Delayed responses to electrical stimuli reflect C-fiber responsiveness in human microneurography

The slowing of impulse conduction during the relative refractory period has often been used to assess activation of C-fibers, in particular, in human microneurography. This study aimed to evaluate the sensitivity of this method and the factors affecting it. Thirty cutaneous C-fibers were recorded from the peroneal nerves of healthy human subjects. Intracutaneous electrical stimulation in the receptive field at 4 s intervals, after some minutes of adaptation, induced spike discharges at constant latency. One or more conditioning stimulus pulses were interpolated at different intervals and the increase in latency after the subsequent regular pulse was assessed. The latency shift was found to depend on the number of interposed pulses, on the time interval between conditioning and conditioned stimulus, and on the conduction velocity of the C-unit. The increase in latency was larger with greater distance between stimulating and recording electrodes, indicating a contribution of the conductile membrane over its whole length. On the other hand, slowing was more pronounced, on average, in slower conducting C-units and conduction velocities were slower when recordings were performed more distally. These findings indicate that the slower terminal nerve branches contribute most to the latency increases. Even a single additional spike in between two regular pulses caused a reliable latency shift of 1.2±0.2 ms (mean ±SEM) and additional pulses lead to an approximately linear latency increase (2 pulses: 2.3±0.3 ms; 4 pulses: 5.9±0.7 ms). In contrast to the number of interposed stimuli, different intervals between interposed and regular stimuli had only a minor impact on the latency shifts. It is concluded that latency shifts are reliable indicators of C-fiber activation, being sensitive enough to detect even single spike responses. Furthermore, latency increases may be used as a relative measure of C-fiber activation, e.g., when comparing responses to stimuli of different strength.     

Different mechanical transduction mechanisms for the immediate and delayed responses of rat C-fiber nociceptors.

1. In this electrophysiological study, action potentials from single C-fibers were recorded in fine filaments teased from the rat saphenous nerve. We evaluated the effect of pharmacological agents on the responses of C-fiber mechanoheat nociceptors (C-MH; n = 53) after sustained suprathreshold and subthreshold stimuli. 2. Sustained suprathreshold mechanical stimuli elicit an immediate burst of activity that quickly adapts to a low-level firing that is maintained during the stimulus. Sustained subthreshold stimuli activate C-MHs after a delay and elicit a constant, low-level firing. 3. Gentamicin, a known suppressor of mechanosensory cell activity, blocked the initial rapid burst response to suprathreshold stimuli (n = 11) but had no effect on the adaptive low-level firing. The latency of the delayed activation of C-MHs induced by sustained subthreshold stimuli was not affected by gentamicin. 4. Sphingosine, a protein kinase inhibitor, increased the latency of the delayed activation of C-MHs (n = 7) to sustained subthreshold stimuli; phorbol 12-myristate 13-acetate (TPA), a protein kinase C activator, decreased the latency of the delayed activation of C-MHs (n = 9); and 4 alpha-phorbol, an inactive isomer of TPA, had no effect on the latency of the delayed activation (n = 7). Sphingosine, TPA, and 4 alpha-phorbol had no affect on the initial burst response induced by suprathreshold stimuli. 5. K+ channel blockers, 4-aminopyridine (n = 9) and noxiustoxin (n = 5), decreased the latency of the delayed activation of C-MHs to sustained subthreshold stimuli but had no effect on the initial burst response of C-MHs to suprathreshold stimuli.(ABSTRACT TRUNCATED AT 250 WORDS)     

Hyper-responsivity in a subset of C-fiber nociceptors in a model of painful diabetic neuropathy in the rat

While clinical characteristics of diabetic painful neuropathy are well described, the underlying electrophysiological basis of the exaggerated painful response to stimuli, as well as the presence of spontaneous pain, are poorly understood. In order to elucidate peripheral contributions to painful diabetic neuropathy, we quantitatively evaluated the function of C-fibers in a rat model of painful diabetic neuropathy, diabetes induced by the pancreatic beta-cell toxin streptozotocin. While there was no significant effect of diabetes on conduction velocity, mechanical threshold or spontaneous activity, the number of action potentials in response to sustained threshold and suprathreshold mechanical stimuli was significantly increased in the diabetic rats. Moreover, there was a clustering of responses of C-fibers in diabetic rats; while two-thirds of C-fibers fired at the same mean frequency as C-fibers in control rats, one-third of C-fibers in diabetic rats were markedly hyper-responsive, demonstrating a threefold increase in firing frequency. The high-firing-frequency C-fibers in rats with diabetes also had faster conduction velocity than the low-firing-frequency C-fibers in rats with diabetes or in C-fibers in control rats. The hyper-responsiveness was characterized by a selective increase of the shortest interspike intervals (<100ms) in the burst component (first 10s) of the response to a sustained suprathreshold stimulus; in the plateau phase (last 50s) of the response to a 60-s suprathreshold stimulus, we found a selective increase of interspike intervals between 100 and 300ms in hyper-responsive C-fibers in rats with diabetes. The hyper-responsiveness did not correlate with mechanical threshold, presence of spontaneous activity or location of the fiber's receptive field. In summary, in an established model of painful diabetic neuropathy in the rat, a subset of C-fibers demonstrated a marked hyper-responsiveness to mechanical stimuli. The subset was also found to have a greater mean conduction velocity than the fibers not demonstrating this hyper-responsivity. The present findings suggest that study of individual neurons in vitro may allow elucidation of the ionic basis of enhanced nociception in diabetic neuropathy.     

Peripheral coding of tonic mechanical cutaneous pain: comparison of nociceptor activity in rat and human psychophysics

These experiments investigated temporal summation mechanisms of tonic cutaneous mechanical pain. Human volunteers provided psychophysical estimates of pain intensity, which were compared with discharge patterns of rat cutaneous nociceptors tested with identical stimulus protocols. Human subjects made either intermittent or continuous ratings of pain intensity during stimulation of the skin between the thumb and first finger. Stimulus intensities of 25, 50, and 100 g were applied with a probe of contact area of 0.1 mm(2) for 2 min. Pain perception significantly increased during stimulation (temporal summation) for the 50- and 100-g stimulus intensities. Sequential conduction block of the myelinated fibers supplying the stimulated skin was used to investigate the role of A-fiber mechanoreceptors and nociceptors in this temporal summation. Conduction block of the Abeta fibers resulted in an increase in mechanically evoked pain estimates and an increase in temporal summation, consistent with loss of Abeta-mediated inhibition. When only conduction in the unmyelinated fibers remained, pain estimates were reduced to the preblock levels, but temporal summation was still present. Electrophysiological recordings were made from filaments of the sciatic nerve supplying receptors in the plantar skin of barbiturate-anesthetized rats. Forty units fulfilled the identification criteria for nociceptors: 20 A-fiber and 20 C-fiber nociceptors. Each unit was characterized by recording its responses to graded mechanical and heat stimuli. Nociceptors were also tested with stimuli identical to those applied to the human subjects. The responses of all units to sustained mechanical stimuli were adaptive-that is, they exhibited a gradual decline in response with time. However, the time course of adaptation varied among units. All the C-fiber nociceptors and one-half of the A-fiber nociceptors had rapidly adapting responses. The remainder of the A-fibers displayed slowly adapting responses. One-third of all units also showed short-duration increases in firing rate during stimulation. The latency after stimulus onset of this rate acceleration was inversely related to stimulus intensity. Despite the apparent disparity between perceptual temporal summation and nociceptor adaptation, central and peripheral mechanisms are proposed that can reconcile the relationship between nociceptor activity and pain perception.     

Response of cutaneous A- and C-fiber nociceptors in the monkey to controlled-force stimuli

The goal of this study was to determine the capacity of primary afferent nociceptive fibers (nociceptors) to encode information about noxious mechanical stimuli in primates. Teased-fiber techniques were used to record from 14 A-fiber nociceptors and 18 C-fiber nociceptors that innervated the hairy skin. Stimulus-response functions were examined with an ascending series of force-controlled stimuli. Stimulus-interaction effects were examined with use of a series of paired stimuli in which the interval between the stimulus pairs was varied systematically. Both A-fiber and C-fiber nociceptors exhibited a slowly adapting response to the stepped force stimuli. The response of the A fibers increased monotonically with increasing force, whereas the response of the C fibers reached a plateau at low force levels. The slope of the stimulus-response function for the A fibers was significantly steeper than that for the C fibers, and the total response was greater. The A fibers also provided more discriminative information regarding stimulus intensity. The C fibers demonstrated a significant fatigue in response when the interstimulus interval between the paired stimuli was 相似文献   

The spinal projection of individual identified A-delta- and C-fibers

1. Recordings were made from individual sensory neurons with an A-delta peripheral conduction velocity, either intrasomally in the L7 dorsal root ganglion, or extracellularly in Lissauer's Tract or in the dorsal root close to the root entry zone. The spinal projection of these afferents was assessed by their antidromic response to stimulation of the dorsal columns (DC) or Lissauer's Tract (LT) at the L5/L6 border. The adequate stimulus was also ascertained. 2. A-delta-fibers could be divided into two groups: high-threshold mechanoreceptors from either skin or muscle (HTMRs) and low-threshold mechanoreceptors (LTMs), primarily Down Hairs. A third group of cells recorded intrasomally had broad spikes with shoulders on the downstroke characteristic of A-delta-nociceptors and were so classified provisionally, although no adequate stimulus could be identified. HTMRs and broad spike cells projected either in DC or LT, but LTMs projected only in DC, never in LT. About one-quarter of both groups failed to project rostrally as far as L5/L6. 3. Cells with unmyelinated axons recorded intrasomally were found to supply either low-threshold or high-threshold mechanoreceptors. Unlike A-delta-cells, all these cells had broad spikes with shoulders on the downstroke. Proportionally fewer C-fibers than A-delta-fibers projected as far as one segment rostral from their root entry zone. Of those that did, axons supplying low-threshold mechanoreceptors projected only in DC, whereas those innervating high-threshold mechanoreceptors could project either through LT or DC. 4. A-delta-fibers supplying LTMs and HTMRs exhibited a similar reduced conduction velocity was reduced even further in the spinal cord but much more for HTMRs than for LTMs. For C-fibers the conduction velocity decrease was more substantial in the dorsal root for HTMRs than for LTMs. 5. These findings suggest that axons innervating different peripheral receptors exhibit characteristic cellular properties. They confirm that the primary afferent component of Lissauer's Tract is specialized as a "pain pathway" but also indicate that the dorsal columns may play some role in the transmission of nociceptive information.     

Modulation of heat evoked nociceptive withdrawal reflexes by painful intramuscular conditioning stimulation

Convergence between cutaneous heat nociceptors and muscles afferents was investigated by applying a phasic, conditioning electrical stimulus to the tibialis anterior muscle (a train of five 1 ms pulses over 21 ms) at varying time intervals relative to a thermal test stimulus used for evoking the withdrawal reflex in humans. The 200 ms thermal stimulus was applied on the dorsum of the foot at an intensity of two times the pain threshold. The conditioning electrical stimulus was applied at an intensity of two times the pain threshold via a set of intramuscular needle electrodes. The conditioning-test interval was varied between –400 ms and 8,000 ms at 17 different intervals. The mean reflex onset latency of reflexes evoked by thermal stimuli alone was 354 ± 9 ms. A facilitation of the reflex was seen when the conditioning stimulus was applied 275 ms (174 ± 30% compared to control) and 300 ms (162 ± 32% compared to control) after the test stimulus onset indicating sensory convergence between muscle afferents (group I–III) and cutaneous Aδ heat nociceptors arriving simultaneously at the spinal cord.     

Characterization of Adelta- and C-fibers innervating the plantar rat hindpaw one day after an incision

Primary hyperalgesia after tissue injury is suggested to result from sensitization of primary afferent fibers, but sensitization to mechanical stimuli has been difficult to demonstrate. In the companion study, sensitization of mechano-responsive Adelta- and C-fibers did not explain pain behaviors 45 min after an incision in the rat hindpaw. In the present study, we examined mechanical response properties of Adelta- and C-fibers innervating the glabrous skin of the plantar hindpaw in rats 1 day after an incision or sham procedure. In behavioral experiments, median withdrawal thresholds to von Frey filaments were reduced from 522 mN before to 61 mN 2 and 20 h after incision; median withdrawal thresholds after sham procedure were stable (522 mN). Responses to a nonpunctate mechanical stimulus were increased after incision. In neurophysiological experiments in these same rats, 67 single afferent fibers were characterized from the left tibial nerve 1 day after sham procedure (n = 39) or incision (n = 28); electrical stimulation was used as the search stimulus to identify a representative population of Adelta- and C-fibers. In the incision group, 11 fibers (39%) had spontaneous activity with frequencies ranging from 0.03 to 39.3 imp/s; none were present in the sham group. The median response threshold of Adelta-fibers was less in the incision (56 mN, n = 13) compared with sham (251 mN, n = 26) group, mainly because the proportion of mechanically insensitive afferents (MIAs) was less (8 vs. 54% after sham procedure). Median C-fiber response thresholds were similar in incised (28 mN, n = 15) and sham rats (56 mN, n = 13). Responsiveness to monofilaments was significantly enhanced in Adelta-fibers 1 day after incision; stimulus response functions of C-fibers after incision and after sham procedure did not differ significantly. Only Adelta-fibers but not C-fibers sensitized to the nonpunctate mechanical stimulus. The size of receptive fields was increased in Adelta- and C-fibers 1 day after incision. The results indicate that sensitization of Adelta- and C-fibers is apparent 1 day after incision. Because sensitization of afferent fibers to mechanical stimuli correlated with behavioral results, sensitization may contribute to the reduced withdrawal threshold after incision. Spontaneous activity in Adelta- and C-fibers may account for nonevoked pain behavior and may also contribute to mechanical hyperalgesia by amplifying responses centrally.     

Evidence of a specific spinal pathway for the sense of warmth in humans

While research on human sensory processing shows that warm input is conveyed from the periphery by specific, unmyelinated primary sensory neurons, its pathways in the central nervous system (CNS) remain unclear. To gain physiological information on the spinal pathways that convey warmth or nociceptive sensations, in 15 healthy subjects, we studied the cerebral evoked responses and reaction times in response to laser stimuli selectively exciting Adelta nociceptors or C warmth receptors at different levels along the spine. To minimize the conduction distance along the primary sensory neuron, we directed CO(2)-laser pulses to the skin overlying the vertebral spinous processes. Using brain source analysis of the evoked responses with high-resolution electroencephalography and a realistic model of the head based on individual magnetic resonance imaging scans, we also studied the cortical areas involved in the cerebral processing of warm and nociceptive inputs. The activation of C warmth receptors evoked cerebral potentials with a main positive component peaking at 470-540 ms, i.e., a latency clearly longer than that of the corresponding wave yielded by Adelta nociceptive input (290-320 ms). Spinal neurons activated by the warm input had a slower conduction velocity (2.5 m/s) than the nociceptive spinal neurons (11.9 m/s). Brain source analysis of the cerebral responses evoked by the Adelta input yielded a very strong fit for one single generator in the mid portion of the cingulate gyrus; the warmth-related responses were best explained by three generators, one within the cingulate and two in the right and left opercular-insular cortices. Our results support the existence of slow-conducting second-order neurons specific for the sense of warmth.     

Altered temporal pattern of evoked afferent activity in a rat model of vincristine-induced painful peripheral neuropathy

It is known that the level of activity in nociceptive primary afferent nerve fibers increases in neuropathic conditions that produce pain, but changes in the temporal patterning of action potentials have not been analyzed in any detail. Because the patterning of action potentials in sensory nerve fibers might play a role in the development of pathological pain states, we studied patterning of mechanical stimulus-evoked action potential trains in nociceptive primary afferents in a rat model of vincristine-induced painful peripheral neuropathy. Systemic administration of vincristine (100 microg/kg) caused approximately half the C-fiber nociceptors to become markedly hyperresponsive to mechanical stimulation. Instantaneous frequency plots showed that vincristine induced an irregular pattern of action-potential firing in hyperresponsive C-fibers, characterized by interspersed occurrences of high- and low-frequency firing. This pattern was associated with an increase in the percentage of interspike intervals 100-199 ms in duration compared with that in C-fibers from control rats and vincristine-treated C-fibers that did not become hyperresponsive. Variability in the temporal pattern of action potential firing was quantified by determining the coefficient of variability (CV2) for adjacent interspike intervals. This analysis revealed that vincristine altered the pattern of action-potential timing, so that combinations of higher firing frequency and higher variability occurred that were not observed in control fibers.The abnormal temporal structure of nociceptor responses induced by vincristine in some C-fiber nociceptors could contribute to the pathogenesis of chemotherapy-induced neuropathic pain, perhaps by inducing activity-dependent post-synaptic effects in sensory pathways.     

Effects of odor stimulation on antidromic spikes in olfactory sensory neurons

Spikes were evoked in rat olfactory sensory neuron (OSN) populations by electrical stimulation of the olfactory bulb nerve layer in pentobarbital anesthetized rats. The latencies and recording positions for these compound spikes showed that they originated in olfactory epithelium. Dual simultaneous recordings indicated conduction velocities in the C-fiber range, around 0.5 m/s. These spikes are concluded to arise from antidromically activated olfactory sensory neurons. Electrical stimulation at 5 Hz was used to track changes in the size and latency of the antidromic compound population spike during the odor response. Strong odorant stimuli suppressed the spike size and prolonged its latency. The latency was prolonged throughout long odor stimuli, indicating continued activation of olfactory receptor neuron axons. The amounts of spike suppression and latency change were strongly correlated with the electroolfactogram (EOG) peak size evoked at the same site across odorants and across stimulus intensities. We conclude that the curve of antidromic spike suppression gives a reasonable representation of spiking activity in olfactory sensory neurons driven by odorants and that the correlation of peak spike suppression with the peak EOG shows the accuracy of the EOG as an estimate of intracellular potential in the population of olfactory sensory neurons. In addition, these results have important implications about traffic in olfactory nerve bundles. We did not observe multiple peaks corresponding to stimulated and unstimulated receptor neurons. This suggests synchronization of spikes in olfactory nerve, perhaps by ephaptic interactions. The long-lasting effect on spike latency shows that action potentials continue in the nerve throughout the duration of an odor stimulus in spite of many reports of depolarization block in olfactory receptor neuron cell bodies. Finally, strong odor stimulation caused almost complete block of antidromic spikes. This indicates that a very large proportion of olfactory axons was activated by single strong odor stimuli.     

Sensory receptors with unmyelinated (C) fibers innervating the skin of the rabbit's ear

The cutaneous receptive properties of unmyelinated (C) fibers of the rabbit's great auricular nerve were determined by single-unit recordings. The majority of C-fiber units could be excited by cutaneous stimulation, and such sensory units fell into three major categories on the basis of responses to mechanical and thermal stimulation of their cutaneous receptive fields: low-threshold mechanoreceptors, nociceptors, or specific thermoreceptors. The majority of afferent elements were nociceptive, and all nociceptors responded to strong mechanical stimulation. Three types of nociceptors could be distinguished by their responses to thermal stimuli. Polymodal nociceptors responded to heat with thresholds of 40-55 degrees C and typically displayed enhanced responses or sensitization after noxious heating of their receptive fields. High-threshold mechanoreceptors failed to respond promptly to heat before noxious cutaneous stimulation which, however, elicited subsequent back-ground activity or sensitivity to heat. A third type of nociceptor responded to cold but not to heat. Low-threshold mechanoreceptors were identified by their brisk responses to very gentle, slowly moving mechanical stimulation of their receptive fields, and were readily distinguished from any element classified as nociceptive by their lower mechanical thresholds. Rapid innocuous warming or cooling excited some of the low-threshold mechanoreceptors. Specific thermoreceptors, both warming and cooling types, were rare, insensitive to mechanical stimulation, and responded to very slight changes in temperature. In contrast to the sensitization to heat, which was characteristic of most nociceptors, specific warming receptors displayed depressed thermal responses after noxious heating of their receptive fields. These results provide further evidence of the similarity of C-fiber receptors innervating hairy skin of different species. Some differences from past reports and additional features are described.     

Monkey superior colliculus: properties of single cells and their afferent inputs.

1. Receptive-field (RF) properties of 212 single cells in the superior colliculus of paralyzed macaque monkeys were studied with microelectrodes. Units were divided into superficial (0-1 mm) and deep (1-2.5 mm) layers. Orthodromic action potentials were evoked in these cells by shocking optic chiasm. 2. The vast majority of superficial cells responded to stationary or moving stimuli with transient bursts of activity and were nondirectionally selective. Moving stimuli were most effective and three main cell groups, based on response patterns to leading and trailing stimulus edges, were identified. 3. All cells had chromatically nomopponent RFs, as judged by their spectral response functions in the presence of neutral and chromatic backgrounds and on their lack of response to moving, equal-luminance chromatic borders. 4. With the exception of some very short and very long values, orthodromic latencies were unimodally distributed with a mean of 7.8 ms. The prime determinant of a cell's latency was its depth below the collicular surface rather than a specific RF feature. 5. Cells with shorter latencies (located in superficial layers) were able to reliably signal high-velocity stimulus movement; those with longer latencies (located in deeper layers) reliably signaled low-velocity motion only. 6. Results support the hypothesis that response latency is related to differences in RF organization between layers.     

Characteristics of the pupillary light reflex in the macaque monkey: metrics

To investigate whether the simian light reflex is a reasonable model for the human light reflex, we elicited pupillary responses in three behaving rhesus macaques. We measured the change in pupillary area in response to brief (100 ms), intermediate (1 s), and long (3-5 s) light flashes delivered by light-emitting diodes while the monkey fixated a stationary target. Individual responses in the same monkey to either 100-ms or 1-s stimuli of the same light intensity were quite variable. Nevertheless, in response to the 100-ms stimulus, average pupillary constriction and peak constriction velocity increased and latency decreased linearly with the log of stimulus luminance. The minimum average constriction latency across monkeys for the brightest flash was 136 ms. A linear decrease of constriction latency with stimulus luminance also occurs in humans, but their latencies are approximately 70 ms longer. In addition, peak constriction velocity was highly correlated with the decrease in pupillary area. Dilation metrics were not as well related to stimulus luminance as were constriction metrics. The latency from flash offset to the onset of dilation was relatively constant, averaging approximately 480 ms. Peak dilation velocity was also correlated, but less well, with the increase in pupillary area. Constriction generally was greater and of longer duration for 1-s light pulses than for 100-ms pulses of equal luminance. The initial time courses of the responses to the two stimuli of different durations were identical until approximately 150 ms after response onset. Human pupillary responses for long and short flashes also have identical initial time courses. For very long (3-5 s) and very bright constant-luminance stimuli, the simian pupil underwent oscillations at frequencies of 0.9-1.6 Hz. Similar oscillations, called hippus, occur in the human pupillary light reflex. Like humans, the monkeys also exhibited consensual and binocular pupillary responses. Except for response latency, the pupillary responses in the two primate species are otherwise quite similar. Therefore any knowledge we gain about the neuronal substrate of the simian light reflex can be expected to have considerable relevance when extrapolated to humans.     

Microneurographic single-unit recordings to assess receptive properties of afferent human C-fibers

Action potentials in unmyelinated peripheral axons can be recorded in awake humans by microneurography with small electrodes placed in a peripheral nerve. This technique provides extracellular recordings of single C-fibers and thus enables characterization of their sensory and axonal properties. By using microneurographical basic properties of afferent C-fibers such as conduction velocities, innervation territories, sensory thresholds and chemical responsiveness were measured. Moreover, axonal excitability changes induced by repetitive activation were assessed. Sensory and axonal properties of the different fiber classes cluster. Based on those specific properties, unitary functional classes of nociceptors (such as polymodal nociceptors and mechano-insensitive nociceptors) and non-nociceptors (such as tactile afferents and warm fibers) were classified. With normal data available, sensitization and desensitization of afferent fibers have been found in pathophysiologic states as detected in chronic pain patients. As subjects and patients are awake during the recording, microneurography provides a unique tool to correlate the discharge behaviour of afferent nerve fibers with the sensation evoked by certain stimuli.     

On- versus off-responses of raccoon glabrous skin rapidly adapting cutaneous mechanoreceptors

1. The on- and off-responses of 50 raccoon median nerve fibers associated with rapidly adapting cutaneous mechanoreceptors in glabrous skin were examined under experimental conditions designed to allow comparable opportunities for on- and off-responses to occur. Trapezoidal stimuli were utilized, providing for equal stimulus indentation and retraction velocities and equal static displacement times and intertrial intervals. Principal findings were as follows: 2. At stimulus levels well above displacement and velocity thresholds for on-responses, 80% of units yielded a more vigorous on-response than off-response (as measured by the total number of ramp impulses); in 6%, the reverse was true; while in the remaining 14%, the off-discharge was absent. 3. On and off displacement thresholds were approximately equal (on median, 43 micron; off median, 42 micron). However, on velocity thresholds were significantly lower than off velocity thresholds (on median, 1.0 micron/ms; off median, 3.8 micron/ms). 4. Exponents (b) of power functions relating discharge rate to ramp velocity (frequency = a x velocityb) were consistently greater for on-responses than for off-responses, but intercept constants (a) were consistently greater for off-responses than for on-responses. 5. Previous findings that mammalian rapidly adapting (RA) mechanoreceptors possess a "linear directionality" generally favoring on-responses were confirmed. 6. Results are discussed in relation to the role of viscoelastic properties of RA mechanoreceptors and neighboring skin. It is suggested that, when considerations is also given to the mechanical properties of surrounding tissues, the Loewenstein and Skalak (18) analysis of the mode of operation of Pacinian corpuscles might also apply, at least qualitatively, to the simple dermal (rapidly adapting) corpuscle of raccoon glabrous skin.     

Increased responsiveness of sensory neurons in the saphenous nerve of the streptozotocin-diabetic rat.

1. This study examined sensory neurons in the saphenous nerve of rats treated with streptozotocin to induce diabetes (STZ-D). Several physiological properties of sensory neurons were not significantly different in STZ-D compared with control (CON) rats, including percentage and rate of spontaneous activity seen in the whole nerve and mechanical and thermal thresholds of individual C-fibers. 2. The response of STZ-D and CON C-fibers to a sustained (1 min) mechanical stimulus of threshold force was similar. However, during the 5 min immediately after removal of this stimulus, there was a much greater afterdischarge in STZ-D rats (STZ-D: n = 35; 14.6 +/- 5.1 action potentials/5 min, mean +/- SE; CON: n = 34; 3.9 +/- 0.7 action potentials/5 min). The number of action potentials during a sustained (1 min) suprathreshold mechanical (445 g) stimulus was also significantly greater in the C-fibers from STZ-D rats (STZ-D: n = 44; 149.7 +/- 18.4 action potentials; CON: n = 45; 84.7 +/- 12.2 action potentials). The afterdischarge during the 5 min immediately after removal of the sustained suprathreshold stimulus was also greater in C-fibers from STZ-D rats (STZ-D: 38.7 +/- 13.1 action potentials/5 min; CON: 9.3 +/- 2.3 action potentials/5 min). 3. There was a significant difference between C-fibers from STZ-D and CON rats with respect to the distribution among certain sensory classes.(ABSTRACT TRUNCATED AT 250 WORDS)     

The influence of stimulus temperature rise rate, adapting temperature, and stimulus duration on suprathreshold responses evoked by noxious heat in the glabrous skin of the limb Comparison of neuronal discharge in the rat spinal dorsal horn with human sensations

 The influence of stimulus temperature rise rate (2.5oC/s, 5.0oC/s, and 10.0oC/s), adapting (baseline) temperature (25oC, 30oC, and 35oC), and duration of peak stimulus temperature (1.0 s, 2.5 s, 5.0 s, and 10.0 s) on responses evoked by noxious heat stimuli of suprathreshold intensity was studied in wide dynamic range (WDR) neurons of the rat spinal dorsal horn. The spinal neuronal responses were compared with human psychophysical data obtained using the same stimuli. Noxious heat stimuli with a peak temperature of 54oC were applied with a contact thermostimulator to the glabrous skin of the hindfoot in rats or to the palmar skin in humans. With the highest ramp rate and the highest adapting temperature, the sensory and spinal neuronal response latencies were decreased more than expected on the basis of the change in physical parameters of the stimulus. The magnitudes of sensory and spinal neuronal response were independent of the stimulus ramp rate, whereas pain magnitude estimates and spinal neuronal impulse counts evoked by the same peak stimulus temperature were increased with an increase in the adapting stimulus temperature. The onset latencies of pain reactions and spinal neuronal responses were independent of the peak stimulus duration, whereas the latency of the maximum discharge in spinal neurons increased with prolongation of the peak stimulus. The sensory magnitude estimate of pain and the neuronal impulse count were increased with increase in stimulus duration. Following spinalization, the spinal neuronal responses were stronger and the stimulus duration-dependent increase in the impulse count developed faster. Moreover, the peak frequency of spinal neuronal response increased significantly with prolongation of the heat stimuli after spinalization, but not in animals with an intact spinal cord. The results indicate that stimulus rise rate, stimulus duration, and the adapting temperature are important factors in determining the sensory and spinal neuronal responses to high-intensity heat stimuli. The changes in the total impulse counts evoked by varying supraliminal heat stimuli in spinal dorsal horn WDR neurons corresponded well with the changes in pain magnitude estimates in humans. Also, the changes in spinal neuronal response onset latencies were accompanied by corresponding changes in onset latencies of human pain reactions but not with pain magnitude estimates. The effect of spinalization indicated that descending pathways control not only the response magnitude in the spinal dorsal horn WDR neurons but also the temporal characteristics of the spinal neuronal response. Received: 24 August 1998 / Accepted: 25 January 1999     

Responses of spinothalamic lamina I neurons to maintained noxious mechanical stimulation in the cat

Noxious mechanical stimuli that are maintained for minutes produce a continuous sensation of pain in humans that augments during the stimulus. It has recently been shown with systematic force-controlled stimuli that, while all mechanically responsive nociceptors adapt to these stimuli, the basis for such pain can be ascribed to A-fiber rather than C-fiber nociceptors, based on distinctions in their respective response profiles and stimulus-response functions. The present experiments investigated whether similar distinctions could be made in subsets of nociceptive lamina I spinothalamic tract (STT) neurons using similar maintained stimuli. Twenty-eight lamina I STT neurons in the lumbosacral dorsal horn of barbiturate-anesthetized cats were tested with noxious mechanical stimuli applied with a probe of 0.1 mm(2) contact area at forces of 25, 50, and 100 g for 2 min. The neurons were classified as nociceptive-specific (NS, n = 14) or polymodal nociceptive (HPC, n = 14) based on their responses to quantitative thermal stimuli. The NS neurons had greater responses and showed less adaptation than the HPC neurons in response to these stimuli, and they encoded stimulus intensity better. Comparison of the normalized response profiles of all 28 nociceptive lamina I STT neurons, independent of cell classification, revealed 2 subgroups that differed significantly: "Maintained" cells with responses that remained above 50% of the initial peak rate during stimulation and "Adapting" cells with responses that quickly declined to <50%. The Maintained neurons encoded the intensity of the mechanical stimuli better than the Adapting neurons, based on ratiometric functions. A k-means cluster analysis of all 28 cells distinguished the identical two subgroups. These categories corresponded closely to the NS and HPC categories: Maintained cells were mostly NS neurons (10 NS, 3 HPC), and Adapting cells were mostly HPC neurons (4 NS, 11 HPC). Thus the present data are consistent with the distinctions between A-fiber and C-fiber nociceptors observed previously, because A-fiber nociceptors are the predominant input to NS lamina I STT neurons and C-fiber nociceptors are the predominant input to HPC neurons. These findings support the view that NS, but perhaps not HPC, lamina I STT neurons have a role in the pain caused by maintained mechanical stimuli and contribute to the sensations of "first" pain and "sharpness." Nonetheless, none of the units studied showed increasing responses during the stimuli, suggesting a role for other ascending neurons or forebrain integration in the augmenting pain produced by maintained mechanical stimulation.     

Stimulus and response ERP analyses of a two-level reaction time task

Higher cognitive processes include the ability to reliably transform sensory or mnemonic information. These processes either occur automatically or they are consciously controlled. To compare these two types of information processing, we developed a reaction time task that requires either a rule operation or else a direct sensory association. We were interested in evaluating the brain's electrical activity corresponding to both tasks, using event-related potentials (ERPs). In order to gain complete insight into the electrical activity of a stimulus-response segment, we analyzed the ERPs corresponding to the processing of the stimulus and the ERPs corresponding to the preparation of the response. To complete the analysis, we also evaluated the lateralized readiness potential (LRP) matched to the stimulus and to the response onset. Compared with the sensory association task, rule operation generated a higher negative potential field at frontocentral scalp areas in a latency range of 312–512 ms after the stimulus. In contrast, the LRP showed a negative component in the sensory association task which was absent during the rule operation; the latency of the difference was in the range 374–532 ms after the stimulus. The ERP component obtained by the response onset analysis was more negative in the rule condition up to a latency of –214 ms before the generation of the movement; the effect was localized at frontal and central scalp regions. We failed to find any significant difference in the LRP matched to the response onset. These results suggest that the brain computation of the rule operation takes place approximately in the middle of the stimulus-response time interval and that it is an additive process to the sensory association response.