Effects of systemic morphine on escape latency and a hindlimb reflex response in the rat.

The present study uses focal electrical stimulation of myelinated nociceptors to simultaneously assess behavioral responses that are organized at spinal and supraspinal sites in the rat. Hindlimb reflex amplitude and the latency to operant escape responses by a forelimb were recorded for each stimulus presentation to a hindlimb across a wide range of intensities. This paradigm provided a tool whereby effects of morphine on conscious escape responses could be delineated from effects on a segmental flexion reflex over a range of doses. Administration of morphine (3 mg/kg and 10 mg/kg, subcutaneously) increased the latency of escape responses and decreased the amplitude of reflex responses in a dose-dependent manner. However, morphine produced a greater suppression of reflex responses compared with the increase in effects on escape latencies. The effects of morphine on escape latency were not expressed at the highest stimulus intensities (0.6 to 0.8 mA), whereas reflex responses were attenuated at all suprathreshold stimulus intensities. Thus, electrically evoked, spinal-mediated responses of rats are not affected by morphine in the same manner as electrically evoked supraspinal-mediated nociceptive behaviors. However, both measures confirm evidence that responses elicited by activation of myelinated afferents are less powerfully affected by morphine than responses to input from unmyelinated nociceptors.     

The effect of maximal exercise on temporal summation of second pain (windup) in patients with fibromyalgia syndrome

Exercise activates endogenous opioid and adrenergic systems, but attenuation of experimental pain by exercise has not been shown consistently. In this study, effects of exercise on temporal summation of late pain responses to stimulation of unmyelinated (C) nociceptors were assessed. When a preheated thermode was applied repetitively to glabrous skin of the hand in a series of brief contacts at rates of 0.2 to 0.5 Hz, the perceived intensity of late thermal sensations increased after successive contacts. This summation of pain sensations provides information regarding the status of central opioid and N-methyl-D-aspartate receptor systems. For normal subjects, temporal summation of late pain sensations was substantially attenuated when testing began 1.5 or 10 minutes after exercise. Individuals diagnosed with fibromyalgia syndrome (FMS) report generalized chronic pain that is increased after exercise. Therefore, we hypothesized that strenuous exercise would increase summation of late pain sensations in this cohort. Patients with FMS and control subjects exerted to similarly high metabolic rates, as shown by physiologic monitoring. Ratings of late pain sensations increased for patients with FMS after exercise, an effect opposite to a decrease in ratings for age/sex-matched control subjects. In contrast to this result for experimentally induced pain, clinical pain ratings were not substantially altered after strenuous exercise by patients with FMS.     

Analgesic effect of vibration and cooling on pain induced by intraneural electrical stimulation

Psychophysical experiments were carried out on 16 human subjects to determine how low intensity mechanical and thermal skin stimuli interfere with the sensation of pain. Moderate or intense pain was induced by low frequency (2 Hz) electrical stimulation within cutaneous fascicles of the median nerve at wrist level, and vibration, pressure, cooling or warming were applied for short periods (usually 20-60 sec) within or outside the skin area to which the pain was projected. Vibration within the area of projected pain reduced the sensation of pain more efficiently than vibration outside that area. Moderate pain was sometimes completely inhibited but intense pain was only moderately reduced. Pressure and cooling produced some pain relief whereas mild warming had an ambiguous effect. Since the painful input derived from stimulation of fibres in the nerve trunk, and not from peripheral nociceptors, the pain suppressing effects of vibration and cooling are not explicable in terms of lowered excitability of the nociceptive nerve endings in the skin. Instead, the results indicate that activity in low threshold mechanoreceptive and cold sensitive units suppresses pain at central (probably segmental) levels.     

Masseter inhibitory periods and sensations evoked by electrical tooth pulp stimulation

The masseter inhibitory period and sensations evoked by electrical tooth pulp stimulation were assessed in 30 human subjects. Five intensities of electrical stimuli, producing sensations varying from below sensory detection threshold to suprathreshold pain, were applied to upper central incisors. At each stimulus intensity a train of 30, 1-msec, cathodal pulses with an interpulse interval of 2 sec was applied. The averaged masseter activity evoked by the 30 pulses at a fixed stimulus intensity was compared to the quality of the sensation elicited.The threshold for the masseter inhibitory period coincided approximately with an individual's detection threshold for the tooth pulp stimulation. Three configurations of masseter inhibitory periods (single, double and merged) were produced by different stimulus intensities. However, no particular configuration was associated unequivocally with pain sensation. Increases in stimulus intensity evoked changes both in the configuration of the masseter inhibitory period and in the quality of the sensation produced. Chi square analyses showed significant, but progressively weaker, associations between: (1) masseter inhibitory period configuration and stimulus intensity; (2) quality of sensation and stimulus intensity; and (3) quality of sensation and masseter inhibitory period configuration. The weakness of the association between the quality of sensation and masseter inhibitory period configuration also was demonstrated in a double-blind study of the effects of a narcotic analgesic, fentanyl. Although the strengths of non-pain and pain sensations were reduced significantly after fentanyl, there were no changes in the masseter inhibitory periods.     

The efficacy of hypnosis- and relaxation-induced analgesia on two dimensions of pain for cold pressor and electrical tooth pulp stimulation

This study evaluated the efficacy of hypnosis- and relaxation-induced suggestions for analgesia for reducing the strength and unpleasantness dimensions of pain evoked by noxious tooth pulp stimulation and by cold pressor stimulation. The Tellegen Absorption Questionnaire was used to assess hypnotic susceptibility for 28 subjects in order to match treatment groups according to sex and susceptibility scores. Tooth pulp stimulation consisted of a 1 sec train of 1 msec pulses at a frequency of 100 Hz, applied at 20 sec intervals to the central incisor. Six stimuli, selected between subject's pain and tolerance thresholds, were presented 3 times each in random order. Cold pressor stimulation consisted of forearm immersion in a circulating water bath maintained at 0-1 degrees C. Subjects made threshold determinations of pain and tolerance and used Visual Analogue Scales to rate the strength and the unpleasantness of both noxious stimuli before and after receiving either hypnosis- or relaxation-induced analgesia. There were no significant differences in pain reductions between hypnosis- and relaxation-induced interventions. However, the percent reduction in both strength and unpleasantness varied significantly as a function of the type of pain. Both hypnosis and relaxation significantly reduced the strength and the unpleasantness of tooth pulp stimulation, but only the unpleasantness dimension of cold pressor pain. The pain reductions were not correlated with subjects' hypnotic susceptibility levels. The results indicate that the extent and the quality of the analgesia produced by these cognitive-based therapies vary not only according to subjects' characteristics and the efficacy of the intervention, but also according to the nature of the noxious stimuli. Tooth pulp and cold pressor stimulation represent qualitatively different stimuli with respect to both the type of nerves activated and the mode of stimulus application. Discrete, randomly presented levels of noxious electrical stimulation to the teeth activate predominantly small fibers and produce brief pain sensations that vary unpredictably in intensity. In contrast, continuous cold stimulation to the forearm activates a variety of nociceptive and non-nociceptive fibers and produces progressive cold and pain sensations with a predictable increase in intensity from cold sensations to paresthesia and severe pain.     

Vocalizations as measures of pain in monkeys

Because vocalizations have been utilized as measures of pain reactivity and are reduced in frequency by systemic morphine in rodents, vocalization patterns of monkeys were analyzed in detail to determine whether specific relationships to pain could be established. Vocalizations were recorded as monkeys performed on tasks that presented the opportunity either to acquire food reinforcement or escape electrical stimulation (ES) of one leg. Three of 5 monkeys vocalized during sessions on the escape task, and 2 of 3 monkeys vocalized while performing for food reinforcement. The amplitudes and durations of vocalizations did not vary significantly over bins of time within the intertrial intervals of 1 min, and these aspects of the monkeys' calls were not affected by the intensity of the electrocutaneous stimulation or by morphine. Although the frequency of vocalizations was greatest within a reactive period of 6-12 sec following onset of a trial, vocalization frequency was not uniquely related to the occurrence of painful stimulation. Rates of vocal calls in the reactive period were higher following presentation only of a tone (that had been paired with shock in previous sessions) than following electrocutaneous stimulation, and vocalization frequency was not directly related to the intensity of painful stimulation. Furthermore, the vocalization patterns were similar for monkeys performing aversive or appetitive responses. Finally, systemic morphine reduced the frequency of vocalizations overall, without evidence for a selective effect on vocal calls elicited by painful stimulation. This result suggests a direct effect of morphine on the neural circuitry subserving vocalizations. Spectrographs of vocalizations revealed that 2 monkeys emitted a 'broken scream' call that occurred most often as the first vocalization following strong electrocutaneous stimulation, and 0.25 mg/kg of morphine reduced the frequency with which strong shock elicited these vocalizations. Although broken screams appeared to represent vocalizations in response to aversion, they also occurred following presentation of a tone that had been paired with shock, and therefore they do not reliably indicate the presence of pain.     

Thermoreceptive innervation of human glabrous and hairy skin: a contact heat evoked potential analysis

The human palm has a lower heat detection threshold and a higher heat pain threshold than hairy skin. Neurophysiological studies of monkeys suggest that glabrous skin has fewer low threshold heat nociceptors (AMH type 2) than hairy skin. Accordingly, we used a temperature-controlled contact heat evoked potential (CHEP) stimulator to excite selectively heat receptors with C fibers or Adelta-innervated AMH type 2 receptors in humans. On the dorsal hand, 51 degrees C stimulation produced painful pinprick sensations and 41 degrees C stimuli evoked warmth. On the glabrous thenar, 41 degrees C stimulation produced mild warmth and 51 degrees C evoked strong but painless heat sensations. We used CHEP responses to estimate the conduction velocities (CV) of peripheral fibers mediating these sensations. On hairy skin, 41 degrees C stimuli evoked an ultra-late potential (mean, SD; N wave latency: 455 (118) ms) mediated by C fibers (CV by regression analysis: 1.28 m/s, N=15) whereas 51 degrees C stimuli evoked a late potential (N latency: 267 (33) ms) mediated by Adelta afferents (CV by within-subject analysis: 12.9 m/s, N=6). In contrast, thenar responses to 41 and 51 degrees C were mediated by C fibers (average N wave latencies 485 (100) and 433 (73) ms, respectively; CVs 0.95-1.35 m/s by regression analysis, N=15; average CV=1.7 (0.41) m/s calculated from distal glabrous and proximal hairy skin stimulation, N=6). The exploratory range of the human and monkey palm is enhanced by the abundance of low threshold, C-innervated heat receptors and the paucity of low threshold AMH type 2 heat nociceptors.     

Pain behavior in the formalin test persists after ablation of the great majority of C-fiber nociceptors

Although the formalin test is a widely used model of persistent pain, the primary afferent fiber types that underlie the cellular and behavioral responses to formalin injection are largely unknown. Here we used a combined genetic and pharmacological approach to investigate the effect of ablating subsets of primary afferent nociceptors on formalin-induced nocifensive behaviors and spinal cord Fos protein expression. Intrathecal capsaicin-induced ablation of the central terminals of TRPV1 + neurons greatly reduced the behavioral responses and Fos elicited by low-dose (0.5%) formalin. In contrast, genetic ablation of the MrgprD-expressing subset of non-peptidergic unmyelinated afferents, which constitute a largely non-overlapping population, altered neither the behavior nor the Fos induced by low-dose formalin. Remarkably, nocifensive behavior following high-dose (2%) formalin was unchanged in mice lacking either afferent population, or even in mice lacking both populations, which together make up the great majority of C-fiber nociceptors. Thus, at high doses, which are routinely used in the formalin test, formalin-induced “pain” behavior persists in the absence of the vast majority of C-fiber nociceptors, which points to a contribution of a large spectrum of afferents secondary to non-specific formalin-induced tissue and nerve damage.     

Periaqueductal grey stimulation: an association between selective inhibition of dorsal horn neurones and changes in peripheral circulation

In barbiturate-anaesthetized and paralysed cats, dorsal horn neurones were studied during electrical stimulation of the periaqueductal grey matter (PAG) and the midbrain ventral tegmentum (VT). Responses to impulses in unmyelinated primary afferents were selectively inhibited by stimulation in the PAG, whereas stimulation in the VT non-selectively reduced both these responses and those to innocuous cutaneous stimuli. Stimulation in the PAG but not the VT produced changes in peripheral circulation. This was observed as a rise in the levels of carbon dioxide in expired air, a rise in muscle temperature in the hind limb and a fall in skin temperature of the pinna or glabrous skin. The combination of suppression of spinal transmission of impulses related to pain and an increase in perfusion of muscles may be a mechanism appropriate to coping with a potentially injurious environment.     

Interaction of a combination of morphine and ketamine on the nociceptive flexion reflex in human volunteers

Experimental studies in animals have suggested that a combination of morphine and N-methyl-D-aspartate (NMDA) receptor antagonists may have additive or synergistic analgesic effects. To further study the nature of the interaction between these two classes of analgesic agents, we analyzed the effects of morphine, ketamine and their combination on electrophysiological recordings of the nociceptive flexion RIII reflex in 12 healthy volunteers. Morphine (0.1 mg/kg), ketamine (0.1 mg/kg followed by 4 microg/kg/min) or their combination were administered intravenously according to a double-blind, placebo controlled and cross-over design. The RIII reflex was recorded from the biceps femoris and elicited by electrical stimulation of the sural nerve. The effects of the drugs were tested on: (1) the stimulus-response curves of the reflex up to the tolerance threshold (frequency of stimulation: 0.1Hz); (2) the progressive increase of the reflex and painful sensations (i.e. wind-up phenomenon) induced by a series of 15 electrical stimuli at a frequency of 1Hz (intensity: 20% above threshold). The stimulus-response curve of the nociceptive RIII reflex was significantly reduced after injection of a combination of ketamine and morphine, but was not modified when placebo or each of the active drugs was administered alone. The wind-up of the RIII reflex and painful sensation was not significantly altered after the injection of placebo, ketamine, morphine or their combination. In conclusion, the present electrophysiological results in humans demonstrate a synergistic interaction between morphine and ketamine, which tends to confirm the interest of using this type of combination in the clinical context. The differential effects observed on the recruitment curve and wind-up indicate, however, that the mechanisms of the interaction between opiates and NMDA receptor antagonists are not univocal but depend on the modality of activation of the nociceptive afferents.     

Role of primary somatosensory cortex in the coding of pain

The intensity and submodality of pain are widely attributed to stimulus encoding by peripheral and subcortical spinal/trigeminal portions of the somatosensory nervous system. Consistent with this interpretation are studies of surgically anesthetized animals, demonstrating that relationships between nociceptive stimulation and activation of neurons are similar at subcortical levels of somatosensory projection and within the primary somatosensory cortex (in cytoarchitectural areas 3b and 1 of somatosensory cortex, SI). Such findings have led to characterizations of SI as a network that preserves, rather than transforms, the excitatory drive it receives from subcortical levels. Inconsistent with this perspective are images and neurophysiological recordings of SI neurons in lightly anesthetized primates. These studies demonstrate that an extreme anterior position within SI (area 3a) receives input originating predominantly from unmyelinated nociceptors, distinguishing it from posterior SI (areas 3b and 1), long recognized as receiving input predominantly from myelinated afferents, including nociceptors. Of particular importance, interactions between these subregions during maintained nociceptive stimulation are accompanied by an altered SI response to myelinated and unmyelinated nociceptors. A revised view of pain coding within SI cortex is discussed, and potentially significant clinical implications are emphasized.     

Trigeminal small-fibre function assessed with contact heat evoked potentials in humans

Contact heat stimuli have been reported to excite mechano-thermal nociceptors and to evoke brain potentials (CHEPs) from the limbs. We investigated whether contact heat evokes reproducible CHEPs from the trigeminal territory and may prove a reliable diagnostic tool in facial neuropathic pain. We applied contact heat stimuli to the perioral and supraorbital regions; CHEPs were recorded from the vertex in 20 controls and 2 patients with facial neuropathic pains, and reflex responses from the orbicularis oculi and masticatory muscles in 5 controls. We studied the correlation between CHEP data and perceptive ratings, site of stimulation, and age. Finally, we compared CHEPs with laser evoked potentials (LEPs). Contact heat stimuli at 51 degrees C evoked vertex potentials consisting of an NP complex similar to that elicited by laser pulses, though with a latency some 100-ms longer. Perioral stimulation yielded higher pain intensity ratings, shorter latency and larger amplitude CHEPs than supraorbital stimulation. CHEP data correlated significantly with age. Contact heat stimuli at 53 degrees C evoked a blink-like response in the relaxed orbicularis oculi muscle and a silent period in the contracted masseter muscle. In patients with facial neuropathic pain the CHEP abnormalities paralleled those seen with LEPs. We were unable to achieve reproducible signals related to C-receptor stimulation by contact heat stimuli at 41 degrees C in the ten subjects in whom they were tested. Contact heat stimulation, as well as laser stimulation, easily yields large-amplitude brain potentials and nociceptive reflexes, both related to the Adelta input. However CHEPs are not suitable for C-fibres potentials recording.     

Recombinant herpes vector-mediated analgesia in a primate model of hyperalgesia.

Some chronic pain syndromes are characterized by episodes of intense burning and hyperalgesia in localized areas of skin. These sensations are thought to be mediated, at least in part, by the activity of damaged, unmyelinated C nociceptors. These phenomena were modeled by assaying responses of macaques to thermal and chemical stimuli that produced periodic activation and sensitization of C nociceptors. Upon validation of this method, a recombinant herpes simplex vector encoding human preproenkephalin was topically applied to the dorsal surface of the feet of the monkeys. Immunohistochemistry and radioimmunoassay revealed that enkephalin peptides were being produced in releasable pools in sensory neurons innervating the treated skin area. Behavioral responses evoked by periodic sensitization and activation of C nociceptors innervating the vector-treated skin area revealed a substantial and long-lasting (at least 20 weeks) antihyperalgesic and analgesic effect limited to the areas to which the virus was applied. This approach may be a viable means of treating localized cutaneous burning pain and hyperalgesia.     

Peripheral suppression of first pain and central summation of second pain evoked by noxious heat pulses

Psychophysical experiments were carried out on 6 human subjects to determine how first and second pain are influenced by peripheral receptor mechanisms and by central nervous system inhibitory and facilitatory mechanisms. For these experiments, brief natural painful stimuli delivered to the hand were a train of 4–8 constant waveform heat pulses generated by a contact thermode (peak temp. = 51.5°C). The magnitude of first and second pain sensations was estimated using cross-modality matching procedures and reaction times were determined. The latter confirmed the relationship between first and second pain and impulse conduction in Aδ and C noxious heat afferents, respectively. The intensity of first pain decreased with each successive heat pulse when the interpulse interval was 80 sec or less. This decrease was most likely the result of heat induced suppression of Aδ heat nociceptors since it did not occur if the probe location changed between successive heat pulses. In contrast, second pain increased in intensity with each successive heat pulse if the interval was 3 sec or less. This summation was most likely due to central nervous system summation mechanisms since it also occurred after blockage of first pain by ulnar nerve compression and when the location of the thermode changed between heat pulses. These observations and their interpretations are supported by our recording of responses of single Aδ heat nociceptive afferents, C polymodal nociceptive afferents, and “warm” afferents of rhesus monkeys to similar trains of noxious heat pulses. Their responses to these heat pulses show a progressive suppression. Furthermore, previous studies have shown that wide dynamic range dorsal horn neurons show summated responses to repeated volleys in C fibers ( ). These spinal cord summation mechanisms could account for the summation of second pain.     

Reappraisal of a proposed neurophysiological mechanism for the relief of joint pain with passive joint movements

Selective stimulation of large diameter joint neural units is a neurophysiological mechanism advanced for the diminished perception of pain obtained with therapeutic methods of passive movement of painful joints. Evidence from electrophysiological studies of normal joints of animals, indicates that passive movements are unlikely to selectively excite a significant proportion of large diameter joint afferents. Within range passive movements of inflamed joints are likely to stimulate predominantly small fibre joint nociceptors. In these respects, this method of peripheral nerve stimulation would be theoretically inappropriate for ‘closing the spinal gate’ to joint pain.     

Counterstimulation and pain perception: effects of electrocutaneous vs. auditory stimulation upon cold pressor pain

This study tested the hypothesis that distraction from a painful stimulus is best achieved by concurrent presentation of a similar stimulus. Specifically, it was hypothesized that pain perception would be interfered with, and thus reduced, when a stimulus similar to the sensory features of a painful stimulus was delivered concurrently. Subjects matched aversiveness thresholds for electrocutaneous or auditory stimulation so that both forms of stimulation could be judged to be subjectively of similar affective value. Subjects were then run in the cold pressor test for 2 min. While control subjects for each modality were not administered counterstimulation concurrently with cold pressor exposure, experimental subjects within each modality condition received concurrent counterstimulation. Magnitude estimation ratings of the aversiveness of counterstimulation were provided concurrently with cold pressor pain ratings, every 30 sec. The results indicated that, as predicted, subjects exposed to concurrent electrical stimulation produced lower pain ratings than subjects exposed to auditory stimulation and controls. In addition, a mutual interference effect between the cold pressor and the tactile counterstimulation was found: subjects also rated electrical stimulation as a less aversive than auditory stimulation over the duration of the cold pressor test.     

Altered C-tactile processing in human dynamic tactile allodynia

Human unmyelinated (C) tactile afferents signal the pleasantness of gentle skin stroking on hairy (nonglabrous) skin. After neuronal injury, that same type of touch can elicit unpleasant sensations: tactile allodynia. The prevailing pathophysiological explanation is a spinal cord sensitization, triggered by nerve injury, which enables Aβ afferents to access pain pathways. However, a recent mouse knockout study demonstrates that C-tactile afferents are necessary for allodynia to develop, suggesting a role for not only Aβ but also C-tactile afferent signaling. To examine the contribution of C-tactile afferents to the allodynic condition in humans, we applied the heat/capsaicin model of tactile allodynia in 43 healthy subjects and in 2 sensory neuronopathy patients lacking Aβ afferents. Healthy subjects reported tactile-evoked pain, whereas the patients did not. Instead, patients reported their C-touch percept (faint sensation of pleasant touch) to be significantly weaker in the allodynic zone compared to untreated skin. Functional magnetic resonance imaging in 18 healthy subjects and in 1 scanned patient indicated that stroking in the allodynic and control zones evoked different responses in the primary cortical receiving area for thin fiber signaling, the posterior insular cortex. In addition, reduced activation in the medial prefrontal cortices, key areas for C-tactile hedonic processing, was identified. These findings suggest that dynamic tactile allodynia is associated with reduced C-tactile mediated hedonic touch processing. Nevertheless, because the patients did not develop allodynic pain, this seems dependent on Aβ signaling, at least under these experimental conditions.     

Modulation of jaw muscle spindle afferent activity following intramuscular injections with hypertonic saline

Transient noxious chemical stimulation of small diameter muscle afferents modulates jaw movement-related responses of caudal brainstem neurons. While it is likely that the effect is mediated from the spindle afferents in the mesencephalic nucleus (Vmes) via the caudally projecting Probst's tract, the mechanisms of pain induced modulations of jaw muscle spindle afferents is not known. In the present study, we tested the hypothesis that jaw muscle nociceptors gain access to muscle spindle afferents in the same muscle via central mechanisms and alter their sensitivity. Thirty-five neurons recorded from the Vmes were characterized as muscle spindle afferents based on their responses to passive jaw movements, muscle palpation, and electrical stimulation of the masseter nerve. Each cell was tested by injecting a small volume (250 microl) of either 5% hypertonic and/or isotonic saline into the receptor-bearing muscle. Twenty-nine units were tested with 5% hypertonic saline, of which 79% (23/29) showed significant modulation of mean firing rates (MFRs) during one or more phases of ramp-and-hold movements. Among the muscle spindle primary-like units (n = 12), MFRs of 4 units were facilitated, five reduced, two showed mixed responses and one unchanged. In secondary-like units (n = 17), MFRs of 9 were facilitated, three reduced and five unchanged. Thirteen units were tested with isotonic saline, of which 77% showed no significant changes of MFRs. Further analysis revealed that the hypertonic saline not only affected the overall output of muscle spindle afferents, but also increased the variability of firing and altered the relationship between afferent signal and muscle length. These results demonstrated that activation of muscle nociceptors significantly affects proprioceptive properties of jaw muscle spindles via central neural mechanisms. The changes can have deleterious effects on oral motor function as well as kinesthetic sensibility.     

Nerve growth factor induces sensitization of nociceptors without evidence for increased intraepidermal nerve fiber density

Nerve growth factor (NGF) is involved in the long-term sensitization of nociceptive processing linked to chronic pain. Functional and structural (“sprouting”) changes can contribute. Thus, humans report long-lasting hyperalgesia to mechanical and electrical stimulation after intradermal NGF injection and NGF-induced sprouting has been reported to underlie cancer bone pain and visceral pain. Using a human-like animal model we investigated the relationship between the structure and function of unmyelinated porcine nociceptors 3 weeks after intradermal NGF treatment. Axonal and sensory characteristics were studied by in vivo single-fiber electrophysiology and immunohistochemistry. C fibers recorded extracellularly were classified based on mechanical response and activity-dependent slowing (ADS) of conduction velocity. Intraepidermal nerve fiber (IENF) densities were assessed by immunohistochemistry in pigs and in human volunteers using the same NGF model. NGF increased conduction velocity and reduced ADS and propagation failure in mechano-insensitive nociceptors. The proportion of mechano-sensitive C nociceptors within NGF-treated skin areas increased from 45.1% (control) to 71% and their median mechanical thresholds decreased from 40 to 20 mN. After NGF application, the mechanical receptive fields of nociceptors increased from 25 to 43 mm². At the structural level, however, IENF density was not increased by NGF. In conclusion, intradermal NGF induces long-lasting axonal and mechanical sensitization in porcine C nociceptors that corresponds to hyperalgesia observed in humans. Sensitization is not accompanied by increased IENF density, suggesting that NGF-induced hyperalgesia might not depend on changes in nerve fiber density but could be linked to the recruitment of previously silent nociceptors.     

Receptive properties of pial afferents

The blood vessels and the pial surface of the brain, spinal cord and its roots are innervated by primary afferent neurones. Here, we have electrophysiologically characterized the functional properties of a subpopulation of these afferent fibres that supply the ventral roots of the cat sacral spinal cord. We have taken advantage of the unique anatomical arrangement of these primary afferent neurones which have their central axon in the dorsal root and project with their peripheral process into the segmental ventral root. In 10 experiments, 14 units were recorded in the dorsal root S2 which responded to electrical stimulation of the segmental ventral root. As judged by their conduction velocity ranging from 0.1 to 2.3 m/sec, all fibres were unmyelinated. In 4 cases a spot-like receptive field was located on the root where the units were reproducibly activated by mechanical stimuli, the most effective being a slight stretch. In two units tested, topical application of hypertonic saline onto the receptive field, but not at other portions of the axon elicited a long-lasting vigorous discharge with intermittent bursts. There was no obvious association of the receptive field with small blood vessels. In 5 of the 14 units including 2 with a mechanosensitive receptive field we observed latency jumps of the action potential with electrical stimulation of the ventral root close to the dorsal root ganglion. In some of these units latency jumps were also observed at other positions when the stimulation electrodes were moved centrally towards the spinal cord. We conclude that a subpopulation of unmyelinated fibres in the spinal ventral root are primary afferents innervating the root proper or its sheath.(ABSTRACT TRUNCATED AT 250 WORDS)