Neuropathic pain caused by miswiring and abnormal end organ targeting.

Nerve injury leads to chronic pain and exaggerated sensitivity to gentle touch (allodynia) as well as a loss of sensation in the areas in which injured and non-injured nerves come together1-3. The mechanisms that disambiguate these mixed and paradoxical symptoms are unknown. Here we longitudinally and non-invasively imaged genetically labelled populations of fibres that sense noxious stimuli (nociceptors) and gentle touch (low-threshold afferents) peripherally in the skin for longer than 10 months after nerve injury, while simultaneously tracking pain-related behaviour in the same mice. Fully denervated areas of skin initially lost sensation, gradually recovered normal sensitivity and developed marked allodynia and aversion to gentle touch several months after injury. This reinnervation-induced neuropathic pain involved nociceptors that sprouted into denervated territories precisely reproducing the initial pattern of innervation, were guided by blood vessels and showed irregular terminal connectivity in the skin and lowered activation thresholds mimicking low-threshold afferents. By contrast, low-threshold afferents-which normally mediate touch sensation as well as allodynia in intact nerve territories after injury4-7-did not reinnervate, leading to an aberrant innervation of tactile end organs such as Meissner corpuscles with nociceptors alone. Genetic ablation of nociceptors fully abrogated reinnervation allodynia. Our results thus reveal the emergence of a form of chronic neuropathic pain that is driven by structural plasticity, abnormal terminal connectivity and malfunction of nociceptors during reinnervation, and provide a mechanistic framework for the paradoxical sensory manifestations that are observed clinically and can impose a heavy burden on patients.

Bacterially produced metabolites protect C. elegans neurons from degeneration.

Caenorhabditis elegans and its cognate bacterial diet comprise a reliable, widespread model to study diet and microbiota effects on host physiology. Nonetheless, how diet influences the rate at which neurons die remains largely unknown. A number of models have been used in C. elegans as surrogates for neurodegeneration. One of these is a C. elegans strain expressing a neurotoxic allele of the mechanosensory abnormality protein 4 (MEC-4d) degenerin/epithelial Na+ (DEG/ENaC) channel, which causes the progressive degeneration of the touch receptor neurons (TRNs). Using this model, our study evaluated the effect of various dietary bacteria on neurodegeneration dynamics. Although degeneration of TRNs was steady and completed at adulthood in the strain routinely used for C. elegans maintenance (Escherichia coli OP50), it was significantly reduced in environmental and other laboratory bacterial strains. Strikingly, neuroprotection reached more than 40% in the E. coli HT115 strain. HT115 protection was long lasting well into old age of animals and was not restricted to the TRNs. Small amounts of HT115 on OP50 bacteria as well as UV-killed HT115 were still sufficient to produce neuroprotection. Early growth of worms in HT115 protected neurons from degeneration during later growth in OP50. HT115 diet promoted the nuclear translocation of DAF-16 (ortholog of the FOXO family of transcription factors), a phenomenon previously reported to underlie neuroprotection caused by down-regulation of the insulin receptor in this system. Moreover, a daf-16 loss-of-function mutation abolishes HT115-driven neuroprotection. Comparative genomics, transcriptomics, and metabolomics approaches pinpointed the neurotransmitter γ-aminobutyric acid (GABA) and lactate as metabolites differentially produced between E. coli HT115 and OP50. HT115 mutant lacking glutamate decarboxylase enzyme genes (gad), which catalyze the conversion of GABA from glutamate, lost the ability to produce GABA and also to stop neurodegeneration. Moreover, in situ GABA supplementation or heterologous expression of glutamate decarboxylase in E. coli OP50 conferred neuroprotective activity to this strain. Specific C. elegans GABA transporters and receptors were required for full HT115-mediated neuroprotection. Additionally, lactate supplementation also increased anterior ventral microtubule (AVM) neuron survival in OP50. Together, these results demonstrate that bacterially produced GABA and other metabolites exert an effect of neuroprotection in the host, highlighting the role of neuroactive compounds of the diet in nervous system homeostasis.

Evaluation of the distribution of mechanoreceptors in the hip joint with severe coxarthrosis in 9 patients: A histologic and stereological study.

Due to its high mobility, hip joint plays a crucial role in executing many movements such as standing, sitting, running, crouching. The distribution of mechanoreceptors and neural elements in anatomical structures that provide stabilization of the hip joint is important in determining the optimal surgical incision site for the hip joint stabilizers in patients with coxarthrosis. Various studies have been conducted about the mechanoreceptors and distribution of neural elements in structures such as the transvers acetabular ligament, teres (round) ligament of femur, acetabular labrum and hip joint capsule with using various staining methods. To our knowledge, there is insufficient information about the mechanoreceptor distribution within the anatomic structures that participate in stabilization of the hip joint. This study is planned to examine the distribution of mechanoreceptors in the transverse acetabular ligament, teres ligament, acetabular labrum and joint capsule in samples obtained during the surgery who are operated for hip replacement surgery due to severe coxarthrosis. Each specimen was stained with silver impregnation technique and density of mechanoreceptors were estimated by stereological method. Teres ligament has the highest number of mechanoreceptors among all other specimens. Within the joint capsule, mechanoreceptors were most abundant at its antero-inferior part, whereas its anterior part contained the lowest number of mechanoreceptors. These results suggest that, as the anterior part of hip capsule bears the lowest number of mechanoreceptors, it might be safer for incision during total hip arthroplasty surgery.

Riveting hammer vibration damages mechanosensory nerve endings.

Hand-arm vibration syndrome (HAVS) is an irreversible neurodegenerative, vasospastic, and musculoskeletal occupational disease of workers who use powered hand tools. The etiology is poorly understood. Neurological symptoms include numbness, tingling, and pain. This study examines impact hammer vibration-induced injury and recoverability of hair mechanosensory innervation. Rat tails were vibrated 12 min/d for 5 weeks followed by 5 week recovery with synchronous non-vibrated controls. Nerve fibers were PGP9.5 immunostained. Lanceolate complex innervation was compared quantitatively in vibrated vs sham. Vibration peak acceleration magnitudes were characterized by frequency power spectral analysis. Average magnitude (2515 m/s2 , root mean squared) in kHz frequencies was 109 times that (23 m/s2 ) in low Hz. Percentage of hairs innervated by lanceolate complexes was 69.1% in 5-week sham and 53.4% in 5-week vibration generating a denervation difference of 15.7% higher in vibration. Hair innervation was 76.9% in 5-weeks recovery sham and 62.0% in 5-week recovery vibration producing a denervation difference 14.9% higher in recovery vibration. Lanceolate number per complex (18.4 ± 0.2) after vibration remained near sham (19.3 ± 0.3), but 44.9% of lanceolate complexes were abnormal in 5 weeks vibrated compared to 18.8% in sham. The largest vibration energies are peak kHz accelerations (approximately 100 000 m/s2 ) from shock waves. The existing ISO 5349-1 standard excludes kHz vibrations, seriously underestimating vibration injury risk. The present study validates the rat tail, impact hammer vibration as a model for investigating irreversible nerve damage. Persistence of higher denervation difference after 5-week recovery suggests repeated vibration injury destroys the capability of lanceolate nerve endings to regenerate.

A meissnerian neurofibroma: Case report of a rare neurofibroma variant.

Structures resembling Meissner corpuscles have been described in various nerve sheath tumors, including schwannomas and neurofibromas. When present, they are focal or scattered, and rarely a prominent feature of the lesion. Here, we report a case of a 39-year-old female who presented with an isolated lesion on her abdomen. Histopathologically, the tumor was almost exclusively composed of Meissner corpuscle-like structures (pseudo-meissnerian bodies). At a small edge of the tumor, there were features of a classic neurofibroma, with a mixture of Schwann cells, fibroblast-like cells, and interspersed mast cells. We propose the term "meissnerian neurofibroma" for this extremely rare variant of neurofibroma.

Therapeutic Potential of Wnt and Notch Signaling and Epigenetic Regulation in Mammalian Sensory Hair Cell Regeneration.

Hearing loss is one of the most prevalent sensory deficits worldwide and can result from the death of mechanosensory hair cells that transduce auditory signals in the cochlea. The mammalian cochlea lacks the capacity to regenerate these hair cells once damaged, and currently there are no biological therapies for hearing loss. Understanding the signaling pathways responsible for hair cell development can inform regenerative strategies and identify targets for treating hearing loss. The canonical Wnt and Notch pathways are critical for cochlear development; they converge on several key molecules, such as Atoh1, to regulate prosensory specification, proliferation, hair cell differentiation, and cellular organization. Much work has focused on Wnt and Notch modulation in the neonatal mouse cochlea, where they can promote hair cell regeneration. However, this regenerative response is limited in the adult cochlea and this might be attributed to age-dependent epigenetic modifications. Indeed, the epigenetic status at key gene loci undergoes dynamic changes during cochlear development, maturation, and aging. Therefore, strategies to improve regenerative success in the adult cochlea might require the modulation of Wnt, Notch, or other pathways, as well as targeted epigenetic modifications to alter the activity of key genes critical for supporting cell proliferation or transdifferentiation.

Histopathological Evaluation of Mechanoreceptors in the Metatarsophalangeal Joint Capsule in Hallux Valgus.

To date, we could find no study concerning the relationship between mechanoreceptors in the joint capsule of the first metatarsophalangeal joint and hallux valgus deformity. We aimed to investigate the presence of mechanoreceptors in samples obtained from the first metatarsophalangeal joint capsules of patients with hallux valgus deformity to improve our understanding of the clinical and histopathological features of the disease. Samples were taken from the first metatarsophalangeal joint capsules of 13 fresh-frozen cadavers with normal anatomy (controls) and 29 patients undergoing surgery for hallux valgus (cases). For light microscopy, excised specimens were fixed in 10% formaldehyde and processed for routine histopathological investigation. All samples were dehydrated in a series of ethanol, cleared in xylene, and embedded in paraffin. Orientation of collagen fibers was determined on Masson's trichrome-stained sections, and mechanoreceptors were evaluated on S-100-immunostained sections. In the sections stained with Masson's trichrome, the orientation of collagen fibers was regular in the control group. However, coarse and disoriented collagen bundles were observed in the hallux valgus cases (P ≤ .05). S-100 immunostaining was positive in the sections of both the cases and controls. Finally, free nerve endings were more abundant in the samples obtained from the capsules of hallux valgus cases than from the control group (P ≤ .05). An increase in the number of free nerve endings within the capsules of the first metatarsophalangeal joints in feet with hallux valgus deformity might have a role in the development of clinically relevant joint pain and instability.

Ageing of the somatosensory system at the periphery: age-related changes in cutaneous mechanoreceptors.

Decline of tactile sensation associated with ageing depends on modifications in skin and both central and peripheral nervous systems. At present, age-related changes in the periphery of the somatosensory system, particularly concerning the effects on mechanoreceptors, remain unknown. Here we used immunohistochemistry to analyse the age-dependent changes in Meissner's and Pacinian corpuscles as well as in Merkel cell-neurite complexes. Moreover, variations in the neurotrophic TrkB-BDNF system and the mechanoprotein Piezo2 (involved in maintenance of cutaneous mechanoreceptors and light touch, respectively) were evaluated. The number of Meissner's corpuscles and Merkel cells decreased progressively with ageing. Meissner's corpuscles were smaller, rounded in morphology and located deeper in the dermis, and signs of corpuscular denervation were found in the oldest subjects. Pacinian corpuscles generally showed no relevant age-related alterations. Reduced expression of Piezo2 in the axon of Meissner's corpuscles and in Merkel cells was observed in old subjects, as well was a decline in the BDNF-TrkB neurotrophic system. This study demonstrates that cutaneous Meissner's corpuscles and Merkel cell-neurite complexes (and less evidently Pacinian corpuscles) undergo morphological and size changes during the ageing process, as well as a reduction in terms of density. Furthermore, the mechanoprotein Piezo2 and the neurotrophic TrkB-BDNF system are reduced in aged corpuscles. Taken together, these alterations might explain part of the impairment of the somatosensory system associated with ageing.

Hyperplastic sensory corpuscles in nevus sebaceus of labia minora pudendi. A case report.

A vulvar case of nevus sebaceus is presented. During the routine histopatological examination, attention was drawn by several corpuscular structures. Immunohistochemistry demonstrated that they were sensory corpuscles, identified respectively as Meissner-like and glomerular corpuscles. Nevertheless, compared with typical Meissner corpuscles from digital glabrous skin, Meissner-like corpuscles identified here were bigger, the axon showed an irregular course, and the lamellar cells were smaller. Regarding the glomerular corpuscles they were bigger but with a normal arrangement of the corpuscular constituents. These findings suggest that these cutaneous sensory corpuscles are part of the nevus sebaceus hamartoma.

Assessment of thermotactile and vibrotactile thresholds for detecting sensorineural components of the hand-arm vibration syndrome (HAVS).

BACKGROUND: Thermotactile thresholds and vibrotactile thresholds are measured to assist the diagnosis of the sensorineural component of the hand-arm vibration syndrome (HAVS). OBJECTIVES: This study investigates whether thermotactile and vibrotactile thresholds distinguish between fingers with and without numbness and tingling. METHODS: In 60 males reporting symptoms of the hand-arm vibration syndrome, thermotactile thresholds for detecting hot and cold temperatures and vibrotactile thresholds at 31.5 and 125 Hz were measured on the index and little fingers of both hands. RESULTS: In fingers reported to suffer numbness or tingling, hot thresholds increased, cold thresholds decreased, and vibrotactile thresholds at both 31.5 and 125 Hz increased. With sensorineural symptoms on all three phalanges (i.e. numbness or tingling scores of 6), both thermotactile thresholds and both vibrotactile thresholds had sensitivities greater than 80% and specificities around 90%, with areas under the receiver operating characteristic curves around 0.9. There were correlations between all four thresholds, but cold thresholds had greater sensitivity and greater specificity on fingers with numbness or tingling on only the distal phalanx (i.e. numbness or tingling scores of 1) suggesting cold thresholds provide better indications of early sensorineural disorder. CONCLUSIONS: Thermotactile thresholds and vibrotactile thresholds can provide useful indications of sensorineural function in patients reporting symptoms of the sensorineural component of HAVS.

A mitochondrial targeting tetrapeptide Bendavia protects lateral line hair cells from gentamicin exposure.

The hearing loss induced by aminoglycosides is caused by the permanent loss of mechanosensory hair cells of the inner ear. The aim of the present study is therefore to evaluate the protective effect of Bendavia, a novel antioxidant, on gentamicin-induced hair cell damage in zebrafish lateral lines. The results demonstrated the pretreatment of Bendavia exhibited dose-dependent protection against gentamicin in both acute and chronic exposure. We found that Bendavia at 150 µm conferred optimal protection from either acute or chronic exposure with ototoxin. Bendavia reduced uptake of fluorescent-tagged gentamicin via mechanoelectrical transduction channels, suggesting its protective effects may be partially due to decreasing ototoxic molecule uptake. The intracellular death pathways inhibition triggered by gentamicin might be also included as no blockage of gentamicin was observed. Our data suggest that Bendavia represents a novel otoprotective drug that might provide a therapeutic alternative for patients receiving aminoglycoside treatment.

Changes of mechanoreceptors in different-state remnants of ruptured anterior cruciate ligament.

OBJECTIVE: To observe the changes in the quantity and morphology of mechanoreceptors in different-state remnant stumps of ruptured anterior cruciate ligaments (ACLs). METHODS: Specimens of completely ruptured ACL remnants were collected from 57 patients. The injury time from injury to surgery was recorded. According to the degree of pre-operative anterior displacement of knee joint, these patients were divided into two groups: group 1 (≤ 6 mm) and group 2 (> 6 mm). The morphology type of ligament remnant in each patient was identified. The correlations of mechanoreceptor number in the remnant stumps with the morphology of ligament stump, injured knee stability, and injury time were analyzed. Subsequently, based on ACL lesion type, patients were divided into four groups including groups A, B, C, and D, and then, the items above were compared among the four groups. RESULTS: Group 1 contained 20 specimens including three with type B and 17 with type C. Group 2 contained 37 specimens including 20 with type A, 1 with type B, 2 with type C, and 14 with type D. The distributions of four-type remnant morphologies (X2 = 49.406, P = 0.000) and mechanoreceptors (X2 = 13.84, P = 0.002) were all significantly different between the two groups. The number of mechanoreceptors was positively correlated with the injured knee stability (r = 0.63,P = 0.018). The number of the mechanoreceptors was not obviously correlated with the injury time in group 1 (r = - 0.37,P = 0.136), while it was negatively correlated with the injury time in group 2 (r = - 0.51,P = 0.022). There was a significant difference in pre-operative anterior displacement of knee joint among groups A, B, C, and D (F = 85.59, P = 0.000), and the pre-operative anterior displacement of knee joint was less in groups B and C than in groups A and D. There was a significant difference in the distribution of typical and atypical mechanoreceptors among groups A, B, C, and D (X2 = 68.16, P = 0.032). CONCLUSIONS: The ruptured ACL remnants connecting the femur to tibia can still play a role in maintaining knee stability; thus, the mechanoreceptors can persist in these remnants for a long time.

Quantitative correlation of mechanoreceptors in tibial remnant of ruptured human anterior cruciate ligament with duration of injury and its significance: an immunohistochemistry-based observational study.

BACKGROUND: Proprioception is a specialized sensory modality encompassing the movement of the joint and its position in space. Reconstruction of the anterior cruciate ligament (ACL) does not always yield expected outcome, suggesting that successful reconstruction depends on not only the ultimate strength of the graft but also recovery of proprioception. Treatment delay is a significant concern in developing countries, e.g., in Asia. Thus, presence of mechanoreceptors is one of the factors having paramount importance for successful outcome. We conducted this study to identify mechanoreceptors via immunohistochemical staining and correlate their presence with duration of injury. MATERIALS AND METHODS: A total of 38 injured native ACL stumps were harvested from patients undergoing ACL reconstruction and stained with neurofilament protein stain to detect functional mechanoreceptors. RESULTS: Of the specimens, 44.7% stained positive for monoclonal antibody. No association was found between duration of injury and presence of mechanoreceptors (p = 0.897). No correlation was seen between age and side. CONCLUSIONS: No correlation was found between duration of injury and presence of viable mechanoreceptors, hence it is beneficial to preserve the native ACL stump irrespective of the time interval between injury and surgery. LEVEL OF EVIDENCE: III.

Involvement of sensory innervation in the skin of SOD1(G93A) ALS mice.

Sensory alterations have been described in both amyotrophic lateral sclerosis (ALS) patients and mouse models. While involvement of intraepidermal and subepidermal axons has been shown in skin biopsies of ALS patients, it is unclear if the SOD1(G93A) mouse presents similar alterations. We analyzed the epidermal and dermal innervation, based on PGP9.5 immunostaining, of SOD1(G93A) mice at different stages. The results showed a marked reduction of intraepidermal nerve fibers, Meissner's corpuscles, and subepidermal nerve density already at 4 weeks. This loss of innervation progressed over time. Dermal axonal density decreased at a later stage of the disease. There was a gradient of axonal loss, with a more severe decline in the epidermis compared with deeper structures, indicating a distal axonal neuropathy as the mechanism of degeneration. These findings suggest that the analysis of the cutaneous sensory innervation may be an accessible and useful tool to assess the neurodegeneration process in motoneuron diseases.

Morphologic Characterization of Nerves in Whole-Mount Airway Biopsies.

RATIONALE: Neuroplasticity of bronchopulmonary afferent neurons that respond to mechanical and chemical stimuli may sensitize the cough reflex. Afferent drive in cough is carried by the vagus nerve, and vagal afferent nerve terminals have been well defined in animals. Yet, both unmyelinated C fibers and particularly the morphologically distinct, myelinated, nodose-derived mechanoreceptors described in animals are poorly characterized in humans. To date there are no distinctive molecular markers or detailed morphologies available for human bronchopulmonary afferent nerves. OBJECTIVES: Morphologic and neuromolecular characterization of the afferent nerves that are potentially involved in cough in humans. METHODS: A whole-mount immunofluorescence approach, rarely used in human lung tissue, was used with antibodies specific to protein gene product 9.5 (PGP9.5) and, for the first time in human lung tissue, 200-kD neurofilament subunit. MEASUREMENTS AND MAIN RESULTS: We have developed a robust technique to visualize fibers consistent with autonomic and C fibers and pulmonary neuroendocrine cells. A group of morphologically distinct, 200-kD neurofilament-immunopositive myelinated afferent fibers, a subpopulation of which did not express PGP9.5, was also identified. CONCLUSIONS: PGP9.5-immunonegative nerves are strikingly similar to myelinated airway afferents, the cough receptor, and smooth muscle-associated airway receptors described in rodents. These have never been described in humans. Full description of human airway nerves is critical to the translation of animal studies to the clinical setting.

Can Bassett's ligament be removed?

PURPOSE: To investigate the functional characteristics of Bassett's ligament in the ankle, focusing on mechanoreceptors and potential problems following resection of Bassett's ligament. METHODS: Bassett's ligament, the anterior talofibular ligament (ATFL), and synovium were obtained from 20 ankles of 10 fresh-frozen cadavers. Histologically, mechanoreceptors were identified and classified as Ruffini (type I), Vater-Pacini (type II), Golgi-Mazzoni (type III) corpuscles, and free nerve endings (type IV). Differences in receptor densities were compared. RESULTS: Type I clusters were observed with three to six ramifications; type II mechanoreceptors were encapsulated in clusters of two to four with ovoid or cylindrical shape; type III were amorphous, long and wide, and fusiform- or spindle-shaped; and type IV were long and fine without a defined shape. Differences in the densities of the mechanoreceptors inside three soft tissues (Bassett's ligament, ATFL, and synovium) were not significant. CONCLUSION: There were no significant differences in the densities of the four types of mechanoreceptors among the soft tissues studied. In Bassett's ligament, type I mechanoreceptors were present at significantly higher densities than the other receptors.

Protective role of L-ascorbic acid, N-acetylcysteine and apocynin on neomycin-induced hair cell loss in zebrafish.

Hair cells are highly sensitive to environmental insults and other therapeutic drugs. The adverse effects of drugs such as aminoglycosides can cause hair cell death and lead to hearing loss and imbalance. The objective of the present study was to evaluate the protective activity of L-ascorbic acid, N-acetylcysteine (NAC) and apocynin on neomycin-induced hair cell damage in zebrafish (Danio rerio) larvae at 5 days post fertilization (dpf). Results showed that the loss of hair cells within the neuromasts of the lateral lines after neomycin exposure was evidenced by a significantly lower number of neuromasts labeled with fluorescent dye FM1-43FX observed under a microscope. Co-administration with L-ascorbic acid, NAC and apocynin protected neomycin-induced hair cell loss within the neuromasts. Moreover, these three compounds reduced the production of reactive oxygen species (ROS) in neuromasts exposed to neomycin, indicating that their antioxidant action is involved. In contrast, the neuromasts were labeled with specific fluorescent dye Texas-red conjugated with neomycin to detect neomycin uptake. Interestingly, the uptake of neomycin into hair cells was not influenced by these three antioxidant compounds. These data imply that prevention of hair cell damage against neomycin by L-ascorbic acid, NAC and apocynin might be associated with inhibition of excessive ROS production, but not related to modulating neomycin uptake. Our findings conclude that L-ascorbic acid, NAC and apocynin could be used as therapeutic drugs to protect aminoglycoside-induced listening impairment after further confirmatory studies.

Immunohistochemical analysis of mechanoreceptors in the human posterior cruciate ligament: association with aging male.

INTRODUCTION: The aim of this study was to evaluate the association between frequency of the posterior cruciate ligament (PCL) mechanoreceptors and age in men. METHODS: Nineteen normal right knees harvested from human male cadavers were evaluated. Age ranged from 17 to 64 years with a mean of 35 years old. PCL was separated for sampling in femoral and tibial portions. Topographic distribution and frequency within the ligament texture were determined employing the Pro-Image digital analysis system. Mechanoreceptors were counted and classified according to the criteria proposed by Freeman & Wyke. RESULTS: A total of 1820 mechanoreceptors were found, type II being the most frequent one. Analysis of the femoral portion of the ligament showed an equivalent predominance of Types II and IV mechanoreceptors. Tibial portion had a predominance of type II mechanoreceptors, followed by type IV. At this portion, receptors Types I and III were less commonly identified. CONCLUSION: In the tibial portion of the PCL, there is predominance of Type II mechanoreceptors followed by types IV, I and III mechanoreceptors, respectively. No relationship was found between the total number of mechanoreceptors and age in the femoral and tibial portions of the PCL.

Comparative analysis of inter- and intraligamentous distribution of sensory nerve endings in ankle ligaments: a cadaver study.

BACKGROUND: The aim of this study was to analyze the inter-, intraligamentous, and side-related patterns of sensory nerve endings in ankle ligaments. METHODS: A total of 140 ligaments from 10 cadaver feet were harvested. Lateral: calcaneofibular, anterior-, posterior talofibular; sinus tarsi: lateral- (IERL), intermediate-, medial-roots inferior extensor retinaculum, talocalcaneal oblique and canalis tarsi (CTL); medial: tibionavicular (TNL), tibiocalcaneal (TCL), superficial tibiotalar, anterior/posterior tibiotalar portions; syndesmosis: anterior tibiofibular. Following immunohistochemical staining, the innervation and vascularity was analyzed between ligaments of each anatomical complex, left/right feet, and within the 5 levels of each ligament. RESULTS: Significantly more free nerve endings were seen in all ligaments as compared to Ruffini, Pacini, Golgi-like, and unclassifiable corpuscles (P ≤ .005). The IERL had significantly more free nerve endings and blood vessels than the CTL (P ≤ .001). No significant differences were seen in the side-related distribution, except for Ruffini endings in right TCL (P = .016) and unclassifiable corpuscles in left TNL (P = .008). The intraligamentous analysis in general revealed no significant differences in mechanoreceptor distribution. CONCLUSIONS: The IERL at the entrance of the sinus tarsi contained more free nerve endings and blood vessels, as compared to the deeper situated CTL. Despite different biomechanical functions in the medial and lateral ligaments, the interligamentous distribution of sensory nerve endings was equal. CLINICAL RELEVANCE: The intrinsic innervation patterns of the ankle ligaments provides an understanding of their innate healing capacities following injury as well as the proprioception properties in postoperative rehabilitation.

Study of the nerve endings and mechanoreceptors of the medial meniscotibial ligament of the knee: A structural and distribution analysis.

BACKGROUND: The aim of the present study is to describe the morphology and distribution of the nerve endings of the meniscotibial ligament (MTL) of the knee, in order to understand the interaction between the proprioceptive system and knee mechanics. METHODS: Twenty medial MTLs were obtained from deceased organ donors. The ligaments were measured, weighed and cut. Sections (10 mm) were prepared on hematoxylin and eosin-stained slides for analysis of tissue integrity, and 50 mm sections were submitted to immunofluorescence with the protein gene product (PGP) 9.5 as primary antibody and Alexa Fluor 488 as secondary antibody, followed by microscopic analysis. RESULTS: The medial MTL was identified in 100% of the dissections, with average length, width, thickness and weight of 7.07 ± 1.34 mm, 32.25 ± 3.09 mm, 3.53 ± 0.27 mm and 0.67 ± 0.13 g, respectively. The hematoxylin and eosin-stained histological sections exhibited typical ligament structure, with dense well-organized collagen fibers and vascular tissue. All the specimens analyzed contained type I (Ruffini) mechanoreceptors and free (type IV) nerve endings, varying from parallel to intertwined fibers. Nerve endings not classified with different irregular shapes were also found. Most type I mechanoreceptors were found close to the MTL insertions on the tibial plateau, while the free nerve endings were found adjacent to the capsule. CONCLUSION: The medial MTL showed a peripheral nerve structure, primarily type I and IV mechanoreceptors. These findings suggest that the medial MTL is important for proprioception and medial knee stabilization.