BACKGROUND AND PURPOSE: Diagnosing small-fiber neuropathy (SFN) is challenging because there is no gold-standard test and few diagnostic tests. This study investigated the clinical symptom profile and its associations with the results of quantitative sensory testing (QST) and the quantitative sudomotor axon reflex test (QSART) as well as the quality of life (QOL) in patients with clinically suspected SFN. METHODS: This study involved 63 patients with clinically suspected length-dependent SFN. Assessments were performed using QST, QSART, SFN Symptoms Inventory Questionnaire, Neuropathic Pain Symptom Inventory, ‘Sirim’ frequency and ‘Sirim’ (cold) pain severity, and 36-item Short-Form Health Survey. Multiple logistic and linear regression analyses were performed to predict risk factors for QST or QSART abnormalities and QOL, respectively. RESULTS: ‘Sirim’ and ‘Sirim’ pain was the most-common (84%) and the most-severe complaint (mean score of 6.3 on a numerical rating scale ranging from 0 to 10) in patients with clinically suspected SFN. The findings of QST [cold detection threshold (CDT)] and QSART were abnormal in 71% (n=45/57) and 62% (n=39/56) of the patients, respectively. An abnormal CDT was correlated with more-severe stabbing pain (odds ratio=2.23, 95% CI=1.02–4.87, p=0.045). Restless-leg symptoms (β=−7.077) and pressure-evoked pain (β=−5.034) were independent predictors of the physical aspects of QOL. CONCLUSIONS: ‘Sirim’ pain, similar to cold pain, should be considered a major neuropathic pain in SFN. Among pain characteristics, stabbing pain of a spontaneous paroxysmal nature may be more pronounced in the setting of dysfunctional Aδ fibers with functional autonomic C fibers.
Axons ; Diagnostic Tests, Routine ; Erythromelalgia ; Health Surveys ; Humans ; Linear Models ; Nerve Fibers, Unmyelinated ; Neuralgia ; Quality of Life ; Reflex ; Risk Factors

The superficial dorsal horn of the spinal cord plays an important role in pain transmission and opioid activity. Several studies have demonstrated that opioids modulate pain transmission, and the activation of µ-opioid receptors (MORs) by opioids contributes to analgesic effects in the spinal cord. However, the effect of the activation of MORs on GABAergic interneurons and the contribution to the analgesic effect are much less clear. In this study, using transgenic mice, which allow the identification of GABAergic interneurons, we investigated how the activation of MORs affects the excitability of GABAergic interneurons and synaptic transmission between primary nociceptive afferent and GABAergic interneurons. We found that a selective µ-opioid agonist, [D-Ala², NMe-Phe⁴, Gly-ol]-enkephanlin (DAMGO), induced an outward current mediated by K⁺ channels in GABAergic interneurons. In addition, DAMGO reduced the amplitude of evoked excitatory postsynaptic currents (EPSCs) of GABAergic interneurons which receive monosynaptic inputs from primary nociceptive C fibers. Taken together, we found that DAMGO reduced the excitability of GABAergic interneurons and synaptic transmission between primary nociceptive C fibers and GABAergic interneurons. These results suggest one possibility that suppression of GABAergic interneurons by DMAGO may reduce the inhibition on secondary GABAergic interneurons, which increase the inhibition of the secondary GABAergic interneurons to excitatory neurons in the spinal dorsal horn. In this circumstance, the sum of excitation of the entire spinal network will control the pain transmission.
Analgesics, Opioid ; Animals ; Enkephalin, Ala(2)-MePhe(4)-Gly(5)- ; Excitatory Postsynaptic Potentials ; GABAergic Neurons* ; Interneurons ; Mice ; Mice, Transgenic ; Nerve Fibers, Unmyelinated ; Neurons ; Spinal Cord ; Spinal Cord Dorsal Horn* ; Substantia Gelatinosa ; Synaptic Transmission

PURPOSE: Naftopidil ((±)-1-[4-(2-methoxyphenyl) piperazinyl]-3-(1-naphthyloxy) propan-2-ol) is prescribed in several Asian countries for lower urinary tract symptoms suggestive of benign prostatic hyperplasia. Previous animal experiments showed that intrathecal injection of naftopidil abolished rhythmic bladder contraction in vivo. Naftopidil facilitated spontaneous inhibitory postsynaptic currents in substantia gelatinosa (SG) neurons in spinal cord slices. These results suggest that naftopidil may suppress the micturition reflex at the spinal cord level. However, the effect of naftopidil on evoked excitatory postsynaptic currents (EPSCs) in SG neurons remains to be elucidated. METHODS: Male Sprague-Dawley rats at 6 to 8 weeks old were used. Whole-cell patch-clamp recordings were made using SG neurons in spinal cord slices isolated from adult rats. Evoked EPSCs were analyzed in Aδ or C fibers. Naftopidil or prazosin, an α1-adrenoceptor blocker, was perfused at 100 μM or 10 μM, respectively. RESULTS: Bath-applied 100 μM naftopidil significantly decreased the peak amplitudes of Aδ and C fiber-evoked EPSCs to 72.0%±7.1% (n=15) and 70.0%±5.5% (n=20), respectively, in a reversible and reproducible manner. Bath application of 10μM prazosin did not inhibit Aδ or C fiber-evoked EPSCs. CONCLUSIONS: The present study suggests that a high concentration of naftopidil reduces the amplitude of evoked EPSCs via a mechanism that apparently does not involve α1-adrenoceptors. Inhibition of evoked EPSCs may also contribute to suppression of the micturition reflex, together with nociceptive stimulation.
Adult ; Animal Experimentation ; Animals ; Asian Continental Ancestry Group ; Baths ; Excitatory Postsynaptic Potentials ; Humans ; In Vitro Techniques* ; Inhibitory Postsynaptic Potentials ; Injections, Spinal ; Lower Urinary Tract Symptoms ; Male ; Nerve Fibers, Unmyelinated ; Neurons* ; Prazosin ; Prostatic Hyperplasia ; Rats ; Rats, Sprague-Dawley ; Reflex ; Spinal Cord ; Substantia Gelatinosa* ; Urinary Bladder ; Urination

Chemotherapy-induced peripheral neuropathy (CIPN) is one of the most serious complications associated with anticancer drugs. CIPN leads to a lower quality of life and dysfunction of the sensory, motor, and autonomic systems, and often causes patients to discontinue chemotherapy. It is usually misdiagnosed and undertreated due to a lack of consensus and unclear pathophysiology, for which many mechanisms have been suggested, including mitochondrial dysfunction, various pain mediators, abnormal spontaneous discharge in A and C fibers, and others. To date, no agents have been shown to effectively prevent CIPN, leading to debate as to the standard protocol. Duloxetine has demonstrated a moderate therapeutic effect against CIPN. Although tricyclic antidepressants (such as nortriptyline or desipramine), gabapentin, and a topical gel containing baclofen (10 mg), amitriptyline HCL (40 mg), and ketamine (20 mg) showed inconclusive results in CIPN trials, these agents are currently considered the best options for CIPN treatment. Therefore, further studies on the pathophysiology and treatment of CIPN are needed.
Amitriptyline ; Antidepressive Agents, Tricyclic ; Baclofen ; Consensus ; Drug Therapy* ; Humans ; Ketamine ; Nerve Fibers, Unmyelinated ; Neuralgia* ; Nortriptyline ; Peripheral Nervous System Diseases ; Quality of Life ; Duloxetine Hydrochloride

BACKGROUND: The current perception threshold (CPT) could be quantified by stimulating Abeta and C fibers at 2,000 and 5 Hz, respectively. C fibers play a role in the autonomic nervous system and are involved in temperature and pain sensation. We evaluated the usefulness of CPT for diagnosing distal polyneuropathy (DPN) and cardiovascular autonomic neuropathy (CAN) in diabetic patients. METHODS: The CPT was measured in the index finger (C7 level) and in the third toe (L5 level) in diabetic patients aged 30 to 69 years. We assessed DPN according to the neuropathy total symptom score-6 (NTSS-6) and 10-g monofilament pressure sensation. Subjects with a NTSS-6 >6 or with abnormal 10-g monofilament sensation were defined to have DPN. CAN was evaluated by spectral analysis of heart rate variability and by Ewing's traditional tests. RESULTS: The subjects with DPN had significantly higher CPT at all of the frequencies than the subjects without DPN (P<0.05). Abnormal 10-g monofilament sensation and NTSS-6 >6 could be most precisely predicted by CPT at 2,000 and 5 Hz, respectively. However, only 6.5% and 19.6% of subjects with DPN had an abnormal CPT at 2,000 Hz at the C7 and L5 levels. Although CPT at 5 Hz showed a negative correlation with the power of low and high frequency in the spectral analysis (P<0.05), only 16.7% of subjects with CAN exhibited an abnormal CPT at the same frequency. CONCLUSION: Although the CPT is significantly associated with neuropathic symptoms or signs corresponding to the nerve fiber stimulated, it provides little additional information compared with conventional evaluations.
Autonomic Nervous System ; Diabetes Mellitus* ; Diabetic Neuropathies* ; Fingers ; Heart Rate ; Humans ; Nerve Fibers ; Nerve Fibers, Unmyelinated ; Polyneuropathies ; Sensation ; Toes

INTRODUCTION: Mammalian tooth pulp is densely innervated by sensory nerves that are mostly C fibers and A delta fibers. However, there is evidence suggesting that many unmyelinated axons in the pulp are in fact parent meylinated axons. MATERIALS AND METHODS: The pulp was removed from healthy premolars and 3rd molars extracted from juveniles and adults undergoing orthodontic treatment, and immunohistochemical staining were applied with NPF200 antibodies, which specifically dye myelinated axons. The specimens underwent an electron microscopy examination with diaminobenzidine (DAB) immunostaining after observation and analysis by fluorescence and confocal laser scanning microscopy. RESULTS: The NPF200 immuno-positive axons in the radicular pulp areas were observed as bundles of many nerve fibers. Many small bundles were formed with fewer axons when firing to the coronal pulp areas and then reachrd a different direction. CONCLUSION: Myelinated fibers innervated to the dental pulp maintain their myelins in the radicular portion, but these fibers lost myelins in the coronal portion. Afterthe loss of myelin, the size of the axoplasm also decreased.
Adult ; Antibodies ; Axons ; Bicuspid ; Demyelinating Diseases ; Dental Pulp ; Fires ; Fluorescence ; Humans ; Microscopy, Electron ; Molar ; Myelin Sheath ; Nerve Fibers ; Nerve Fibers, Unmyelinated ; Parents ; Tooth

Long-term potentiation (LTP) of C-fiber evoked field potentials in spinal dorsal horn is first reported in 1995. Since then, the mechanisms underlying the long-lasting enhancement in synaptic transmission between primary afferent C-fibers and neurons in spinal dorsal horn have been investigated by different laboratories. In this article, the related data were summarized and discussed.
Animals ; Evoked Potentials ; Long-Term Potentiation ; Nerve Fibers, Unmyelinated ; physiology ; Posterior Horn Cells ; cytology ; Rats, Sprague-Dawley ; Synaptic Transmission

To determine the peripheral mechanisms involved in thermal sweating during the hot summers in July before acclimatization and after acclimatization in September, we evaluated the sweating response of healthy subjects (n=10) to acetylcholine (ACh), a primary neurotransmitter involved in peripheral sudomotor sensitivity. The quantitative sudomotor axon reflex test (QSART) measures sympathetic C fiber function after iontophoresed ACh evokes a measurable reliable sweat response. The QSART, at 2 mA for 5 min with 10% ACh, was applied to determine the directly activated (DIR) and axon reflex-mediated (AXR) sweating responses during ACh iontophoresis. The AXR sweat onset-time by the axon reflex was 1.50+/-0.32 min and 1.84+/-0.46 min before acclimatization in July and after acclimatization in September, respectively (p<0.01). The sweat volume of the AXR(1) [during 5 min 10% iontophoresis] by the axon reflex was 1.45+/-0.53 mg/cm2 and 0.98+/-0.24 mg/cm2 before acclimatization in July and after acclimatization in September, respectively (p<0.001). The sweat volume of the AXR(2) [during 5 min post-iontophoresis] by the axon reflex was 2.06+/-0.24 mg/cm2 and 1.39+/-0.32 mg/cm2 before and after acclimatization in July and September, respectively (p<0.001). The sweat volume of the DIR was 5.88+/-1.33 mg/cm2 and 4.98+/-0.94 mg/cm2 before and after acclimatization in July and September, respectively (p<0.01). These findings suggest that lower peripheral sudomotor responses of the ACh receptors are indicative of a blunted sympathetic nerve response to ACh during exposure to hot summer weather conditions.
Acclimatization ; Acetylcholine ; Axons ; Hot Temperature ; Iontophoresis ; Nerve Fibers, Unmyelinated ; Neurotransmitter Agents ; Receptors, Cholinergic ; Reflex ; Sweat ; Sweating ; Weather

BACKGROUND/AIMS: Hepatic nerve innervation plays important roles in hepatic metabolism and hemodynamic mechanisms. We compared the distribution patterns of hepatic nerves between normal livers and two liver diseases to elucidate the effects of liver disease on the distribution of hepatic nerves. METHODS: Tissue specimens were obtained by ultrasonography-guided needle biopsies from 10 normal controls, 74 patients with chronic hepatitis (CH), and 35 patients with liver cirrhosis (LC). The obtained specimens were immunohistochemically stained using antibodies for S-100 protein and alpha-smooth-muscle actin (alpha-SMA). The degree of the expression in liver tissues was quantified by manual counting of positively stained nerve fibers under light microscopy. The serum hyaluronic acid level was assayed in all subjects to evaluate hepatic fibrosis. Electron microscopy examinations were also performed. RESULTS: The hepatic nerve innervation was significantly lower in LC than in normal controls, as indicated by S-100 protein staining. alpha-SMA and hyaluronic acid levels were higher in LC and CH than in normal controls. Electron microscopy revealed that unmyelinated nerve fiber bundles in the intralobar connective tissue coursed in the vicinity of hepatic triads. CONCLUSIONS: These results suggest that hepatic nerve innervation can be decreased by hepatic inflammatory responses and/or fibrotic changes in LC patients. Further study is needed to clarify this observation.
Actins ; Antibodies ; Biopsy, Needle ; Connective Tissue ; Fibrosis ; Hemodynamics ; Hepatitis, Chronic ; Humans ; Hyaluronic Acid ; Liver Cirrhosis* ; Liver Diseases ; Liver* ; Metabolism ; Microscopy ; Microscopy, Electron ; Nerve Fibers* ; Nerve Fibers, Unmyelinated ; S100 Proteins

The vanilloid receptor TRPV1 has been suggested to play an important role in thermal nociception and inflammatory hyperalgesia. In our previous study, we examined the expression of TRPV1 and colocalization of TRPV1 with substance P (SP) and calcitonin gene related peptide (CGRP) through fluorescence immunocytochemistry. Here, we investigated ultrastructural characteristics of TRPV1 immunoreactive fibers in the human tooth pulp through preembedding immunocytochemistry. TRPV1 immunoreactivity was present in the unmyelinated nerve fibers in the tooth pulp. There were two types of TRPV1 IR nerve fibers identified in the human tooth pulp: one containing clear round vesicles and many dense-cored vesicles, the other containing clear round vesicles and few dense-cored vesicles. TRPV1 immunoreactive fibers were constant in diameter without swellings along the length. Boutons en passant and boutons terminaux usually observed in the CNS were not observed in the TRPV1 immunoreactive fibers. Many vesicles were accumulated in the TRPV1 immunoreactive fibers, however synaptic structure was not found. It is known that dense-cored vesicles contain neuropeptides such as SP and CGRP and clear round vesicles contain neurotransmitter such as glutamate. Taken together, our results suggest that TRPV1 immunoreactive fibers showing distinct ultrastructructural features may be involved in inflammatory hyperalgesia and thermal nociception in the tooth pulp.
Calcitonin Gene-Related Peptide ; Fluorescence ; Glutamic Acid ; Humans* ; Hyperalgesia ; Immunohistochemistry ; Nerve Fibers ; Nerve Fibers, Unmyelinated ; Neuropeptides ; Neurotransmitter Agents ; Nociception ; Substance P ; Tooth*