Serpinin in the Skin

The serpinins are relatively novel peptides generated by proteolytic processing of chromogranin A and they are comprised of free serpinin, serpinin-RRG and pGlu-serpinin. In this study, the presence and source of these peptides were studied in the skin. By Western blot analysis, a 40 kDa and a 50 kDa protein containing the sequence of serpinin were detected in the trigeminal ganglion and dorsal root ganglia in rats but none in the skin. RP-HPLC followed by EIA revealed that the three serpinins are present in similar, moderate amounts in rat dorsal root ganglia, whereas in the rat skin, free serpinin represents the predominant molecular form. There were abundant serpinin-positive cells in rat dorsal root ganglia and colocalization with substance P was evident. However, much more widespread distribution of the serpinins was found in dorsal root ganglia when compared with substance P. In the skin, serpinin immunoreactivity was found in sensory nerves and showed colocalization with substance P; as well, some was present in autonomic nerves. Thus, although not exclusively, there is evidence that serpinin is a constituent of the sensory innervation of the skin. The serpinins are biologically highly active and might therefore be of functional significance in the skin.

NGF Enhances CGRP Release Evoked by Capsaicin from Rat Trigeminal Neurons: Differential Inhibition by SNAP-25-Cleaving Proteases

Nerve growth factor (NGF) is known to intensify pain in various ways, so perturbing pertinent effects without negating its essential influences on neuronal functions could help the search for much-needed analgesics. Towards this goal, cultured neurons from neonatal rat trigeminal ganglia—a locus for craniofacial sensory nerves—were used to examine how NGF affects the Ca2+-dependent release of a pain mediator, calcitonin gene-related peptide (CGRP), that is triggered by activating a key signal transducer, transient receptor potential vanilloid 1 (TRPV1) with capsaicin (CAP). Measurements utilised neurons fed with or deprived of NGF for 2 days. Acute re-introduction of NGF induced Ca2+-dependent CGRP exocytosis that was inhibited by botulinum neurotoxin type A (BoNT/A) or a chimera of/E and/A (/EA), which truncated SNAP-25 (synaptosomal-associated protein with Mr = 25 k) at distinct sites. NGF additionally caused a Ca2+-independent enhancement of the neuropeptide release evoked by low concentrations (<100 nM) of CAP, but only marginally increased the peak response to ≥100 nM. Notably, BoNT/A inhibited CGRP exocytosis evoked by low but not high CAP concentrations, whereas/EA effectively reduced responses up to 1 µM CAP and inhibited to a greater extent its enhancement by NGF. In addition to establishing that sensitisation of sensory neurons to CAP by NGF is dependent on SNARE-mediated membrane fusion, insights were gleaned into the differential ability of two regions in the C-terminus of SNAP-25 (181–197 and 198–206) to support CAP-evoked Ca2+-dependent exocytosis at different intensities of stimulation.

Delta opioid receptors on nociceptive sensory neurons mediate peripheral endogenous analgesia in colitis

Background Inflammatory visceral pain is endogenously controlled by enkephalins locally released by mucosal CD4+ T lymphocytes in mice. The present study aimed at identifying opioid receptor(s) expressed on nociceptive sensory nerves involved in this peripheral opioid-mediated analgesia. Methods The peripheral analgesia associated with the accumulation of CD4+ T lymphocytes within the inflamed colonic mucosa was assessed in conditional knockout mice specifically deleted for either of the two opioid receptors for enkephalins (i.e., µ (MOR) and δ (DOR) receptors) in Nav1.8-expressing sensory neurons in the dextran sulfate sodium (DSS)-induced colitis model. Results Endogenous analgesia is lost in conditional knockout mice for DOR, but not MOR at the later phase of the DSS-induced colitis. The absence of either of the opioid receptors on sensory nerves had no impact on both the colitis severity and the rate of T lymphocytes infiltrating the inflamed colonic mucosa. Conclusion The key role of DOR on primary afferents in relieving intestinal inflammatory pain opens new therapeutic opportunities for peripherally restricted DOR analgesics to avoid most of the side effects associated with MOR-targeting drugs used in intestinal disorders.

The Evolution of Peripheral Nerve Treatment for Trigeminal Neuralgia - Peripheral Injections

Trigeminal neuralgia presents as a characteristic severe painful condition that usually afflicts the area(s) innervated by the branches of the facial sensory nerves, especially the elderly females. The diagnosis can usually be made based solely on the presenting clinical signs and symptoms. Early literatures had revealed that there have always been two major means of treatment for trigeminal neuralgia; medical and surgical. Medical treatments involved systemic intake of various drugs or the topical applications of many different materials, not forgetting that bleeding and purging has been tried in the past. The introduction of anti-convulsants during the second World War had changed completely the way this painful condition was treated as this therapy later become the mainstay treatment for trigeminal neuralgia. Their beneficial effects, however may not be long lasting. This review summarises the evolution of peripheral nerve injection as a treatment for trigeminal neuralgia over the last 150 years.

Sensory nerves enhance triple-negative breast cancer migration and metastasis via the axon guidance molecule PlexinB3

In breast cancer, nerve presence has been correlated with more invasive disease and worse prognosis, yet the mechanisms by which different types of peripheral nerves drive tumor progression remain poorly understood. In this study, we identified sensory nerves as more abundant in human triple-negative breast cancer (TNBC) tumors. Coinjection of sensory neurons isolated from the dorsal root ganglia (DRG) of adult female mice with human TNBC cells in immunocompromised mice increased the number of lung metastases. Direct in vitro co-culture of human TNBC cells with the dorsal root ganglia (DRG) of adult female mice revealed that TNBC cells adhere to sensory neuron fibers leading to an increase in migration speed. Species-specific RNA sequencing revealed that co-culture of TNBC cells with sensory nerves upregulates the expression of genes associated with cell migration and adhesion in cancer cells. We demonstrate that the axon guidance molecule Plexin B3 mediates cancer cell adhesion to and migration on sensory nerves. Together, our results identify a novel mechanism by which nerves contribute to breast cancer migration and metastasis by inducing a shift in TNBC cell gene expression and support the rationale for disrupting neuron-cancer cell interactions to target metastasis.SignificanceThe presence of nerves in breast tumors has been associated with poor outcome. Understanding the mechanisms by which nerves contribute to tumor progression could help identify novel strategies to target metastatic disease.

Application of Microspectral Imaging in Motor and Sensory Nerve Classification

Objective. It aimed to explore the application of the microscopic hyperspectral technique in motor and sensory nerve classification. Methods. The self-developed microscopic hyperspectral acquisition system was applied to collect the data of anterior and posterior spinal cord sections of white rabbits. The joint correction algorithm was employed to preprocess the collected data, such as noise reduction. On the basis of pure linear light source index, a new pixel purification algorithm based on cross contrast was proposed to extract more regions of interest, which was used for feature extraction of motor and sensory nerves. Besides, the ML algorithm was employed to classify motor and sensory nerves based on feature extraction results. Results. The joint correction algorithm was adopted to preprocess the data collected by the microscopic hyperspectral technique, so as to eliminate the influence of the incident light source and the system and improve the classification accuracy. The axon and myelin spectrum curves of the two kinds of nerves in the stained specimens had the same trend, but the values of all kinds of spectrum of sensory nerves were higher than those of motor nerves. However, the myelin sheath spectrum curves of motor nerves in the unstained specimens were greatly different from the curves of sensory nerves. The axon spectrum curves had the same trend, but the axon spectrum values of sensory nerves were higher than those of motor nerves. The ML algorithm had high accuracy and fast speed in motor and sensory nerve classification, and the classification effect of stained specimens was better than that of unstained specimens. Conclusion. The microscopic hyperspectral technique had high feasibility in sensory and motor nerve classification and was worthy of further research and promotion.

Neurogenic Inflammation in the Context of Endometriosis—What Do We Know?

Endometriosis (EM) is an estrogen-dependent disease characterized by the presence of epithelial, stromal, and smooth muscle cells outside the uterine cavity. It is a chronic and debilitating condition affecting ~10% of women. EM is characterized by infertility and pain, such as dysmenorrhea, chronic pelvic pain, dyspareunia, dysuria, and dyschezia. Although EM was first described in 1860, its aetiology and pathogenesis remain uncertain. Recent evidence demonstrates that the peripheral nervous system plays an important role in the pathophysiology of this disease. Sensory nerves, which surround and innervate endometriotic lesions, not only drive the chronic and debilitating pain associated with EM but also contribute to a growth phenotype by secreting neurotrophic factors and interacting with surrounding immune cells. Here we review the role that peripheral nerves play in driving and maintaining endometriotic lesions. A better understanding of the role of this system, as well as its interactions with immune cells, will unearth novel disease-relevant pathways and targets, providing new therapeutics and better-tailored treatment options.