New basic insights on the potential of a chitosan-based medical device for improving functional recovery after radical prostatectomy.

OBJECTIVES: To evaluate: (i) the neuro-regenerative potential of chitosan membrane (CS-Me) on acutely axotomised autonomic neurones in vitro; (ii) to exclude the possibility that a pro-regenerative biomaterial could interfere with the proliferation activity of prostate cancer cell lines; (iii) to provide an in vivo proof of the biocompatibility and regeneration promoting effect of CS-Me in a standardised rat model of peripheral nerve injury and repair; (iv) finally, to evaluate the tissue reaction induced by the degrading material; as previous studies have shown promising effects of CS-Me for protection of the neurovascular bundles for potency recovery in patients that undergo nerve-sparing radical prostatectomy (RP). MATERIALS AND METHODS: Addressing aim (i), the neuro-regenerative potential, organotypic cultures derived from primary sympathetic ganglia were cultured on CS-Me over 3 days and neurite extension and axonal sprouting were evaluated. Addressing aim (ii), effects of CS on cancer cells, different human prostate cancer cell lines (PC3, DU-145, LN-Cap) were seeded on CS-coated plates or cultured in the presence of CS-Me dissolution products. Addressing aims (iii) and (iv), functional recovery of peripheral nerve fibres and tissue reaction with the biomaterial, CS-Me and CS nerve guides were used to repair a median nerve injury in the rat. Functional recovery was evaluated during the post-recovery time by the behavioural grasping test. RESULTS: CS-Me significantly stimulated axon elongation from autonomic ganglia in comparison to control conditions in organotypic three-dimensional cultures. CS coating, as well as the dissolution products of CS-Me, led to a significantly lower proliferation rate of prostate cancer cell lines in vitro. Tissue reaction towards CS-Me and standard CS nerve guides was similar in the rat median nerve model, as was the outcome of nerve fibre regeneration and functional recovery. CONCLUSION: The results of this study provide the first experimental evidence in support of the clinical safety of CS-Me and of their postulated effectiveness for improving functional recovery after RP. The presented results are coherent in demonstrating that acutely axotomised autonomic neurones show increased neurite outgrowth on CS-Me substrate, whilst the same substrate reduces prostate cancer cell line proliferation in vitro. Furthermore, CS-Me do not demonstrate any disadvantage for peripheral nerve repair in a standard animal model.

Hyperpolarization-activated cyclic-nucleotide-gated channels potentially modulate axonal excitability at different thresholds.

Hyperpolarization-activated cyclic-nucleotide-gated (HCN) channels mediate differences in sensory and motor axonal excitability at different thresholds in animal models. Importantly, HCN channels are responsible for voltage-gated inward rectifying (Ih) currents activated during hyperpolarization. The Ih currents exert a crucial role in determining the resting membrane potential and have been implicated in a variety of neurological disorders, including neuropathic pain. In humans, differences in biophysical properties of motor and sensory axons at different thresholds remain to be elucidated and could provide crucial pathophysiological insights in peripheral neurological diseases. Consequently, the aim of this study was to characterize sensory and motor axonal function at different threshold. Median nerve motor and sensory axonal excitability studies were undertaken in 15 healthy subjects (45 studies in total). Tracking targets were set to 20, 40, and 60% of maximum for sensory and motor axons. Hyperpolarizing threshold electrotonus (TEh) at 90-100 ms was significantly increased in lower threshold sensory axons times (F = 11.195, P < 0.001). In motor axons, the hyperpolarizing current/threshold (I/V) gradient was significantly increased in lower threshold axons (F = 3.191, P < 0.05). The minimum I/V gradient was increased in lower threshold motor and sensory axons. In conclusion, variation in the kinetics of HCN isoforms could account for the findings in motor and sensory axons. Importantly, assessing the function of HCN channels in sensory and motor axons of different thresholds may provide insights into the pathophysiological processes underlying peripheral neurological diseases in humans, particularly focusing on the role of HCN channels with the potential of identifying novel treatment targets.NEW & NOTEWORTHY Hyperpolarization-activated cyclic-nucleotide-gated (HCN) channels, which underlie inward rectifying currents (Ih), appear to mediate differences in sensory and motor axonal properties. Inward rectifying currents are increased in lower threshold motor and sensory axons, although different HCN channel isoforms appear to underlie these changes. While faster activating HCN channels seem to underlie Ih changes in sensory axons, slower activating HCN isoforms appear to be mediating the differences in Ih conductances in motor axons of different thresholds. The differences in HCN gating properties could explain the predilection for dysfunction of sensory and motor axons in specific neurological diseases.

Median nerve fascicular anatomy as a basis for distal neural prostheses.

INTRODUCTION: Functional electrical stimulation (FES) serves as a possible therapy to restore missing motor functions of peripheral nerves by means of cuff electrodes. FES is established for improving lower limb function. Transferring this method to the upper extremity is complex, due to a lack of anatomical data on the physiological configuration of nerve fascicles. Our study's aim was to provide an anatomical basis for FES of the median nerve in the distal forearm and hand. METHODS: We investigated 21 distal median nerves from 12 body donors. The peripheral fascicles were traced back by removing the external and interfascicular epineurium and then assigned to 4 quadrants. RESULTS: A distinct motor and sensory distribution was observed. The fascicles innervating the thenar eminence and the first lumbrical muscle originated from the nerves' radial parts in 82%. The fascicle supplying the second lumbrical muscle originated from the ulnar side in 78%. No macroscopically visible plexus formation was observed for the distal median nerve in the forearm. CONCLUSIONS: The findings on the distribution of the motor branches of the median nerve and the missing plexus formation may likely serve as an anatomical basis for FES of the distal forearm. However, due to the considerable variability of the motor branches, cuff electrodes will need to be adapted individually in FES. Taking into account the sensory distribution of the median nerve, FES may also possibly be applied in the treatment of regional pain syndromes.

Differential sensitivity to surface compliance by tactile afferents in the human finger pad.

We undertook a neurophysiological investigation of the responses of low-threshold mechanoreceptors in the human finger pad to surfaces of differing softness. Unitary recordings were made from 26 slowly adapting type I (SAI), 17 fast-adapting type I (FAI), and 9 slowly adapting type II (SAII) afferents via tungsten microelectrodes inserted into the median nerve at the wrist. A servo-controlled stimulator applied ramp-and-hold forces (1, 2, 4 N) at a constant loading and unloading rate (2 N/s) via a flat silicone disc over the center of the finger pad. Nine discs were used, which linearly increased in stiffness across the range. Population responses of the SAI afferents showed the greatest sensitivity to compliance, with a steep monotonic increase in mean firing rate with increasing stiffness (decreasing compliance) of the surface during the loading and plateau (but not unloading) phases. FAI afferents also showed a linear increase in firing during the loading but not unloading phase, although the slope was significantly lower than that of the SAI afferents at all amplitudes. Conversely, SAII afferents were influenced by object compliance only in certain conditions. Given their high density in the finger pads and their linear relationship between firing rate and object compliance during the loading and plateau phases, SAI afferents (together with FAI afferents during the loading phase) are ideally suited to contributing information on surface compliance to the overall estimation of softness, but the SAII afferents appear to play only a minor role.

Laser-activated adhesive films for sutureless median nerve anastomosis.

A novel chitosan adhesive film that incorporates the dye 'Rose Bengal' (RB) was used in conjunction with a green laser to repair transected rat median nerves in vivo. Histology and electrophysiological recording assessed the impact of the laser-adhesive technique on nerves. One week post-operatively, the sham-control group (laser-adhesive technique applied on un-transected nerves) conserved the average number and size of myelinated fibres in comparison to its contralateral side and electrophysiological recordings demonstrated no significant difference with un-operated nerves. Twelve weeks after the laser-adhesive anastomoses, nerves were in continuity with regenerated axons that crossed the anastomotic site.

Clarifying distal axonal properties of the median nerve.

INTRODUCTION: Although length-dependent axonal excitability changes have been reported in the median nerve, the mechanisms underlying these changes remain to be further clarified. METHODS: Axonal excitability studies were performed on median nerve at the palm and wrist in 20 healthy controls, with responses recorded over the abductor pollicis brevis. RESULTS: The strength-duration time constant was significantly shorter (palm: 0.35 ± 0.01 ms; wrist: 0.48 ± 0.03 ms; P < 0.001), whereas rheobase was significantly increased (palm: 2.90 ± 1.12 mA; wrist: 2.09 ± 1.11 mA; P < 0.05) at the palm. In addition, there was a significant increase in depolarizing threshold electrotonus at 90-100 ms (P < 0.001) and a reduction in S2 accommodation (P < 0.001) and late subexcitability (P < 0.001) at the palm. The changes in excitability were independent of factors influencing median nerve cross-sectional area. CONCLUSIONS: The present study reveals significant length dependent changes in median nerve excitability which may reflect differences in intrinsic membrane properties.

Do anthropometric measurements of the hand impact the histological structure of the human median nerve at the level of the carpal tunnel?

INTRODUCTION: The literature lacks data on the histological structure of the median nerve on the level of the carpal tunnel, and its possible correlations with the anthropometric measurements of the hand. AIM: The aim of this study was to assess the anthropometric measurements of human cadaver hands and their median nerves histological structure and whether a correlation existed between these two. MATERIAL & METHODS: This study has been conducted using cadavers stored in a 10% solution of formaldehyde at the Department of Anatomy of the Jagiellonian University Medical College (JUMC) and cadavers from the Department of Forensic Medicine JUMC. Before dissection anthropometric measurements were carried out. After dissection the median nerves were stained with haematoxylin and eosin and histological slides were prepared. These were later photographed (16 x magnification) and analysed using ImageJ software. RESULTS: The studied group comprised 8 women and 22 men (age between 23-92 years). Anthropometric measurements comparison by gender revealed statistically significantly larger CR-CU, MR-MU and TS-ID distances in men then in women. When comparing sides, the cross-sectional area (CSA) of the right median nerve (0.216 +/- 0.06 cm2) was statistically significantly larger (p = 0.017) then the CSA of the left median nerve (0.173 +/- 0.05 cm2). No correlation was noted between the anthropometric and histological measurements obtained in this study. CONCLUSIONS: Anthropometric measurements of the hand do not impact the histological structure of the human median nerve at the level of the carpal tunnel. Nerve bundles of the median nerve, at the level of the carpal tunnel, display no particular type of arrangement.

Properties of low-threshold motor axons in the human median nerve.

This study investigated the excitability and accommodative properties of low-threshold human motor axons to test whether these motor axons have greater expression of the persistent Na(+) conductance, I(NaP). Computer-controlled threshold tracking was used to study 22 single motor units and the data were compared with compound motor potentials of various amplitudes recorded in the same experimental session. Detailed comparisons were made between the single units and compound potentials that were 40% or 5% of maximal amplitude, the former because this is the compound potential size used in most threshold tracking studies of axonal excitability, the latter because this is the compound potential most likely to be composed entirely of motor axons with low thresholds to electrical recruitment. Measurements were made of the strength-duration relationship, threshold electrotonus, current-voltage relationship, recovery cycle and latent addition. The findings did not support a difference in I(NaP). Instead they pointed to greater activity of the hyperpolarization-activated inwardly rectifying current (I(h)) as the basis for low threshold to electrical recruitment in human motor axons. Computer modelling confirmed this finding, with a doubling of the hyperpolarization-activated conductance proving the best single parameter adjustment to fit the experimental data. We suggest that the hyperpolarization-activated cyclic nucleotide-gated (HCN) channel(s) expressed on human motor axons may be active at rest and contribute to resting membrane potential.

Non-viral genetic transfection of rat Schwann cells with FuGENE HD© lipofection and AMAXA© nucleofection is feasible but impairs cell viability.

PURPOSE: To determine transfection efficiency of FuGENE HD© lipofection and AMAXA© nucleofection on rat Schwann cells (SC). METHODS: The ischiadic and median nerves of 6-8 week old Lewis rats were cultured in modified melanocyte-growth medium. SCs were genetically transfected with green fluorescent protein (GFP) as reporter gene using FuGENE HD© lipofection and AMAXA© nucleofection. Transfection rates were determined by visualization of GFP fluorescence under fluorescence microscopy and cell counting. Transfected cell to non-transfected cell relation was determined. RESULTS: Purity of Schwann cell culture was 88% as determined by immunohistologic staining. Transfection rate of FuGENE HD© lipofection was 2%, transfection rate of AMAXA© nucleofection was 10%. With both methods, Schwann cells showed pronounced aggregation behavior which made them unfeasible for further cultivation. Settling of Schwann cells on laminin and poly-L-ornithine coated plates was compromised by either method. CONCLUSION: Non-viral transfection of rat SC with FuGENE HD© lipofection and AMAXA© nucleofection is basically possible with a higher transfection rate for nucleofection than for lipofection. As cell viability is compromised by either method however, viral transfection is to be considered if higher efficiency is required.

Efficacy of various durations of in vitro predegeneration on the cell count and purity of rat Schwann-cell cultures.

The efficacy of Schwann-cell cultivation can be enhanced by in vitro predegeneration of the harvested cells compared to immediate culture. The aim of this study was to improve Schwann-cell culture efficacy by comparing three different durations of predegeneration. The sciatic and median nerves of 6-8-week-old Lewis rats were harvested and subjected to either 2-day, 7-day, or 14-day predegeneration in Dulbecco's Modified Eagle's Medium supplemented with 10% fetal calf serum and 1% Penicillin/Streptomycin. Afterward, tissue was enzymatically dissociated and placed in a modified melanocyte growth medium. The cell count was determined immediately after dissociation while the cell purity was determined one subculture/trypsinization cycle later after cell attachment to the culture plate by means of optical microscopy and immunocytochemistry. Particular attention was then paid to the Schwann-cell-to-fibroblast relation. The cumulative cell count in the culture was 5.8 x 10(5) for 2-day, 1.12 x 10(6) for 7-day, and 1.48 x 10(6) for 14-day predegeneration. The culture purity was approximately equal for 2- and 7-day predegeneration (88% Schwann cells, 12% fibroblasts after 2 days; 85% Schwann cells, 15% fibroblasts after 7 days). After 14 days, however, cell cultures were significantly debased by fibroblast proliferation (57% Schwann cells, 43% fibroblasts). In vitro predegeneration is a particularly suitable procedural method to increase the cultural Schwann-cell yield. The number of cultivated rat Schwann cells is doubled by 7-day in vitro predegeneration in comparison to 2-day predegeneration. After 14-day predegeneration, however, the culture is significantly debased by fibroblasts. Therefore, 7-day in vitro predegeneration is an advisable predegeneration period.

Neuropathy patterns differ in patients with diabetic complications.

PURPOSE: Diabetic polyneuropathy (PNP) is an important risk factor for foot ulcers. Diabetic dermopathy is more frequent in patients with diabetic neuropathy. We compared clinical and electrophysiological characteristics of PNP localizations/recurrences of foot ulcers, and diabetic dermopathy (DD) between sexes. METHODS: Eighty-eight diabetic patients (44 men, 44 women) had an evaluation regarding detailed history of their diseases, lesion-related data, and clinical examination. Nerve conduction velocities (NCV), compound motor action potentials (CMAP), distal latencies (DL), and sensory nerve action potentials were assessed from the right and left peroneal, right median/ulnar nerves. RESULTS: The presence of DD was more common in men (p < 0.001). The mean NCV of ulnar nerves was slower (p < 0.001); mean CMAP values were lower (p = 0.006); and mean DL was longer in men with compared to women (p = 0.003). Although EMG features of peroneal nerves showed no significant difference, diabetic men had more common and severe peroneal nerve involvement (p = 0.004). Carpal tunnel syndrome was more common in women, though not significant. Patients with right-sided ulcers had lower CMAP amplitudes on the right peroneal nerves in regard to left peroneal nerves (p = 0.009). CONCLUSIONS: Our findings suggest that ulnar nerves are more commonly involved in men, with lower CMAP slower NCV values, and longer DL values.

Neural prostheses: electrophysiological and histological evaluation of central nervous system alterations due to long-term implants of sieve electrodes to peripheral nerves in cats.

We have investigated the alterations that the long-term implant of sieve electrodes to the peripheral nerves could evoke in the central nervous system by studying the neural activity at various levels of the somatosensory system [the implanted nerves, the dorsal column nuclei (DCN), and the primary somatosensory cortex (SI)] up to 30 months after implantation of the electrode in the distal median nerve in adult cats. This long survival period, which could correspond to 15 years within a human lifespan, enabled us to confirm the biocompatibility of the electrode. We also performed histological and molecular studies on sections of the spinal cord, DCN, and SI and electrophysiological recordings on of DCN and SI. Although in the "implanted" regions (ipsilateral nerve, ipsilateral DCN, and contralateral SI) there was apparently a good recovery of a number of molecular markers, mostly related to local metabolism and neurotransmission in central relay structures, the expression of calcium-binding proteins in the cortex, which identifies inhibitory interneurons, remained clearly abnormal, although they were never as altered as in case of irreversible, chronic denervations. Also, prominent anatomical disorganization was detected in the normal spatial arrangement of neural clusters within the DCN. With respect to the electrical activity the "implanted side" showed minor changes in response latency, intensity, and somatotopy, compared to control recordings. These findings show that central sensory-processing structures achieve fair, but not complete, levels of structural and functional reorganization following chronic intraneural implants of sieve electrodes.

Paired stimulation study of the median nerve sensory action potential in diabetic patients.

OBJECTIVES: Conventional nerve conduction studies (NCS) are not sensitive to detect mild diabetic neuropathy. In order to detect subtle changes, we compared the conventional NCS with the relative refractory period (RRP) measurement of the median sensory nerve action potential by a paired stimulation method. METHODS: Subjects were 29 diabetic patients whose conventional NCS were all normal. They were divided into two groups: neurologically symptomatic and asymptomatic groups. Twenty-eight age-matched control subjects were also studied. RESULTS: The RRP of the symptomatic diabetic patients (5.9 +/- 0.5 ms) and that of the asymptomatic patients (5.6 +/- 0.5 ms) was significantly longer than that of the control subjects (4.9 +/- 0.6 ms). There was no significant difference in RRP between the symptomatic and asymptomatic patients. This may be due to the fact that NCS reflects mainly large myelinated fiber function and early symptoms represent mainly thin myelinated or unmyelinated fiber function. CONCLUSIONS: The RRP measurement could reveal some mild involvement of peripheral nerves undetectable by conventional NCS, even though they caused no clinical symptoms.

Characterization of the induced neuropeptide Y-like immunoreactivity in primary sensory neurons following complete median nerve transection.

In this study, we examined characteristics of the neuropeptide Y-like immunoreactive (NPY-LI) dorsal root ganglion (DRG) neurons after complete median nerve transection (CMNT). With fluorogold (FG) injection into normal median nerves, numerous FG-labeled DRG neurons were localized predominantly in the C6 and C7 DRGs, where the focal regions were examined after CMNT. With NPY immunohistochemistry, a few NPY-LI neurons were detected in the ipsilateral but not contralateral DRGs after FG injection into the nerve. As early as 3 days after CMNT a few NPY-LI neurons could be detected, reaching a maximum in the DRGs at 4 weeks, subsiding thereafter over 20 weeks. The NPY-LI DRG neurons were primarily medium-sized and large neurons. With FG injection into the transected median nerve, we found that approximately 99% of NPY-LI neurons were labeled for FG, suggesting that they were derived from the injured but not intact DRG neurons. Using double fluorescent dyes tracing, we detected that some of the injured DRG neurons were NPY-LI neurons that projected to the cuneate nucleus (CN). Following dorsal rhizotomy, our data indicated that after CMNT the induced NPY-LI fibers in the ipsilateral CN originated exclusively from the injured DRG neurons. Taken together, these findings suggest that injury-induced NPY-LI fibers in the CN may originate from the injured DRG neurons via the median primary afferent fibers, affect the excitability of cuneothalamic projection neurons (CTNs), and involve neuropathic sensation following CMNT.

Interference of tactile and pain stimuli on thalamocortical signal processing in humans revealed by median nerve SEPs.

OBJECTIVE: We investigated the interference of tactile and painful stimuli on human early somatosensory evoked potentials (SEPs) including high frequency oscillations (HFOs) to further study thalamocortical processing of somatosensory information. METHODS: Multi-channel median nerve SEPs were recorded during (1) no interference, (2) sensory interference by tactile stimulation to digits 2 and 3, and (3) application of pain to the same digits. Spatio-temporal source analysis separated brain stem (S1), thalamic (S2) and two cortical sources (S3, S4), which were evaluated for the low (20-450 Hz) and high (450-750 Hz) frequency portion of the signal. RESULTS: Low frequency SEPs showed a decrease of activity at cortical source S3 during both conditions, while thalamic source S2 was significantly increased during pain interference. HFOs showed an increase of cortical source S3 and in trend of thalamic source S2 and cortical source S4 during both kinds of interference. CONCLUSIONS: Although the painful stimulus might not be specific for the nociceptive afferents, the present data affirm that at this early stage of sensory information processing within the primary sensory cortex (area 3b, area 1) pain is handled similar to sensory interference. SIGNIFICANCE: HFOs might represent an intrinsic "somatosensory alerting" system which reacts to both interference stimuli in a similar way, therefore indicating an interference without a qualitative evaluation.

Axonal excitability properties in amyotrophic lateral sclerosis.

OBJECTIVE: To investigate axolemmal ion channel function in patients diagnosed with sporadic amyotrophic lateral sclerosis (ALS). METHODS: A recently described threshold tracking protocol was implemented to measure multiple indices of axonal excitability in 26 ALS patients by stimulating the median motor nerve at the wrist. The excitability indices studied included: stimulus-response curve (SR); strength-duration time constant (tauSD); current/threshold relationship; threshold electrotonus to a 100 ms polarizing current; and recovery curves to a supramaximal stimulus. RESULTS: Compound muscle action potential (CMAP) amplitudes were significantly reduced in ALS patients (ALS, 2.84+/-1.17 mV; controls, 8.27+/-1.09 mV, P<0.0005) and the SR curves for both 0.2 and 1 ms pulse widths were shifted in a hyperpolarized direction. Threshold electrotonus revealed a greater threshold change to both depolarizing and hyperpolarizing conditioning stimuli, similar to the 'fanned out' appearance that occurs with membrane hyperpolarization. The tauSD was significantly increased in ALS patients (ALS, 0.50+/-0.03 ms; controls, 0.42+/-0.02 ms, P<0.05). The recovery cycle of excitability following a conditioning supramaximal stimulus revealed increased superexcitability in ALS patients (ALS, 29.63+/-1.25%; controls, 25.11+/-1.01%, P<0.01). CONCLUSIONS: Threshold tracking studies revealed changes indicative of widespread dysfunction in axonal ion channel conduction, including increased persistent Na+ channel conduction, and abnormalities of fast paranodal K+ and internodal slow K+ channel function, in ALS patients. SIGNIFICANCE: An increase in persistent Na+ conductances coupled with reduction in K+ currents would predispose axons of ALS patients to generation of fasciculations and cramps. Axonal excitability studies may provide insight into mechanisms responsible for motor neuron loss in ALS.

Tests for presynaptic modulation of corticospinal terminals from peripheral afferents and pyramidal tract in the macaque.

The efficacy of sensory input to the spinal cord can be modulated presynaptically during voluntary movement by mechanisms that depolarize afferent terminals and reduce transmitter release. It remains unclear whether similar influences are exerted on the terminals of descending fibres in the corticospinal pathway of Old World primates and man. We investigated two signatures of presynaptic inhibition of the macaque corticospinal pathway following stimulation of the peripheral nerves of the arm (median, radial and ulnar) and the pyramidal tract: (1) increased excitability of corticospinal axon terminals as revealed by changes in antidromically evoked cortical potentials, and (2) changes in the size of the corticospinal monosynaptic field potential in the spinal cord. Conditioning stimulation of the pyramidal tract increased both the terminal excitability and monosynaptic fields with similar time courses. Excitability was maximal between 7.5 and 10 ms following stimulation and returned to baseline within 40 ms. Conditioning stimulation of peripheral nerves produced no statistically significant effect in either measure. We conclude that peripheral afferents do not exert a presynaptic influence on the corticospinal pathway, and that descending volleys may produce autogenic terminal depolarization that is correlated with enhanced transmitter release. Presynaptic inhibition of afferent terminals by descending pathways and the absence of a reciprocal influence of peripheral input on corticospinal efficacy would help to preserve the fidelity of motor commands during centrally initiated movement.

Lateral asymmetry of motor unit number estimate (MUNE).

The aspects of lateral asymmetry of the peripheral nervous system have been investigated to a lesser extent than the aspects of lateral asymmetry in the central nervous system. We utilized a statistical method of quantitative MUNE to demonstrate lateral asymmetry of the motor units in healthy individuals, revealing higher values in the nondominant hand. Awareness of this phenomenon will improve the accuracy and reliability of this MUNE method when used in clinical trials.

Does sympathetic nerve discharge affect the firing of myelinated cutaneous afferents in humans?

In clinical practise, the notion that some complex regional pain syndromes (CRPS) are associated with sympathetic facilitation of nociceptive transmission is widespread. However, physiological increases in cutaneous sympathetic nerve activity have not been found to influence the firing properties of cutaneous polymodal nociceptive (high-threshold mechano-heat sensitive) fibers in human subjects. Whether the same applies to low-threshold cutaneous mechanoreceptors is not known. Such an effect could be relevant for sympathetic facilitation of nociception, given that tactile afferents are implicated in the allodynia associated with CRPS. This issue was addressed by recording the responses of single cutaneous mechanoreceptors in the glabrous skin of the finger pads to constant mechanical stimuli, at rest and during physiological increases in cutaneous sympathetic activity produced by arousal stimuli. Unitary recordings were made from 17 rapidly adapting (15 FAI and 2 FAII) and 20 slowly adapting (9 SAI and 11 SAII) afferents located in the finger pads via tungsten microelectrodes inserted percutaneously into the median nerve at the wrist in nine subjects. A servomotor applied 1 s constant-displacement ramp-and-hold indentations to the receptor-bearing digit every 3 s. Displacement and compression force were recorded. Blood flow in the finger pad and sweating in the palm were measured contralaterally. Increases in cutaneous sympathetic outflow caused only modest changes in the spontaneous and compression-evoked firing of tactile afferents. These changes were usually (for 26/37 afferents) related to the associated decreases in skin blood flow. The latency from the start of the ramp stimulus to the onset of firing was inversely correlated to flow (i.e. unit response was delayed during vasoconstriction) for 11/31 units (7/15 FAI, 1/2 FAII, 2/9 SAI, 1/5 SAII), whereas no units showed a positive correlation. Compression-evoked firing rates were positively correlated to flow (i.e. vasoconstriction reduced firing rates) for 14/31 units (2/15 FAI, 1/2 FAII, 7/9 SAI, 4/5 SAII), whereas no units showed a negative correlation. 10/11 SAII afferents exhibited spontaneous background firing, which increased for 4 and decreased for 4 in response to arousal stimuli, presumably reflecting their sensitivity to changes in skin stretch associated with sympathetically mediated reductions in blood volume in the finger pad. Two afferents showed no change, but nor was there significant vasoconstriction in these recordings. Thus, arousal stimuli reduced rather than augmented tactile afferent firing. The close relation to blood flow for all types of afferents, and the different responses among SAII afferents, suggest that sympathetically mediated changes in afferent firing properties are indirect, i.e. secondary to changes in the mechanoreceptors' tissue environment rather than to a direct sympathetic effect on the endings.