Relationship between stimulus strength and the cutaneous silent period

During sustained muscle contraction, an interval of reduced activity follows an electrical cutaneous stimulus, called the cutaneous silent period (CSP). To evoke a CSP, a single stimulus must be painful. We used single sural nerve stimuli to evoke a CSP in ipsilateral soleus muscle, and studied the relationships between stimulus strength, sensory action potential (SAP) morphology, and subjective experience. Near nerve electrodes were employed to record the sural SAP in order to record activity in slower conducting fibers in addition to Aα fibers. In 6 normal subjects, the stimulus strength required to evoke a CSP ranged from 8 to 10 times threshold intensity. Pain threshold was slightly below that necessary to evoke the CSP. SAP shape changed with stimulus strength; main component amplitude occasionally increased as strength increased beyond 10 times threshold, and slowly conducting late components became more prominent. At stimulus intensities or at less than CSP threshold, components were seen conducting from 15–20 m/s that were not observed at lower intensities. We suggest that activation of sensory axons with conduction velocities in the range of Aδ fibers are necessary to evoke the CSP, and that their potentials can be discerned in the SAP. © 1993 John Wiley & Sons, Inc.     

Conduction velocity in motor,cutaneous afferent,and muscle afferent fibers within the same mixed nerve

Mammalian axons subserving different functions have different conduction velocities (CV); motor fibers conduct more slowly than cutaneous fibers, which conduct slower than muscle afferents. However, human studies have yielded conflicting results. We studied isolated fiber populations in human sciatic nerve to examine further this question. Motor studies were performed in standard fashion, stimulating at gluteal fold (GF) and popliteal fossa (PF) and recording soleus. In addition, conduction velocity of a pure motor nerve volley was calculated for 3 subjects. Stimulating and recording electrodes were needles placed close to the nerve. Cutaneous afferents were studied by stimulating the sural nerve at the ankle and recording at PF and GF. Muscle afferent velocity was assessed by comparing soleus H reflex latency with stimulation at PF and GF. Results in 10 subjects showed muscle afferent CV of 57.6, cutaneous afferent CV of 55.1, motor CV of 52.4. and mixed nerve CV of 56.3 m/s. Although statistically significant, these differences are much smaller than in animal studies. These results have implications for understanding what fibers contribute to Spinal reflexes. © 1994 John Wiley & Sons, Inc.     

Deep innervation of sural nerve

Discharges of 37 sural afferents in the Aα to C fiber range have been recorded during stimulation of subcutaneous tissues after removal of the skin. Except for one Aα unit with muscle spindle properties, fibers were not easily excited by muscle stretching. The more slowly conducting fibers tended to have higher thresholds. After repeated stimulation, most Aδ and C units displayed a persistent afterdischarge which lasted from several minutes to more than half an hour.     

The effect of differential and complete nerve block on experimental muscle pain in humans.

We have attempted to examine the nerve fiber population mediating experimentally induced muscle pain in humans. Two established methods induced muscle pain: continuous, intramuscular, electrical stimulation and intramuscular infusion of hypertonic saline. A progressive nerve block was achieved by a combination of compression nerve block and intravenous regional anesthesia. Regular tests of muscle pain intensity were performed during the blocking period of 60 min. At the same time, the blocking of thick and thin afferents was monitored by assessment of proprioception and cutaneous touch, pin-prick, pressure pain, and heat-detection thresholds. Electrically induced muscle pain was inhibited (P < 0.0001) in parallel with proprioception, touch, and pin-prick, which were mediated by thick and thin myelinated nerve fibers. Saline-induced muscle pain was inhibited (P < 0.002) synchronously with heat detection and pressure pain, which are mediated by unmyelinated nerve fibers. Based on the present psychophysical experiments, it is suggested that: (1) myelinated afferents mediated mainly electrically induced muscle pain, and (2) unmyelinated afferents mediated mainly saline-induced muscle pain.     

Response to an itch-producing substance in cat. II. Cutaneous receptor populations with unmyelinated axons

Within the sampled population of cutaneous unmyelinated afferent neurons (n = 94), only the C-polymodal nociceptor population was reactive to the pruritogen cowhage. Of 62 C-polymodal neurons tested, 11 were unresponsive to cowhage. No C-polymodal neurons were more responsive to inactive, than to active, cowhage (n = 17) and all were responsive to mechanical (n = 62) stimuli and noxious heat (n = 24). The range of conduction velocities obtained by single-unit recording techniques was similar to that found by signal averaging the activity from larger strands of nerve. Hence, it is concluded that our recording technique was capable of recording from the smallest afferent fibers in a cutaneous nerve and it was unlikely that we would have missed finding a slowly conducting, pruritus-signaling neuron due to sampling bias. A search of slowly conducting afferents (n = 314) using electrocutaneous stimulation gave no evidence to suggest the existence of an unknown population of unmyelinated fibers that might signal pruritus. A number of alternative mechanisms by which the sensation of itch might be encoded were discussed, the most favored being the activation of a subset of the C-polymodal nociceptive population.     

Photochemically-induced ischemic injury of the rat sciatic nerve: a light- and electron microscopic study

Lesion of presumably ischemic origin of the rat sciatic nerve was induced photochemically by laser irradiation combined with systemic administration of a photosensitizing organic dye, erythrosin B. We have studied the pathologic features of the nerve after the photochemical insult with light- and electronmicroscopy and related them to behavioral signs of neuropathic pain. At the irradiated nerve site, occlusion of blood vessels was seen and the vessels were packed with aggregated thrombocytes, fibrins and deformed erythrocytes, supporting the notion that photochemical reaction caused intraneural ischemia. The degree of the nerve injury at the center of irradiation was related to the duration of the laser exposure. Brief irradiation (30 seconds) only caused identifiable injury to myelinated fibers, whereas longer irradiation (2 minutes) caused greater injury to myelinated and unmyelinated fibers, characterized by extensive axonal degeneration and demyelination. The rats irradiated for 2 minutes, but not 30 seconds, exhibited neuropathic pain-like behaviors, expressed as mechanical and cold allodynia. The nerve injury was most severe 7 days after ischemia and regeneration of both myelinated and unmyelinated fibers was observed 3 months later. The nerve caudal to the irradiation exhibited Wallerian degeneration 7 days after the insult, whereas at 10 mm proximal to the irradiation the nerve was largely normal. It is thus concluded that photochemically induced intraneural ischemia caused injury to both myelinated and unmyelinated fibers, with myelinated fibers being more susceptible. However, the development of neuropathic pain-like behaviors may require injury to the unmyelinated fibers.     

A case of hereditary sensory autonomic neuropathy type IV

Hereditary sensory autonomic neuropathy type IV (HSAN -IV), also known as congenital insensitivity to pain with anhidrosis, is a very rare condition that presents in infancy with anhidrosis, absence of pain sensation and self -mutilation. Developmental delay and mental retardation are usually present. Ultrastructural study of the peripheral nerves demonstrates loss of the unmyelinated and small myelinated fibers. We here report a 8 year -old boy with HSAN IV with typical clinical features where the diagnosis was supported by nerve biopsy findings. However, our case was unusual since mental development was normal.     

Muscle chemoreflexes and exercise in humans

This review focuses on the role afferent nerves from the contracting muscles play in linking muscle metabolism to the cardiovascular adjustments during exercise by means of a muscle chemoreflex. In the 1930s Alam and Smirk provided the first clear evidence that human (and animal) skeletal muscles are innervated by chemosensitive afferents that can evoke increases in arterial blood pressure. They proposed that the purpose of the increase in pressure was to improve blood flow to the active muscles. Subsequent studies have identified the slowly conducting group IV afferents as the major class of fibres participating in the sensory arm of this reflex. Most of these fibres travel via the dorsal roots to the ipsilateral spinal cord where they synapse in the substantia gelatinosa and release substance P or other peptide transmitters. The second order (or higher) neurons cross to the contralateral side of the spinal cord and travel rostrally to stimulate brainstem cardiovascular centres and increase arterial pressure. Current evidence favours the concept that substances associated with muscle acidosis provide the stimulus to the afferents. In humans, chemosensitive afferent activation causes a marked increase in vasoconstrictor efferent muscle sympathetic nerve activity. It is unclear if the muscle chemoreflex improves blood flow to underperfused active muscles by augmenting arterial pressure, or if the increase in sympathetic outflow restrains metabolic vasodilatation to regulate arterial blood pressure during activities like running or cycling.     

Increase in hypothalamic nicotinic acetylcholine receptors in prepuberal female rats administered estrogen

Discharges of 37 sural afferents in the A alpha to C fiber range have been recorded during stimulation of subcutaneous tissues after removal of the skin. Except for one A alpha unit with muscle spindle properties, fibers were not easily excited by muscle stretching. The more slowly conducting fibers tended to have higher thresholds. After repeated stimulation, most A delta and C units displayed a persistent afterdischarge which lasted from several minutes to more than half an hour.     

Central sprouting of uninjured small fiber afferents in the adult rat spinal cord following spinal nerve ligation

Partial nerve injury results in chronic pain that is difficult to treat effectively. To investigate the anatomic basis of this phenomenon we used wheat germ agglutinin-horseradish peroxidase (WGA-HRP) to label the central projections of uninjured small fibers (Adelta and C) in a well-established model of neuropathic pain created by selective spinal nerve ligation in the adult. We found extensive sprouting of uninjured WGA-HRP-labeled afferents into the central termination field in lamina II of dorsal horn normally occupied by L5 afferents whose peripheral axons had been ligated distal to the dorsal root ganglion. The formation of new projections by uninjured fibers into a functionally but not anatomically deafferented field in the adult may play a role in the development of chronic pain.     

Novel purinergic sensitivity develops in injured sensory axons following sciatic nerve transection in rat

Teased fibers were made from 153 spontaneous A afferents ending in sciatic nerve end neuromas of 3-14 days standing, 21 A afferents from intact sensory endings in the contralateral sciatic nerve, and 50 intact A afferents from the sciatic nerve in intact rats. Ninety-two percent of the injured fibers responded to adenosine 5'-triphosphate (ATP) (i.v.). However, few fibers from the contralateral nerve or nerves from intact animals responded to ATP. P2 receptor antagonist suramin or reactive blue 2 blocked the ATP-induced response in 76% of the fibers tested, whereas the P1 receptor antagonist aminophylline blocked the ATP-evoked effect in only 18% of the fibers tested. Sympathectomy did not affect the ATP-induced effects in injured axons. Close-arterial injection of ATP caused similar results as i.v. injection of ATP. The present study suggests that a novel purinergic sensitivity is developed at the injury site after sciatic nerve transection in rats, which may play a role in neuropathic pain under some conditions such as sympathetic activation.     

Identity of myelinated cutaneous sensory neurons projecting to nocireceptive laminae following nerve injury in adult mice

It is widely thought that, after peripheral injury, some low‐threshold mechanoreceptive (LTMR) afferents “sprout” into pain‐specific laminae (I–II) of the dorsal horn and are responsible for chronic pain states such as mechanical allodynia. Although recent studies have questioned this hypothesis, they fail to account for a series of compelling results from single‐fiber analyses showing extensive projections from large‐diameter myelinated afferents into nocireceptive layers after nerve injury. Here we show that, in the thoracic spinal cord of naïve adult mouse, all myelinated nociceptors gave rise to terminal projections throughout the superficial dorsal horn laminae (I–II). Most (70%) of these fibers had large‐diameter axons with recurving flame‐shaped central arbors that projected throughout the dorsal horn laminae I–V. This morphology was reminiscent of that attributed to sprouted LTMRs described in previous studies. After peripheral nerve axotomy, we found that LTMR afferents with narrow, uninflected somal action potentials did not sprout into superficial laminae of the dorsal horn. Only myelinated noiceptive afferents with broad, inflected somal action potentials were found to give rise to recurving collaterals and project into superficial “pain‐specific” laminae after axotomy. We conclude that the previously undocumented central morphology of large, myelinated cutaneous nociceptors may very well account for the morphological findings previously thought to require sprouting of LTMRs. J. Comp. Neurol. 508:500–509, 2008. © 2008 Wiley‐Liss, Inc.     

Do large diameter cutaneous afferents have a role in the transmission of nociceptive messages?

In recent studies, it has been reported that high-frequency stimulation restricted to Aαβ fibers in man can be perceived as painful and evoke a nociceptive flexion reflex. These results would indicate that some patterns of activity in low-threshold mechanoreceptors can lead to painful sensations. Because of the theoretical importance of this question, the above studies were extended by recording the evoked neural activity with the technique of percutaneous microneurography. Painful sensations and the nociceptive reflex did not appear unless the evoked nerve response contained activity in Aδ fibers. The results support the theory that painful sensations occur in normal man only when nociceptor afferents are activated.     

Human microneurography and intraneural microstimulation in the study of neuropathic pain

Psychophysical experiments in combination with microneurography and intraneural microstimulation in awake human subjects have yielded some useful information on somatosensory functions under normal and pathologic conditions. Normally, pain is signaled by nociceptive afferents, and tactile sensations are evoked from activation of low-threshold mechanoreceptors. Following tissue injury, nociceptors are sensitized, and their enhanced responsiveness correlates with hyperalgesia to heat and in some cases to mechanical stimuli. In addition, ongoing activity in sensitized nociceptive afferents may lead to central sensitization in such a way that normally nonpainful gentle stroking the skin evokes pain from activation of low-threshold mechanoreceptors. This particular change in signal processing in the central nervous system is restored when the ongoing nociceptive input is interrupted, whereas other forms of central sensitization can outlast the duration of the nociceptive input. © 1993 John Wiley & Sons, Inc.     

Clinical, electrophysiological and histological analysis of adult onset chronic sensory neuropathy

We reported clinical, electrophysiological and pathological findings in 10 patients with acquired, slowly progressive sensory neuropathy. Group I patients which had delayed sensory nerve conduction velocities (SNCV) or no response of SCV in electrophysiological studies were observed to have marked deep sensory disturbances. On the other hand, Group II who had abnormalities of both SNCV and motor nerve conduction velocities electrophysiologically has tendency to show superficial sensory disturbances more dominantly than that of deep sensation. Histological findings of biopsied sural nerve in Group I were mainly composed of diminution of large myelinated fibers, in Group II the diminution of large myelinated fibers with decreased unmyelinated fibers were observed. However, there were no significant difference between Group I and Group II in the quantitative analysis of myelinated fibers. There were no definite tendency under the basic disease or background factors of these 10 patients. Only 3 of these 10 patients had immunological abnormalities such as RA factors or antinuclear antibodies.     

High frequency discharges in sensory nerves following ischemia

The effects of ischemia and recovery from ischemia on afferent discharges recorded from dorsal root filaments were assessed in anesthesized cats. During ischemia produced by cross-clamping the lumbar aorta, some of the hindlimb afferents originating in muscle spindles exhibited a sustained high frequency discharge of 120--160 Hz, the so-called "explosion." During recovery from ischemia, nerve discharges appeared in previously inactive dorsal root afferent nerve fibers not of muscle spindle origin. The post-ischemic high frequency discharges appeared in bursts of action potentials at frequencies of 200--500 per second, with 6--32 spikes per burst; the bursts recurred at intervals of 120--600 msec. The nerve fibers exhibiting post-ischemic bursts could not be activated by muscle stretch, muscle tension, palpation, or tactile skin stimulation prior to or during the ischemia. No post-ischemic burst discharges could be detected in analogous experiments with the sural nerve. Intermediate size fibers from normal cutaneous and muscle mechanoreceptors were eliminated as possible origins of the post-ischemia activity. Possible sources include dorsal root ganglion cells or fibers whose sensory endings lie in deep structures such as the walls of the larger blood vessels.     

Thermoreceptors and thermosensitive afferents

Cutaneous thermosensation plays an important role in thermal regulation and detection of potentially harmful thermal stimuli. Multiple classes of primary afferents are responsive to thermal stimuli. Afferent nerve fibers mediating the sensation of non-painful warmth or cold seem adapted to convey thermal information over a particular temperature range. In contrast, nociceptive afferents are often activated by both, painful cold and heat stimuli. The transduction mechanisms engaged by thermal stimuli have only recently been discovered. Transient receptor potential (TRP) ion channels that can be activated by temperatures over specific ranges potentially provide the molecular basis for thermosensation. However, non-TRP mechanisms are also likely to contribute to the transduction of thermal stimuli. This review summarizes findings regarding the transduction proteins and the primary afferents activated by innocuous and noxious cold and heat.     

Laser Effects on Myelinated and Nonmyelinated Fibers in the Rat Peroneal Nerve: A Quantitative Ultrastructural Analysis

We have recently shown that Nd:YAG laser irradiation of rat peripheral nerve differentially impairs action potential transmission in small, slowly conducting sensory fibers compared to fast conducting afferents. In addition, the number of small sensory neurons of the A-δ- and C-fiber group labeled with HRP is significantly reduced after laser irradiation, while the number of labeled large sensory neurons and motoneurons was not affected. To further evaluate this laser-induced injury, we examined three distinct regions of the laser-irradiated rat peroneal nerve using ultrastructural morphometric methods. These regions were the site of laser irradiation and zones 10 mm proximal and 5 mm distal to the injury. The contralateral nerve was sham treated. Our results indicate that for the small nonmyelinated fibers, there was a significant increase in both mean fiber size and the number of microtubules per fiber, but a decrease in the number of neurofilaments. In contrast, the number of myelinated and nonmyelinated fibers is not significantly altered at 7 days following laser irradiation, and the mean diameter and frequency distribution of myelinated nerve fibers was unchanged. This study demonstrates that selective functional alterations in laser-irradiated nerves (nerve conduction velocity, HRP transport properties) are accompanied by ultrastructural changes of axonal organelles in nonmyelinated fibers. Nd:YAG laser light might ultimately prove to be a powerful tool to selectively alter functional properties in small, slowly conducting afferent fibers, without causing degeneration at the ultrastructural level at the site of irradiation. We hypothesize further that the laser-induced functional alterations might be related to differential thermally mediated changes.     

Psychophysical detection and pain ratings of incremental thermal stimuli: A comparison with nociceptor responses in humans

The capacity of humans to detect and scale the magnitude of pain elicited by small increments in temperature, delivered by a contact thermal stimulator to localized areas of the arm or leg, was measured on non-painful and painful adaption temperatures. Subjects continuously rated the magnitude of any pain sensation elicited by heat increments superimposed on base temperatures of 38, 44, 47 or 48 °C. Detection threshold was also measured using a two-alternative forced choice method. The increment detection thresholds were lower for a continuously painful base of 47 °C than for a non-painful base of 38 °C in normal skin, and likewise were lower for a base of 38 °C following hyperalgesia induced by a mild burn. Incremental pain thresholds were nearly equal to detection thresholds on the base of 47 °C. The sensitivity with which subjects could scale the magnitude of pain was 2–7 times better for increments delivered on a 48 °C as opposed to a 38 °C base.Evoked responses in 6 single C-fiber mechanoheat nociceptive afferents (CMHs) were recorded percutaneously from the peroneal nerves of 3 humans, who were simultaneously judging pain magnitude. For a base of 38 °C, both the pain and the neural response thresholds were an order of magnitude higher than corresponding thresholds on a base of 48 °C. For a base of 47 °C, response thresholds of the CMHs ranged from 0.1 to 0.5 °C and were comparable to detection thresholds of 0.1 to 0.3 °C. The sensitivity with which most nociceptors could signal increment size was 3–4 times better on a 48 °C than a 38 °C base.Incremental pain sensitivity was not altered by a compression block of activity in myelinated afferents that eliminated the sense of cool and touch. Thus, activity in unmyelinated fibers alone could account for the sensitivity to incremental thermal stimuli that were superimposed on a painful base temperature. Further, it is likely that CMH nociceptors alone could provide the peripheral information necessary to detect and to make magnitude judgments of pain elicited by these stimuli.