BACKGROUND Deep infiltrating endometriosis (DIE) is a specific type of endometriosis, which can be associated with more severe pelvic pain than other forms of endometriotic lesions. However, the ...mechanisms by which pain is generated are not well understood. METHODS DIE (n = 31) and peritoneal endometriotic (n = 40) lesions were sectioned and stained immunohistochemically with antibodies against protein gene product 9.5, neurofilament, nerve growth factor (NGF), NGF receptors tyrosine kinase receptor-A (Trk-A) and p75, substance P, calcitonin gene-related peptide, vesicular acetylcholine transporter, neuropeptide Y, vasoactive intestinal peptide and tyrosine hydroxylase to demonstrate myelinated, unmyelinated, sensory and autonomic nerve fibres. RESULTS There were significantly more nerve fibres in DIE (67.6 ± 65.1/mm2) than in peritoneal endometriotic lesions (16.3 ± 10.0/mm2) (P < 0.01). DIE was innervated abundantly by sensory Aδ, sensory C, cholinergic and adrenergic nerve fibres; NGF, Trk-A and p75 were strongly expressed in endometriotic glands and stroma of DIE. CONCLUSIONS The rich innervation of DIE may help to explain why patients with this type of lesion have severe pelvic pain.
Calcitonin gene-related peptide (CGRP), the most abundant neuropeptide in primary afferent sensory neurons, is strongly implicated in the pathophysiology of migraine headache, but its role in ...migraine is still equivocal. As a new approach to migraine treatment, humanized anti-CGRP monoclonal antibodies (CGRP-mAbs) were developed to reduce the availability of CGRP, and were found effective in reducing the frequency of chronic and episodic migraine. We recently tested the effect of fremanezumab (TEV-48125), a CGRP-mAb, on the activity of second-order trigeminovascular dorsal horn neurons that receive peripheral input from the cranial dura, and found a selective inhibition of high-threshold but not wide-dynamic range class of neurons. To investigate the basis for this selective inhibitory effect, and further explore the mechanism of action of CGRP-mAbs, we tested the effect of fremanezumab on the cortical spreading depression-evoked activation of mechanosensitive primary afferent meningeal nociceptors that innervate the cranial dura, using single-unit recording in the trigeminal ganglion of anesthetized male rats. Fremanezumab pretreatment selectively inhibited the responsiveness of Aδ neurons, but not C-fiber neurons, as reflected in a decrease in the percentage of neurons that showed activation by cortical spreading depression. These findings identify Aδ meningeal nociceptors as a likely site of action of fremanezumab in the prevention of headache. The selectivity in its peripheral inhibitory action may partly account for fremanezumab's selective inhibition of high-threshold, as a result of a predominant A-δ input to high-threshold neurons, but not wide dynamic-range dorsal horn neurons, and why it may not be effective in all migraine patients.
Recently, we reported that humanized CGRP monoclonal antibodies (CGRP-mAbs) prevent activation and sensitization of high-threshold (HT) but not wide-dynamic range trigeminovascular neurons by cortical spreading depression (CSD). In the current paper, we report that CGRP-mAbs prevent the activation of Aδ but not C-type meningeal nociceptors by CSD. This is the first identification of an anti-migraine drug that appears to be selective for Aδ-fibers (peripherally) and HT neurons (centrally). As the main CGRP-mAb site of action appears to be situated outside the brain, we conclude that the initiation of the headache phase of migraine depends on activation of meningeal nociceptors, and that for selected patients, activation of the Aδ-HT pain pathway may be sufficient for the generation of headache perception.
Why do axons differ in caliber? Perge, János A; Niven, Jeremy E; Mugnaini, Enrico ...
The Journal of neuroscience,
2012-Jan-11, 2012-01-11, 20120111, Letnik:
32, Številka:
2
Journal Article
Recenzirano
Odprti dostop
CNS axons differ in diameter (d) by nearly 100-fold (∼0.1-10 μm); therefore, they differ in cross-sectional area (d(2)) and volume by nearly 10,000-fold. If, as found for optic nerve, mitochondrial ...volume fraction is constant with axon diameter, energy capacity would rise with axon volume, also as d(2). We asked, given constraints on space and energy, what functional requirements set an axon's diameter? Surveying 16 fiber groups spanning nearly the full range of diameters in five species (guinea pig, rat, monkey, locust, octopus), we found the following: (1) thin axons are most numerous; (2) mean firing frequencies, estimated for nine of the identified axon classes, are low for thin fibers and high for thick ones, ranging from ∼1 to >100 Hz; (3) a tract's distribution of fiber diameters, whether narrow or broad, and whether symmetric or skewed, reflects heterogeneity of information rates conveyed by its individual fibers; and (4) mitochondrial volume/axon length rises ≥d(2). To explain the pressure toward thin diameters, we note an established law of diminishing returns: an axon, to double its information rate, must more than double its firing rate. Since diameter is apparently linear with firing rate, doubling information rate would more than quadruple an axon's volume and energy use. Thicker axons may be needed to encode features that cannot be efficiently decoded if their information is spread over several low-rate channels. Thus, information rate may be the main variable that sets axon caliber, with axons constrained to deliver information at the lowest acceptable rate.
Background:
The blood-brain barrier (BBB) plays the crucial role of limiting exposure of the central nervous system (CNS) to damaging molecules and cells. Dysfunction of the BBB is critical in a ...broad range of CNS disorders including neurodegeneration, inflammatory or traumatic injury to the CNS, and stroke. In peripheral tissues, the vascular-tissue permeability is normally greater than BBB permeability, but vascular leakage can be induced by efferent discharge activity in primary sensory neurons leading to plasma extravasation into the extravascular space. Whether discharge activity of sensory afferents entering the CNS may open the BBB or blood-spinal cord barrier (BSCB) remains an open question.
Results:
Here we show that peripheral nerve injury (PNI) produced by either sciatic nerve constriction or transecting two of its main branches causes an increase in BSCB permeability, as assessed by using Evans Blue dye or horseradish peroxidase. The increase in BSCB permeability was not observed 6 hours after the PNI but was apparent 24 hours after the injury. The increase in BSCB permeability was transient, peaking about 24–48 hrs after PNI with BSCB integrity returning to normal levels by 7 days. The increase in BSCB permeability was prevented by administering the local anaesthetic lidocaine at the site of the nerve injury. BSCB permeability was also increased 24 hours after electrical stimulation of the sciatic nerve at intensity sufficient to activate C-fibers, but not when A-fibers only were activated. Likewise, BSCB permeability increased following application of capsaicin to the nerve. The increase in permeability caused by C-fiber stimulation or by PNI was not anatomically limited to the site of central termination of primary afferents from the sciatic nerve in the lumbar cord, but rather extended throughout the spinal cord and into the brain.
Conclusions:
We have discovered that injury to a peripheral nerve and electrical stimulation of C-fibers each cause an increase in the permeability of the BSCB and the BBB. The increase in permeability is delayed in onset, peaks at about 24 hours and is dependent upon action potential propagation. As the increase is mimicked by applying capsaicin to the nerve, the most parsimonious explanation for our findings is that the increase in permeability is mediated by activation of TRPV1-expressing primary sensory neurons. Our findings may be relevant to the development of pain and neuroplastic changes in the CNS following nerve injury. In addition, our findings may provide the basis for developing methods to purposefully open the BBB when needed to increase brain penetration of therapeutic agents that might normally be excluded by an intact BBB.
Recent studies have provided evidence of pathology and functional abnormalities of small nerve fibers as a potential correlate of pain in the fibromyalgia syndrome. Here, we aimed to quantify dermal ...unmyelinated nerve fiber diameter at the electron microscopic level to find a potential morphological correlate of the functional disturbance. Thirty-two patients with fibromyalgia syndrome, 12 patients with small fiber neuropathy, and 24 healthy controls were prospectively recruited. Skin biopsies of the distal and proximal legs and index finger were taken and processed for immunofluorescence and for electron microscopy. We determined the diameter of small unmyelinated nerve fibers by measuring ten transversely cut axons of each biopsy. The mean axon diameter was reduced in patients with fibromyalgia syndrome compared with patients with small fiber neuropathy and controls (P < 0.05). Furthermore, we confirmed previous findings of disturbed small fiber function in quantitative sensory testing and of reduced intraepidermal nerve fiber density in patients with fibromyalgia. Our study provides further evidence of small fiber pathology in fibromyalgia syndrome and discloses differences compared with small fiber neuropathy, indicating that different pathomechanisms may lead to small fiber loss in the 2 disorders.
Aims/hypothesis
Corneal confocal microscopy is a rapid non-invasive ophthalmic imaging technique that identifies peripheral and central neurodegenerative disease. Quantification of corneal sub-basal ...nerve plexus morphology, however, requires either time-consuming manual annotation or a less-sensitive automated image analysis approach. We aimed to develop and validate an artificial intelligence-based, deep learning algorithm for the quantification of nerve fibre properties relevant to the diagnosis of diabetic neuropathy and to compare it with a validated automated analysis program, ACCMetrics.
Methods
Our deep learning algorithm, which employs a convolutional neural network with data augmentation, was developed for the automated quantification of the corneal sub-basal nerve plexus for the diagnosis of diabetic neuropathy. The algorithm was trained using a high-end graphics processor unit on 1698 corneal confocal microscopy images; for external validation, it was further tested on 2137 images. The algorithm was developed to identify total nerve fibre length, branch points, tail points, number and length of nerve segments, and fractal numbers. Sensitivity analyses were undertaken to determine the AUC for ACCMetrics and our algorithm for the diagnosis of diabetic neuropathy.
Results
The intraclass correlation coefficients for our algorithm were superior to those for ACCMetrics for total corneal nerve fibre length (0.933 vs 0.825), mean length per segment (0.656 vs 0.325), number of branch points (0.891 vs 0.570), number of tail points (0.623 vs 0.257), number of nerve segments (0.878 vs 0.504) and fractals (0.927 vs 0.758). In addition, our proposed algorithm achieved an AUC of 0.83, specificity of 0.87 and sensitivity of 0.68 for the classification of participants without (
n
= 90) and with (
n
= 132) neuropathy (defined by the Toronto criteria).
Conclusions/interpretation
These results demonstrated that our deep learning algorithm provides rapid and excellent localisation performance for the quantification of corneal nerve biomarkers. This model has potential for adoption into clinical screening programmes for diabetic neuropathy.
Data availability
The publicly shared cornea nerve dataset (dataset 1) is available at
http://bioimlab.dei.unipd.it/Corneal%20Nerve%20Tortuosity%20Data%20Set.htm
and
http://bioimlab.dei.unipd.it/Corneal%20Nerve%20Data%20Set.htm
.
Topical lidocaine (5%) leads to sufficient pain relief in only 29%-80% of treated patients, presumably by small-fiber block. The reasons for nonresponse are unclear; it may be due to different ...underlying pain mechanisms or partly insufficient anesthetic effect. Using quantitative sensory testing (QST) following the protocol of the DFNS (German Research Network on Neuropathic Pain), this study aims to assess the type and extent of somatosensory changes after lidocaine application in healthy volunteers. Twenty-six healthy volunteers underwent QST on the volar forearm, including thermal and mechanical detection and pain thresholds, twice before (for baseline retest reliability) and once after 6-hour simultaneous application with lidocaine patch 5% and contralateral placebo in a double-blinded manner. Pre and post differences of QST parameters were analyzed by paired t-test (Bonferroni-corrected alpha 0.0023). QST profiles did not change between the 2 baseline measurements and after the placebo application. Lidocaine application led to a significant change of only the small-fiber-associated thresholds (increase of thermal detection and mechanical pain thresholds, decrease of mechanical pain sensitivity). Tactile detection thresholds representing Aβ function remained unchanged. Interindividually, the extent of the small-fiber block varied widely (eg, thermal detection thresholds: in 54% of the subjects there were only minimal changes; in only 8% were there changes of >60% of the maximal achievable value). Topical lidocaine (5%) induces thermal hypoesthesia and pinprick hypoalgesia, suggesting an isolated but only partial block of Aδ and C fibers of unpredictable extent. Further studies must analyze the influencing factors and determine whether patients with poor analgesic effect, in particular, are those with insufficient small-fiber block.
Small-fibre neuropathy (SFN), a disorder of thinly myelinated Aδ-fibres and unmyelinated C-fibres, is clinically characterized by neuropathic pain symptoms and autonomic complaints. Diagnosis of SFN ...is challenging as the clinical picture can be difficult to interpret and results from nerve conduction studies are often normal. In cases of suspected SFN, measurement of intraepidermal nerve fibre density and/or analysis of quantitative sensory testing can enable diagnosis. New diagnostic techniques (including measurement of nerve fibre density using corneal confocal microscopy, and nociceptive evoked potentials) may contribute to the diagnostic work-up. SFN can be associated with systemic diseases such as immune-mediated disorders, but remains idiopathic in a substantial proportion of patients. Gain-of-function variants in the Na(v)1.7 sodium channel have recently been found in nearly 30% of patients with idiopathic SFN, but the mechanisms of axonal degeneration in the disorder remain under investigation. Identification of the systemic diseases underlying SFN will enable development of drugs that target affected pathways to improve the management of neuropathic pain and autonomic dysfunction. In this Review, we discuss recent advances in the diagnosis and pathophysiology of SFN, highlighting how improved understanding of these aspects of the disorder will contribute to better patient management.
Mechanical allodynia, induced by normally innocuous low-threshold mechanical stimulation, represents a cardinal feature of neuropathic pain. Blockade or ablation of high-threshold, small-diameter ...unmyelinated group C nerve fibers (C-fibers) has limited effects on mechanical allodynia. Although large, myelinated group A fibers, in particular Aβ-fibers, have previously been implicated in mechanical allodynia, an A-fiber-selective pharmacological blocker is still lacking. Here we report a new method for targeted silencing of A-fibers in neuropathic pain. We found that Toll-like receptor 5 (TLR5) is co-expressed with neurofilament-200 in large-diameter A-fiber neurons in the dorsal root ganglion (DRG). Activation of TLR5 with its ligand flagellin results in neuronal entry of the membrane-impermeable lidocaine derivative QX-314, leading to TLR5-dependent blockade of sodium currents, predominantly in A-fiber neurons of mouse DRGs. Intraplantar co-application of flagellin and QX-314 (flagellin/QX-314) dose-dependently suppresses mechanical allodynia after chemotherapy, nerve injury, and diabetic neuropathy, but this blockade is abrogated in Tlr5-deficient mice. In vivo electrophysiology demonstrated that co-application of flagellin/QX-314 selectively suppressed Aβ-fiber conduction in naive and chemotherapy-treated mice. TLR5-mediated Aβ-fiber blockade, but not capsaicin-mediated C-fiber blockade, also reduced chemotherapy-induced ongoing pain without impairing motor function. Finally, flagellin/QX-314 co-application suppressed sodium currents in large-diameter human DRG neurons. Thus, our findings provide a new tool for targeted silencing of Aβ-fibers and neuropathic pain treatment.
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