Neuropeptide Calcitonin Gene-related Peptide Research Articles

Calcitonin gene-related peptide is a key neurotransmitter in the neuro-immune axis

The question of how the neural and immune systems interact in host defense is important, integrating a system that senses the whole body with one that protects. Understanding the mechanisms and routes of control could produce novel and powerful ways of promoting and enhancing normal functions as well as preventing or treating abnormal functions. Fragmentation of biological research into specialities has resulted in some failures in recognizing and understanding interactions across different systems and this is most striking across immunology, hematology, and neuroscience. This reductionist approach does not allow understanding of the in vivo orchestrated response generated through integration of all systems. However, many factors make the understanding of multisystem cross-talk in response to a threat difficult, for instance the nervous and immune systems share communication molecules and receptors for a wide range of physiological signals. But, it is clear that physical, hard-wired connections exist between the two systems, with the key link involving sensory, unmyelinated nerve fibers (c fibers) containing the neuropeptide calcitonin gene-related peptide (CGRP), and modified macrophages, mast cells and other immune and host defense cells in various locations throughout the body. In this review we will therefore focus on the induction of CGRP and its key role in the neuroimmune axis.

Temporal mismatch between pain behaviour, skin Nerve Growth Factor and intra-epidermal nerve fibre density in trigeminal neuropathic pain

BackgroundThe neurotrophin Nerve Growth factor (NGF) is known to influence the phenotype of mature nociceptors, for example by altering synthesis of neuropeptides, and changes in NGF levels have been implicated in the pathophysiology of chronic pain conditions such as neuropathic pain. We have tested the hypothesis that after partial nerve injury, NGF accumulates within the skin and causes ‘pro-nociceptive’ phenotypic changes in the remaining population of sensory nerve fibres, which could underpin the development of neuropathic pain.ResultsEleven days after chronic constriction injury of the rat mental nerve the intra-epidermal nerve fibre density of the chin skin from had reduced from 11.6 ± 4.9 fibres/mm to 1.0 ± 0.4 fibres/mm; this slowly recovered to 2.4 ± 2.0 fibres/mm on day 14 and 4.0 ± 0.8 fibres/mm on day 21. Cold hyperalgesia in the ipsilateral lower lip was detectable 11 days after chronic constriction injury, although at this time skin [NGF] did not differ between sides. At 14 days post-injury, there was a significantly greater [NGF] ipsilaterally compared to contralaterally (ipsilateral = 111 ± 23 pg/mg, contralateral = 69 ± 13 pg/mg), but there was no behavioural evidence of neuropathic pain at this time-point. By 21 days post-injury, skin [NGF] was elevated bilaterally and there was a significant increase in the proportion of TrkA-positive (the high-affinity NGF receptor) intra-epidermal nerve fibres that were immunolabelled for the neuropeptide Calcitonin Gene-related peptide.ConclusionsThe temporal mismatch in behaviour, skin [NGF] and phenotypic changes in sensory nerve fibres indicate that increased [NGF] does not cause hyperalgesia after partial mental nerve injury, although it may contribute to the altered neurochemistry of cutaneous nerve fibres.

The rat dorsal column nuclei contain a region homologous to the human Locus K

Locus K is a newly identified region within the territory of the human nucleus cuneatus that shares neurochemical and histological features with protopathic second order sensory nuclei (Del Fiacco et al., 2013; Serra et al., 2013; SIAI 2014). This work is aimed at examining the rat dorsal column nuclei in order to ascertain whether a structure homologous to the human Locus K occurs in the rat brain. Rat brainstem sections were observed by means of ABC and fluorescence immunohistochemistry for neuropeptides calcitonin gene-related peptide (CGRP) and substance P (SP), Kluver-Barrera and Nissl staining. Results of the peptide immunoreactive structures in the rat dorsal column nuclei are in general good agreement with findings in previous studies (Hoeflinger et al., 1993). However, at caudalmost levels of the complex, in the territory of the cuneate fascicle and dorsal to the caudal pole of the cuneate nucleus, a small column of gray matter area can be identified that contains a dense plexus of varicose labelled nerve fibres. The observed discrete region has never distinctly described beforehand. Both its position and aspect at neuropeptide-immunoreactivity resemble those of the Locus K we detected in the human dorsal column nuclei, allowing the possibility that it represents the its homologous nucleus in the rat brain. Work funded by Fondazione Banco di Sardegna.

Paclitaxel alters the evoked release of calcitonin gene-related peptide from rat sensory neurons in culture

Peripheral neuropathy (PN) is a debilitating and dose-limiting side effect of treatment with the chemotherapeutic agent, paclitaxel. Understanding the effects of paclitaxel on sensory neuronal function and the signaling pathways which mediate these paclitaxel-induced changes in function are critical for the development of therapies to prevent or alleviate the PN. The effects of long-term administration of paclitaxel on the function of sensory neurons grown in culture, using the release of the neuropeptide calcitonin gene-related peptide (CGRP) as an endpoint of sensory neuronal function, were examined. Dorsal root ganglion cultures were treated with low (10nM) and high (300nM) concentrations of paclitaxel for 1, 3, or 5days. Following paclitaxel treatment, the release of CGRP was determined using capsaicin, a TRPV1 agonist; allyl isothiocyanate (AITC), a TRPA1 agonist; or high extracellular potassium. The effects of paclitaxel on the release of CGRP were stimulant-, concentration-, and time-dependent. When neurons were stimulated with capsaicin or AITC, a low concentration of paclitaxel (10nM) augmented transmitter release, whereas a high concentration (300nM) reduced transmitter release in a time-dependent manner; however, when high extracellular potassium was used as the evoking stimulus, all concentrations of paclitaxel augmented CGRP release from sensory neurons. These results suggest that paclitaxel alters the function of sensory neurons in vitro, and suggest that the mechanisms by which paclitaxel alters neuronal function may include functional changes in TRP channel activity. The described in vitro model will facilitate future studies to identify the signaling pathways by which paclitaxel alters neuronal sensitivity.

Low-level laser therapy and light-emitting diode effects in the secretion of neuropeptides SP and CGRP in rat skin

The phototherapy effects in the skin are related to biomodulation, usually to accelerate wound healing. However, there is no direct proof of the interrelation between the effects of low-level laser therapy (LLLT) and light-emitting diode (LED) in neuropeptide secretion, these substances being prematurely involved in the neurogenic inflammation phase of wound healing. This study therefore focused on investigating LLLT and LED in Calcitonin gene-related peptide (CGRP) and substance P (SP) secretion in healthy rat skin. Forty rats were randomly distributed into five groups with eight rats each: Control Group, Blue LED Group (470 nm, 350 mW power), Red LED Group (660 nm, 350 mW power), Red Laser Group (660 nm, 100 mW power), and Infrared Laser Group (808 nm, 100 mW power) (DMC® Equipamentos Ltda., São Carlos, São Paulo, Brazil). The skin of the animals in the experimental groups was irradiated using the punctual contact technique, with a total energy of 40 J, single dose, standardized at one point in the dorsal region. After 14 min of irradiation, the skin samples were collected for CGRP and SP quantification using western blot analysis. SP was released in Infrared Laser Group (p = 0.01); there was no difference in the CGRP secretion among groups. Infrared (808 nm) LLLT enhances neuropeptide SP secretion in healthy rat skin.

Does Exercise Make Migraines Worse and Tension Type Headaches Better?

Many non-pharmacological treatments have been implicated in the treatment of primary headache, with exercise being a common recommendation. In this review we first provide an overview of the relationship between exercise and primary headaches. We then review the physiology of pain modulation, with focus on the endogenous opioids, endocannabinoids, and neuropeptides calcitonin gene-related peptide (CGRP) and brain-derived neurotrophic factor (BDNF), and their associations with primary headache and exercise. Finally, we summarize current literature evaluating effects of exercise on primary headache in an effort to understand the benefits and disadvantages of exercise in primary headaches.

CGRP in the trigeminovascular system: a role for CGRP, adrenomedullin and amylin receptors?

The neuropeptide calcitonin gene-related peptide (CGRP) is reported to play an important role in migraine. It is expressed throughout the trigeminovascular system. Antagonists targeting the CGRP receptor have been developed and have shown efficacy in clinical trials for migraine. However, no CGRP antagonist is yet approved for treating this condition. The molecular composition of the CGRP receptor is unusual because it comprises two subunits; one is a GPCR, the calcitonin receptor-like receptor (CLR). This associates with receptor activity-modifying protein (RAMP) 1 to yield a functional receptor for CGRP. However, RAMP1 also associates with the calcitonin receptor, creating a receptor for the related peptide amylin but this also has high affinity for CGRP. Other combinations of CLR or the calcitonin receptor with RAMPs can also generate receptors that are responsive to CGRP. CGRP potentially modulates an array of signal transduction pathways downstream of activation of these receptors, in a cell type-dependent manner. The physiological significance of these signalling processes remains unclear but may be a potential avenue for refining drug design. This complexity has prompted us to review the signalling and expression of CGRP and related receptors in the trigeminovascular system. This reveals that more than one CGRP responsive receptor may be expressed in key parts of this system and that further work is required to determine their contribution to CGRP physiology and pathophysiology. This article is part of a themed section on Neuropeptides. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2013.170.issue-7.

Healing of periodontal defects and calcitonin gene related peptide expression following inferior alveolar nerve transection in rats

The roles of nerve and neuropeptides in the process of bone formation and remolding have been studied previously. However, the effects of nervous system and neuropeptide on periodontal alveolar bone formation remained unknown. The aim of this study was to assess the effect of innervation on regeneration of alveolar bone and expression levels of calcitonin gene related peptide (CGRP) in periodontal tissues of rats, so as to have a better understanding of the effect of nerve and its related neuropeptide on periodontal tissue regeneration. Rats received transection of the left inferior alveolar nerve and a surgery to produce bilateral periodontal defect, then the alveolar tissue was obtained from animals of each group at week 1, 2, 4, 6 and 8weeks after operation, respectively. Hematoxylin and eosin staining, and Masson staining were performed to evaluate the ability to restore and repair periodontal tissues at 4, 6 and 8 after surgery. Then new bone formation area and mineralized area were quantified using imagepro-plus6.0 software after pictures were taken under the microscope and SPSS17.0 was used for statistical analysis. Immunohistochemical staining was applied to investigate the expression of CGRP at 1, 2, 4, 6 and 8weeks. Rats received transection of the left inferior alveolar nerve surgery and were then sacrificed at day 1, 3, 7, 14, 21, 28 after the operation. The change of CGRP expression in periodontal tissue was detected using immunohistochemical methods. The results showed that the volume of new bone formation was not significantly difference between the experimental and control groups, but the mineralized new bone area between the two groups was statistically significant. The level of CGRP expression was lower than normal at week 1, and then it began to rise in the next stage. The plateau, at higher than normal level, was reached at 6weeks post-surgery. Results of transection of the left inferior alveolar nerve demonstrated the expression of CGRP was decreased in early stage; it reached the lowest level at day 7. Then the expression level began to increase until it returned to normal level at day 28. The results of this study suggest that nerve and its related neuropeptide CGRP are the important factors that can affect the quality of regenerated alveolar bone by reducing bone density during the mineralization process.

Special AT-rich sequence-binding protein-2 (Satb2) — Independent initiation of cholinergic sweat gland innervation in rat in vivo

The transcription factor special AT-rich sequence-binding protein-2 (Satb2) is induced and critical for the establishment of the cholinergic phenotype in rat superior cervical ganglion cells in culture during switching from a noradrenergic to the cholinergic phenotype upon exposure to soluble differentiation factors. To obtain evidence for Satb2 determining the sympathetic cholinergic sudomotor phenotype also in vivo, we traced the postnatal expression profile of Satb2 in the rat stellate ganglion in comparison to the vesicular acetylcholine transporter (VAChT), choline acetyltransferase (ChAT), and the neuropeptide calcitonin gene-related peptide (CGRP), all required for sudomotor function in adult rats.

Calcitonin Gene-Related Peptide Receptor Antagonists: Beyond Migraine Pain—A Possible Analgesic Strategy for Osteoarthritis?

Osteoarthritis (OA) pain is poorly understood and managed, as current analgesics have only limited efficacy and unwanted side effect profiles. A broader understanding of the pathological mechanisms driving OA joint pain is vital for the development of improved analgesics. Both clinical and preclinical data suggest an association between joint levels of the sensory neuropeptide calcitonin gene-related peptide (CGRP) and pain during OA. Whether a direct causative link exists remains an important unanswered question. Given the recent development of small molecule CGRP receptor antagonists with clinical efficacy against migraine pain, the interrogation of the role of CGRP in OA pain mechanisms is extremely timely. In this article, we provide the background to the importance of CGRP in pain mechanisms and review the emerging clinical and preclinical evidence implicating a role for CGRP in OA pain. We suggest that the CGRP receptor antagonists developed for migraine pain warrant further investigation in OA.

Is CGRP a marker for chronic migraine?

Calcitonin gene-related peptide (CGRP) research was initiated by Poyner et al.,1 who found that the calcitonin gene encodes the 37–amino acid neuropeptide CGRP in neuronal tissue. Within months, the Lund group produced antibodies toward α-CGRP and developed sensitive methods to study the role of this peptide in the cranial circulation. Intracranial vessels and the trigeminal ganglion harbor this potent vasodilator peptide.2 Functionally, CGRP has a substantial role in the trigeminovascular reflex.3 The calcitonin family is now well-characterized and contains 6 members: calcitonin, amylin, adenomedullin-2, adrenomedullin, and CGRP (2 isoforms: α-CGRP and β-CGRP).4 The α- and β-isoforms of CGRP are similar in their biological activities but show different tissue distributions. β-CGRP is mainly found in enteric nerves and in the pituitary gland, while α-CGRP is found predominantly in sensory neurons and in the CNS.5 CGRP causes cranial vasodilatation and facilitates nociception. During a migraine attack, trigeminal activation results in the release of CGRP from presynaptic nerve terminals and induces vasodilatation and neurogenic inflammation in leptomeningeal and extracranial vessels, which gives rise to the typical throbbing pain of migraine. Goadsby and Edvinsson6 showed that plasma concentrations of CGRP are elevated in the external jugular venous blood during migraine headaches and that sumatriptan can abort the rise in CGRP and the headache.4 CGRP given IV causes headache only in migraine patients and CGRP antagonists are effective for the acute treatment of migraine.7 Until now, CGRP elevation in the plasma has not been reproduced in all studies.8 However, technical problems have sometimes hampered the proper measurements of CGRP.9

Biomarkers Associated With Migraine and Their Potential Role in Migraine Management

The focus of this review is to review potential diagnostic and therapeutic biomarkers associated with migraine. Migraine headache is a common disease that affects millions of individuals worldwide. Although well-accepted diagnostic criteria exist for migraine, it is still a complex disorder that remains both underdiagnosed and misdiagnosed. The causes of migraine are likely a mix of genetic, epigenetic, and environmental factors that, together with the individual's life history, translate into the observed clinical heterogeneity. Inherent clinical heterogeneity is an obstacle in developing more effective treatments. The lack of appropriate biomarkers is also an impediment to developing more effective therapeutic/preventive approaches. Ultimately, biomarkers may facilitate the goal of individualized medicine by enabling clinicians to more accurately diagnose and treat migraine and other types of headache. A comprehensive review was conducted of PubMed citations containing the key word "marker" OR "biomarker" combined with "migraine" OR "headache." Other key words included "serum," "saliva," "cerebrospinal fluid," "genes," "blood," and "inflammation." The only restriction was English-language publication. The abstracts of all articles meeting these criteria were reviewed, and full text was retrieved and examined for relevant references. Data from human studies have begun to identify genetic mutations/polymorphisms and altered levels of specific proinflammatory and neuromodulatory molecules that strongly correlate with migraine as well as symptom severity. Results from a smaller number of studies have identified parameters, such as the neuropeptide calcitonin gene-related peptide (CGRP), which are significantly associated with response to specific treatments for acute migraine attacks and prophylaxis. Epigenetic mechanisms may also be involved in the development of migraine, and understanding environmentally induced genetic changes associated with this disease may eventually guide the development of therapies capable of reversing these pathophysiological changes in gene function. The understanding of the etiology of migraine is incomplete. Although the identification and validation of biomarkers has greatly advanced diagnostic precision and measures of therapeutic efficacy in other diseases, there are no currently accepted biomarkers for chronic or episodic migraine. However, the continued investigation and identification of genetic, epigenetic, and molecular biomarkers is likely to facilitate the goal of individualizing medicine by enabling clinicians to more accurately diagnose and treat migraine and other headache disorders.

Antiinflammatory Activities of CGRP Modulating Innate Immune Responses in Health and Disease

Sensory nerves are abundant in lymphoid organs and rapidly release the neuropeptide calcitonin gene-related peptide (CGRP) in response to injury or infection. CGRP directly acts on macrophages and dendritic cells and inhibits the capacity of these cells to produce inflammatory cytokines and to present antigens to T cells. Effector mechanisms, by which CGRP acts on innate immune cells, include upregulation of IL-10, IL-10-independent induction of the inducible cAMP early repressor (ICER) and inhibition of NF-κB activity. Engagement of the CGRP receptor, which is composed of receptor activity modifying protein-1 (RAMP1) and calcitonin receptor-like receptor (CLR), increases cellular cAMP levels leading to the activation of protein kinase A (PKA). PKA appears crucial for mediating the antiinflammatory effects of CGRP. Available evidence therefore indicates that CGRP acts as a negative regulator of innate immune responses and contributes to limiting tissue damage in inflammatory disorders. In sepsis caused by mixed-bacterial infection, however, antiinflammatory activities of CGRP may exaggerate leading to immunosuppression and impaired host defense.

Epidermal Nerve Fibers Modulate Keratinocyte Growth via Neuropeptide Signaling in an Innervated Skin Model

Atopic eczema is a chronic inflammatory skin disease characterized by cutaneous nerve fiber sprouting and epidermal hyperplasia, pointing to an involvement of the peripheral nervous system in cutaneous homeostasis. However, the interaction of sensory neurons and skin cells is poorly understood. Using an innervated skin model, we investigated the influence of sensory neurons on epidermal morphogenesis. Neurons induced the proliferation of keratinocytes, resulting in an increase in the epidermal thickness. Inhibition of calcitonin gene-related peptide (CGRP), but not substance P (SP) signaling, reversed this effect. Human CGRP enhanced keratinocyte proliferation and epidermal thickness in skin models, demonstrating a key role of CGRP in modulating epidermal morphogenesis, whereas SP had only a moderate effect. Innervated skin models composed of atopic skin cells showed increased neurite outgrowth, accompanied by elevated CGRP release. As atopic keratinocytes were sensitized to CGRP owing to higher expression levels of the CGRP receptor components, receptor activity-modifying protein 1 (RAMP1) and receptor component protein (RCP), atopic innervated skin models displayed a thicker epidermis than did healthy controls. We conclude that neural CGRP controls local keratinocyte growth. Our results show that the crosstalk of the cutaneous peripheral nervous system and skin cells significantly influences epidermal morphogenesis and homeostasis in healthy and atopic skin.

Inhibition of Calcitonin Gene-related Peptide (CGRP) has the Potential to Extend First-phase Insulin Secretion

The neuropeptide calcitonin gene-related peptide (CGRP), known to have a strong vasodilation effect, has also been reported to inhibit insulin secretion. However, the physiological effect of CGRP related to insulin secretion is still unknown. Here, we evaluated the effect of whole-body CGRP inhibition by anti-CGRP antibodies in mice using an oral glucose tolerance test. CGRP has 2 isotypes, alpha-CGRP and beta-CGRP, and we confirmed the antibody used in this study inhibits function of both. Then, we evaluated the effect of CGRP inhibition on insulin secretion and discovered that CGRP inhibition lead to extend first-phase insulin secretion in an antibody dose-dependent manner and nearly plateaued at 10 mg/kg, although the effect was not so large and didn't affect plasma glucose level. We then measured the plasma antibody concentration and it was increased depending on administration dose. So, the effect of first-phase insulin secretion extension was determined to be the result of complete inhibition of CGRP by the antibody. These results indicate that CGRP has the potential to inhibit insulin secretion and shorten first-phase insulin secretion. However the effect of CGRP inhibition was not so large at least on healthy condition, and it indicates the effect of CGRP related to insulin secretion on healthy physiological condition may be limited.

1016 PARTIAL BLADDER OUTLET OBSTRUCTION MODULATES THE RELEASE OF SENSORY NEUROPEPTIDES SUBSTANCE P AND CALCITONIN GENE RELATED PEPTIDE FROM PENILE AFFERENT FIBERS

You have accessJournal of UrologySexual Function/Dysfunction/Andrology: Basic Research (II)1 Apr 20131016 PARTIAL BLADDER OUTLET OBSTRUCTION MODULATES THE RELEASE OF SENSORY NEUROPEPTIDES SUBSTANCE P AND CALCITONIN GENE RELATED PEPTIDE FROM PENILE AFFERENT FIBERS Qi Lei, Xiao-Qing Pan, Shaohua Chang, Ariana Smith, Allen Seftel, and Anna Malykhina Qi LeiQi Lei Glenolden, PA More articles by this author , Xiao-Qing PanXiao-Qing Pan Glenolden, PA More articles by this author , Shaohua ChangShaohua Chang Camden, NJ More articles by this author , Ariana SmithAriana Smith Philadelphia, PA More articles by this author , Allen SeftelAllen Seftel Camden, NJ More articles by this author , and Anna MalykhinaAnna Malykhina Glenolden, PA More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2013.02.601AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Erectile dysfunction (ED) and benign prostatic hyperplasia (BPH) are common problems in aging males worldwide. Despite the epidemiological evidence of the link between BPH and ED, the mechanisms underlying this co-morbidity are still unclear. The objective of this work was to evaluate the effects of partial bladder outlet obstruction (PBOO) on function of sensory terminals innervating the corpus cavernosum (CC), and release of sensory neuropeptides Substance P (SP) and calcitonin gene related peptide (CGRP) in the CC using an animal model of PBOO. METHODS Experiments were conducted on adult male Sprague Dawley rats divided into two groups: sham operated and PBOO surgery. PBOO was surgically induced by a partial ligation of the bladder neck during laparotomy. Concentration of the sensory neuropeptides SP and CGRP was measured by ELISA. Contractility and relaxation of the CCSM was studied in vitro and expression of nitric oxide synthase (NOS) was evaluated by Western blotting. RESULTS The results of neuropeptide analysis established that the release of SP and CGRP in the pelvic viscera is tissue dependent. Concentration of SP in the CC was higher (2.01±0.23 ng/ml, n=10) in comparison to the urinary bladder (0.3±0.05 ng/ml, n=8, p≤0.001) under normal physiological conditions. However, basal concentration of CGRP was significantly elevated in the urinary bladder reaching 120.6±37.2 pg/ml in comparison to 14.5±0.9 pg/ml in the CC (p≤0.01). PBOO caused impairment in SP release from sensory terminals as evidenced by a 5-fold down-regulation of SP in the CC (n=10, p≤0.001) without significant changes in the obstructed bladder. Additionally, concentration of CGRP was down-regulated in the urinary bladder by PBOO without parallel changes in the CC, however, the decrease did not reach the level of statistical significance. The contractile responses of CC muscle strips to KCl and phenylephrine were decreased after PBOO, followed by a reduced relaxation response to nitroprusside. A significant decrease in nNOS expression was also detected in the CC of obstructed animals. CONCLUSIONS Our results provide evidence that PBOO leads to the impairment of bladder neck afferent innervation followed by a decrease in CC smooth muscle relaxation, down-regulation of nNOS expression and reduced release of sensory neuropeptides in the CC smooth muscle. These results suggest that nerve damage in PBOO may contribute to LUTS-ED comorbidity and trigger secondary changes in the contraction/relaxation mechanisms of CCSM. © 2013 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 189Issue 4SApril 2013Page: e416-e417 Advertisement Copyright & Permissions© 2013 by American Urological Association Education and Research, Inc.MetricsAuthor Information Qi Lei Glenolden, PA More articles by this author Xiao-Qing Pan Glenolden, PA More articles by this author Shaohua Chang Camden, NJ More articles by this author Ariana Smith Philadelphia, PA More articles by this author Allen Seftel Camden, NJ More articles by this author Anna Malykhina Glenolden, PA More articles by this author Expand All Advertisement Advertisement PDF DownloadLoading ...

1017 ADRENOMEDULLIN AND ANGIOPOIETIN-1 HAVE A INTEGRATED RESTIRATION ACTIVITY ON ERECTILE FUNCTION IN DIABETIC RATS: COMPARISON WITH THE COMBINATION THERAPY WITH VASCULAR ENDOTHELIAL GROWTH FACTOR AND ANGIOPOIETIN-1

ity are still unclear. The objective of this work was to evaluate the effects of partial bladder outlet obstruction (PBOO) on function of sensory terminals innervating the corpus cavernosum (CC), and release of sensory neuropeptides Substance P (SP) and calcitonin gene related peptide (CGRP) in the CC using an animal model of PBOO. METHODS: Experiments were conducted on adult male Sprague Dawley rats divided into two groups: sham operated and PBOO surgery. PBOO was surgically induced by a partial ligation of the bladder neck during laparotomy. Concentration of the sensory neuropeptides SP and CGRP was measured by ELISA. Contractility and relaxation of the CCSM was studied in vitro and expression of nitric oxide synthase (NOS) was evaluated by Western blotting. RESULTS: The results of neuropeptide analysis established that the release of SP and CGRP in the pelvic viscera is tissue dependent. Concentration of SP in the CC was higher (2.01 0.23 ng/ml, n 10) in comparison to the urinary bladder (0.3 0.05 ng/ml, n 8, p 0.001) under normal physiological conditions. However, basal concentration of CGRP was significantly elevated in the urinary bladder reaching 120.6 37.2 pg/ml in comparison to 14.5 0.9 pg/ml in the CC (p 0.01). PBOO caused impairment in SP release from sensory terminals as evidenced by a 5-fold down-regulation of SP in the CC (n 10, p 0.001) without significant changes in the obstructed bladder. Additionally, concentration of CGRP was down-regulated in the urinary bladder by PBOO without parallel changes in the CC, however, the decrease did not reach the level of statistical significance. The contractile responses of CC muscle strips to KCl and phenylephrine were decreased after PBOO, followed by a reduced relaxation response to nitroprusside. A significant decrease in nNOS expression was also detected in the CC of obstructed animals. CONCLUSIONS: Our results provide evidence that PBOO leads to the impairment of bladder neck afferent innervation followed by a decrease in CC smooth muscle relaxation, down-regulation of nNOS expression and reduced release of sensory neuropeptides in the CC smooth muscle. These results suggest that nerve damage in PBOO may contribute to LUTS-ED comorbidity and trigger secondary changes in the contraction/relaxation mechanisms of CCSM.

Acupuncture Mechanisms in Tissue Healing: Contribution of No and Cgrp

In three recent articles published in Acupuncture in Medicine , the possible role of acupuncture in tissue healing has been highlighted. In an article on the hypothetical action of acupuncture in the treatment of tendinopathy in the December 2012 issue of the journal, Neal and Longbottom assert that tendinopathy and tendinalgia are debilitating conditions for which a gold standard treatment strategy does not exist.1 This is probably due to the fact that the pathophysiology of tendalgia is not well understood. However, Neal and Longbottom suggest that there is evidence—small in amount but high in quality—supporting the theory that acupuncture may be able to influence tendon healing by increasing blood flow via local vasodilation and increasing collagen proliferation, and that these effects are most likely the result of an increased release of the neuropeptide calcitonin gene-related peptide (CGRP) from sensory nerve endings. Two pathways for the vasodilation of CGRP have been described: 1. Nitric oxide (NO)-endothelium-independent pathways in which the binding of CGRP to the CGRP1 receptor on vascular smooth muscle cells induces an increase in intracellular cAMP and protein kinase A. This cascade results in opening …

Neuropeptide receptors provide a signalling pathway for trigeminal modulation of olfactory transduction

The mammalian olfactory epithelium contains olfactory receptor neurons and trigeminal sensory endings. The former mediate odor detection, the latter the detection of irritants. The two apparently parallel chemosensory systems are in reality interdependent in various well-documented ways. Psychophysical studies have shown that virtually all odorants can act as irritants, and that most irritants have an odor. Thus, the sensory perception of odorants and irritants is based on simultaneous input from the two systems. Moreover, functional interactions between the olfactory system and the trigeminal system exist on both peripheral and central levels. Here we examine the impact of trigeminal stimulation on the odor response of olfactory receptor neurons. Using an odorant with low trigeminal potency (phenylethyl alcohol) and a non-odorous irritant (CO(2) ), we have explored this interaction in psychophysical experiments with human subjects and in electroolfactogram (EOG) recordings from rats. We have demonstrated that simultaneous activation of the trigeminal system attenuates the perception of odor intensity and distorts the EOG response. On the molecular level, we have identified a route for this cross-modal interaction. The neuropeptide calcitonin-gene related peptide (CGRP), which is released from trigeminal sensory fibres upon irritant stimulation, inhibits the odor response of olfactory receptor neurons. CGRP receptors expressed by these neurons mediate this neuromodulatory effect. This study demonstrates a site of trigeminal-olfactory interaction in the periphery. It reveals a pathway for trigeminal impact on olfactory signal processing that influences odor perception.

α CALCITONIN GENE-RELATED PEPTIDE (αCGRP) PLAYS A PROTECTIVE ROLE IN THE ONSET OF ANGIOTENSIN-II INDUCED HYPERTENSION AND VASCULAR INFLAMMATION/REMODELLING

Sensory nerve-derived neuropeptide calcitonin gene-related peptide (CGRP) acts as a potent vasodilator, and is suggested to be protective in models of hypertension. The aim of this study was to learn...