for ipsilateral nerves.Monosynaptic reflexes to pectoralis major and deep radial motoneurones supplying the physiological flexor muscles were strongly facilitated by hindlimb nerve stimulation, ipsilateral nerves being more effective than contralateral. Monosynaptic reflexes to latissimus dorsi showed a reciprocal pattern of conditioning, being depressed by ipsilateral and facilitated by contralateral hindlimb extensor nerves, the flexor nerves giving the reverse pattern. Monosynaptic reflexes to median and ulnar nerves supplying physiological extensor muscles were not significantly affected by hindlimb nerve conditioning.Polysynaptic reflexes to pectoralis major and deep radial motoneurones received initial strong facilitation followed by prolonged depression, ipsilateral hindlimb nerves being more effective than contralateral. In latissimus dorsi a reciprocal pattern similar to that for monosynaptic reflex testing was found. Polysynaptic reflexes to median and ulnar motoneurones received only prolonged depression.The hindlimb afferent nerves responsible for the discharge in forelimb motoneurones and for the facilitation and depression of forelimb reflexes include groups II and II muscle afferents and group II skin afferents, especially from quadriceps and sartorius muscles, and sural and superficial peroneal nerves, respectively.The ascending long propriospinal pathways are influenced bilaterally from hindlimb nerves and are located in the lower thoracic segments in the ventrolateral funiculus. The pathways mediate effects on ipsilateral and contralateral forelimb reflex systems, the ipsilateral projections being dominant. Part of the long ascending projection terminates monosynaptically on the motoneurones of pectoralis major. It is likely that group II afferents from ipsilateral quadriceps muscle activate the ascending tract monosynaptically and those from contralateral quadriceps disynaptically.The hypothesis is suggested that long propriospinal paths primarily represent intrinsic links between hindlimb and forelimb ‘motor centres’. The pattern of long ascending influences to groups of forelimb motoneurones corresponds closely to the sequences of hindlimb and forelimb stepping observed in normal cats. A functional role in stepping is therefore proposed for long ascending propriospinal pathways.     

Influence of spinalization on spinal withdrawal reflex responses varies depending on the submodality of the test stimulus and the experimental pathophysiological condition in the rat

The influence of midthoracic spinalization on thermally and mechanically induced spinal withdrawal reflex responses was studied in the rat. There were three experimental groups of rats: healthy controls, rats with a spinal nerve ligation-induced unilateral neuropathy, and rats with a carrageenan-induced inflammation of one hindpaw. Tail flick response was induced by radiant heat. Hindlimb withdrawal was induced by radiant heat, ice water, and innocuous or noxious mechanical stimulation of the paw. Prior to spinalization, spinal nerve ligated and carrageenan-treated animals had a marked unilateral allodynia and hyperalgesia. Spinalization tended to induce a facilitation of noxious heat-evoked reflexes. This spinalization-induced facilitation was stronger on tail than hindlimb withdrawal. Spinalization-induced skin temperature change did not explain the facilitation of noxious heat-evoked reflexes. In contrast, spinal withdrawal responses induced by noxious cold or mechanical stimulation were significantly suppressed following spinalization. The spinalization-induced facilitatory effects as well as inhibitory ones on spinal reflexes were enhanced in inflamed/neuropathic animals. The results indicate that the tonic descending control of spinal nocifensive responses varies depending on the submodality of the test stimulus, the segmental level of the reflex (tail vs. hindlimb), and on the pathophysiological condition.     

Multiple sensory neuronal correlates of site-specific sensitization in Aplysia

Noxious stimulation of a restricted site on the skin of Aplysia (training) causes site-specific sensitization of the tail-withdrawal reflex that is associated with several sensory correlates that are evident both 10 min and 2 hr after training. First, extracellularly recorded afferent activity evoked by test stimulation of the trained site increases, indicating peripheral sensory changes. Second, central sensory alterations are manifested by tail sensory neurons within the pleural VC cluster that innervate the trained site and are activated during training. These mechanosensory/nociceptive cells display a number of differences from unactivated tail sensory neurons innervating other sites: slow depolarization of the soma observed immediately after training, decrease in soma action potential threshold, and enhancement of monosynaptic EPSPs to identified motor neurons. Noxious stimulation of a more extensive region also produces site-specific sensitization of the tail-withdrawal reflex and site-specific enhancement of EPSP amplitude measured 1 d after training. This training produced a novel cellular correlate of behavioral enhancement in Aplysia--regenerative bursting responses (2-35 spikes) in response to brief depolarization of the sensory neuron soma. The changes in peripheral and central excitability appear similar to changes associated with mammalian models of primary hyperalgesia. Site-specific enhancement of nociceptive signaling also occurs during aversive associative conditioning in a noxious unconditioned stimulus (US) pathway. These site-specific changes involve activity-dependent extrinsic modulation (ADEM) of the VC sensory neurons, suggesting a close relationship to changes underlying associative conditioning in conditioned stimulus (CS) pathways in Aplysia.     

A fictive tail flick reflex in the rat

The discharges of motor axons participating in the tail flick reflex were recorded from nerve filaments innervating the medial longissimus muscles of anesthetized rats. The reflex discharges evoked by stimulation of the tail with either noxious radiant heat or pinch were recorded before and after paralysis of the animals. Nociceptive discharges recorded from motor axons in the paralyzed state showed a strong correlation with those observed in the absence of the paralytic agent. For this reason, the electrophysiological response triggered by noxious input was termed a ‘fictive tail flick reflex’. To evaluate the potential applicability of this model in the analysis of pain blocking mechanisms, vaginal stimulation was found to produce a profound reduction of the nociceptive discharges of the fictive tail flick reflex. By eliminating movement artifacts from the experimental paradigm, this model expands our ability to study a basic nociceptive response which was previously limited to behavioral observation.     

Differentiation of nociceptive- from stress-induced modulatory influences on human reflexes

This paper describes a new protocol that addresses the question of whether, in human experiments, modulatory effects of remote nociceptive conditioning stimuli on reflex responses are mediated by the stress induced by the conditioning stimuli. The protocol has been illustrated by a study into the effect of a remote nociceptive conditioning stimulus on an inhibitory jaw reflex. Electromyograms were recorded from an active masseter muscle and inhibitory reflexes were evoked by applying electrical stimuli to the upper lip. This protocol utilised the application of discrete electrical conditioning stimuli applied to the sural nerve prior to the test stimulus. A preliminary experiment determined that the optimal interval between the conditioning and test stimuli, which produced modulatory effects was 100 ms. In the definitive study, computer software was used to deliver control and conditioned sweeps in a double-blind randomised sequence. This resulted in a "stress-equal" protocol in which the level of stress would be the same for both control and conditioned sweeps. Therefore any observed modulatory effects on the reflexes could not have been wholly secondary to stress. This protocol could be adapted to the study of the modulation of other reflexes or evoked sensations by nociceptive conditioning stimuli.     

Effect of pinching-evoked pain on jaw-stretch reflexes and exteroceptive suppression periods in healthy subjects.

OBJECTIVE: To investigate the influence of conditioning cutaneous nociceptive inputs by a new "pinch" model on the jaw-stretch reflex and the exteroceptive suppression periods (ES1 and ES2) in jaw muscles. METHODS: The jaw-stretch reflex was evoked with the use of a custom-made muscle stretcher and electrical stimuli were used to evoke an early and late exteroceptive suppression period (ES1 and ES2) in the jaw-closing muscles. Electromyographic (EMG) activity was recorded bilaterally from the masseter and temporalis muscles. These brainstem reflexes were recorded in 19 healthy men (28.8+/-1.1 years) during three different conditions: one painful clip applied to the earlobe; one painful clip applied to the nostril, and four painful clips applied simultaneously to the earlobe, nostril, eyebrow, and lower lip. Pain intensity induced by the application of the clips was scored continuously by the subjects on a 100mm visual analogue scale (VAS). RESULTS: The highest VAS pain scores were evoked by placement of four clips (79+/-0.5mm). There was no significant modulation of the jaw-stretch reflex (ANOVAs: P=0.929), the ES1 (P=0.298) or ES2 (P=0.082) in any of the three painful conditions. CONCLUSIONS: Intense and tonic cutaneous pain could be elicited by this new "pinch" pain model; however, there was no significant modulation on either excitatory or inhibitory brainstem reflex responses. SIGNIFICANCE: The novel observation that high-intensity pinch stimuli applied to the craniofacial region fail to modulate two different brainstem reflexes is in contrast to other experimental pain studies documented facilitation of the jaw-stretch reflexes or inhibition of exteroceptive suppression periods. The clinical implication of the present findings is that only some craniofacial pain conditions could be expected to show perturbation of the brainstem reflex responses.     

Modulation of the withdrawal reflex during hemiplegic gait: effect of stimulation site and gait phase.

OBJECTIVE: The objective of the study was to investigate the sensitivity of the nociceptive withdrawal reflex to stimulation of different locations on the sole of the foot during hemiplegic gait. METHODS: Reflexes were evoked by cutaneous electrical stimulation of 4 locations on the sole of the foot of 7 hemiplegic and 6 age-matched healthy persons. The stimuli were delivered at heel-contact, during foot-flat, at heel-off, and during mid-swing. Reflexes were recorded from muscles of the stimulated and the contralateral leg. Ankle, knee, and hip joints angles were recorded using goniometers. RESULTS: In the hemiplegic persons, the size of tibialis anterior reflexes, and the latency of soleus reflexes were site- and phase-modulated. In both groups, the tibialis anterior reflexes were significantly smaller with stimulation to the fifth metatarsophalangeal joint and the heel compared with the first metatarsophalangeal joint and the arch of the foot. The tibialis anterior reflexes evoked at heel-off and mid-swing were larger in hemiplegic persons than in healthy persons. Reflexes in the proximal and contralateral limb muscles were not site-modulated during hemiplegic gait. The kinematic response at the ankle joint was also different in the two groups during mid-swing. CONCLUSIONS: Hemiplegic and healthy middle-aged people presented different phase-modulation of the kinematic and muscle nociceptive reflex responses evoked by stimulation delivered on the sole of the foot. SIGNIFICANCE: The results have potential application in programs to rehabilitate hemiplegic gait.     

Involvement of spinal α2‐adrenoceptors in prolonged modulation of hind limb withdrawal reflexes following acute noxious stimulation in the anaesthetized rabbit

The role of spinal α ₂‐adrenoceptors in mediating long‐lasting modulation of hind limb withdrawal reflexes following acute noxious chemical stimulation of distant heterotopic and local homotopic locations has been investigated in pentobarbitone‐anaesthetized rabbits. Reflexes evoked in the ankle extensor muscle medial gastrocnemius (MG) by electrical stimulation of the ipsilateral heel, and reflexes elicited in the ankle flexor tibialis anterior and the knee flexor semitendinosus by stimulation at the base of the ipsilateral toes, could be inhibited for over 1 h after mustard oil (20%) was applied to either the snout or into the contralateral MG. The heel–MG response was also inhibited after applying mustard oil across the plantar metatarsophalangeal joints of the ipsilateral foot, whereas this homotopic stimulus facilitated both flexor responses. Mustard oil also caused a significant pressor effect when applied to any of the three test sites. The selective α₂‐adrenoceptor antagonist, RX 821002 (100–300 μg, intrathecally), had no effect on reflexes per se, but did cause a decrease in mean arterial blood pressure. In the presence of the α₂‐blocker, inhibitory and facilitatory effects of mustard oil on reflexes were completely abolished. These data imply that long‐lasting inhibition of spinal reflexes following acute noxious stimulation of distant locations involves activation of supraspinal noradrenergic pathways, the effects of which are dependent on an intact α₂‐adrenoceptor system at the spinal level. These pathways and receptors also appear to be involved in facilitation (sensitization) as well as inhibition of reflexes following a noxious stimulus applied to the same limb.     

Convergent pathways for cardiac- and esophageal-somatic motor reflexes in rats

Chest pain of esophageal and cardiac origin is often difficult to distinguish due to similar sensations and localization. We have shown that spasm-like contractions of the spinotrapezius muscles evoked by noxious cardiac stimulation could potentially sensitize muscle afferent fibers and produce angina-like referred pain. In this study, we proposed that a similar type of spinotrapezius contraction evoked by esophageal stimulation could produce nociceptive responses with similar quality and localization as evoked by cardiac stimulation. An objective of this study was to show convergence of pathways to the spinotrapezius muscles by measuring electromyographic (EMG) activity between the cardiac- and esophageal-motor reflexes. We also investigated afferent pathways of esophageal-motor reflexes by disrupting or activating the left sympathetic chain and vagus nerves; these pathways form the afferent limbs of the cardiac-motor reflexes. Results showed that more than 95% of animals responding to noxious cardiac stimulation also responded to esophageal distension. Transection of the left sympathetic chain to reduce upper thoracic visceral afferent innervation significantly decreased cardiac-evoked EMG activity or total motor unit potentials (t-MUP). In contrast, however, the transection did not significantly decrease t-MUP evoked by esophageal distension. Bilateral vagotomy and vagal afferent stimulation increased and decreased the cardiac-evoked t-MUP, respectively. However, the same vagal manipulations did not influence t-MUP evoked by esophageal distension. This study demonstrated that the spinotrapezius muscle could be activated by noxious stimulation of two different visceral organs. The spinotrapezius muscle contractions evoked by esophageal distension are produced in part by activation of esophageal afferent fibers found in upper thoracic sympathetic nerves, but not by activation of the vagus nerves.     

Inhibitory effects from various types of dorsal column and raphe magnus stimulations on nociceptive withdrawal flexion reflexes

Most of the clinical and research reports agree about the analgesic effects of dorsal column (DC) stimulation, but there is no unanimity about the neural mechanisms involved in this stimulation. The aim of the present study was to compare the effects of segmental and rostral activation of the DCs and to investigate whether these effects are mediated through a brainstem spinal loop. Decerebrate-decerebellate cats were subjected to selective DC lesions at C(1) and C(3) spinal cervical levels and their reflex reactions to natural or electrical nociceptive stimuli were monitored either as withdrawal flexion reflexes or as motorneuronal discharges. Conditioning stimulation was performed as train of shocks (100 Hz, for 1 to 10 min or 300 Hz for 30 ms) applied on the DCs either rostral (DCr) or caudal (DCc) to the spinal lesions or on the raphe magnus (RM). Conditioning trains for 5-10 min applied on DCr inhibited the withdrawal flexion reflexes recorded as toe flexion (90% of the control). Comparisons of the effects of DCr, DCc or RM of conditioning stimuli were made on the discharges of 110 motorneurons recorded in isolated ventral root fibers. Conditioning stimulation applied to DCc produced short lived inhibition (in about 60%) or facilitation (in about 30% of the neurons) while DCr or RM conditioning produced inhibition in 90% of neurons which outlasted the duration of the conditioning trains. It was also shown that repetitive application of conditioning train on either DCr or RM resulted in longer duration of inhibition than that observed following DCc conditioning. We conclude that the stronger inhibition of motorneuronal discharges, evoked by nociceptive stimuli, is obtained by rostral activation of the DCs and that long term effects of DCst are mediated through a DC-brainstem-spinal loop.     

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.     

Intense peripheral electrical stimulation evokes brief and persistent inhibition of the nociceptive tail withdrawal reflex in the rat

In a study of modulation of nociception by sensory inputs, electrical stimulation was applied to specific sites in the hindlimb and effects on the nociceptive tail withdrawal reflex were monitored in the lightly anaesthetized rat. Stimulation was applied to previously defined sites in the hindlimb, meridian points femur-futu (ST-32), fengshi (GB-31) and zusanli (ST-36). It consisted of a 4 Hz train of 2 ms square pulses given for 20 min at 20 × the threshold intensity required for muscle twitch. Tail withdrawal was provoked by application of a noxious heat stimulus applied to the tip of the tail. Results were expressed as a percentage of the maximal possible inhibition which is achieved when the post-treatment latency is 2 × the pre-treatment latency otherwise known as the cut off. During stimulation, the latency of the withdrawal increased to ≈ 70% of the maximal possible inhibition. Following stimulation, the inhibition persisted for > 1 h. Stimulation at 2 or 6 Hz elicited similar effects but stimulation at 8 Hz evoked inhibition during the stimulation only. Stimulation applied to sites away from defined meridian points inhibited tail withdrawal during the stimulation; no post-stimulation effect was produced. In acutely transected animals (≤ 48 h), stimulation of meridian points elicited a small, brief increase in latency but during stimulation only. At 7 and 14 days after spinal transection, this response during stimulation was greater in magnitude and a brief post-stimulation increase was also observed. The return of the of this latter effect was coincident with the return of bladder function. These data suggest that high intensity, low frequency electrical stimulation of hindlimb meridian points in the lightly anaesthetized rat produces both brief and persistent inhibitory effects on the nociceptive tail withdrawal reflex. These effects appear to be elicited by different mechanisms. The persistent effect may represent a plastic change in central inhibitory mechanisms. Data from spinal animals indicate a major participation of supraspinal structures but that spinal mechanisms are also capable of sustaining both types of effect.     

Role of the solitary tract nucleus in mediating nociceptive evoked cardiorespiratory responses

We compared the cardiorespiratory reflex responses evoked by noxious stimulation of the forelimb and cornea. Due to the depressant effects of anaesthesia on visceral reflexes we compared data from an unanaesthetised decerebrate rat model--the working heart-brainstem preparation (WHBP), with the anaesthetised rat. In both experimental models stimulation of the forelimb (mechanical pinch) evoked a tachycardia (WHBP: 19 +/- 2 bpm) and a decrease in respiratory cycle length (WHBP: from 4.1 +/- 0.2 to 2.3 +/- 0.1 s). The magnitude of response in anaesthetised animals depended on anaesthetic depth. Mechanical stimulation of the cornea evoked a bradycardia (-49.2 +/- 4.8 bpm) and an increase in respiratory cycle length from 4 +/- 0.36 to 5.88 +/- 0.2 s which was only present in the WHBP. In the WHBP activation of forelimb and corneal nociceptors both elicited significant pressor effects; in anaesthetised rats there were inconsistent changes in arterial pressure. To determine a role for the nucleus of the solitary tract (NTS) in mediating nociceptive evoked responses in the WHBP, synaptic transmission was blocked reversibly following bilateral microinjections of cobalt chloride. The heart rate responses evoked from either forelimb or corneal nociceptors were attenuated by approximately 50% (P < 0.05). A similar effect was observed using isoguvacine, a GABAA receptor agonist, to hyperpolarise NTS neurones. In conclusion, activation of forelimb and corneal nociceptors evoked contrasting patterns of cardiorespiratory response in the WHBP while in the anaesthetised rat the magnitude of the cardiorespiratory response to forelimb stimulation was quantitatively dependent on anaesthetic dose. In the WHBP, NTS neurones appear important for mediating the cardiac component of the reflex response following stimulation of nociceptive reflex pathways.     

Long-lasting neuronal activity in rat dorsal horn evoked by impulses in cutaneous C fibres during noxious mechanical stimulation

The responses of 44 nociceptive neurones in the lumbar dorsal horn evoked by controlled mechanical stimulation of the skin, with or without conduction block in myelinated afferent fibres, were studied in the halothane-anaesthetized rat, in order to evaluate the effects of impulses in cutaneous nociceptive C fibres on dorsal horn neurones. Continuous non-noxious pinch of the skin evoked a short-latency discharge (mean latency 15 ms) in all the 13 class 2 neurones (i.e. neurones responding to both non-noxious and noxious stimulation of the skin) tested. The short-latency discharge was followed by weak prolonged activity in 6 neurones. Following noxious pinch of the skin a prominent late discharge (peak latency 150 ms-2 s) was evoked, which in all but two class 2 neurones outlasted the stimulation period (5-10 s). The discharge evoked by noxious pinch in class 3 neurones (i.e. neurones responding to noxious stimulation only) did not usually outlast the stimulation period. In all but two nociceptive neurones tested (n = 26) the late activity evoked by noxious pinch remained, albeit at a lower frequency in some neurones, during a conduction block in A fibres2,3. Hence this late discharge is probably mainly generated by impulses in nociceptive C fibers. It is concluded that nociceptive C fibres have an important role in sustaining long-lasting activation of class 2 neurones during noxious stimulation of the skin and that long-lasting discharges in these neurones indicates tissue damage to their receptive fields.