scholarly journals Reactive dicarbonyl compounds cause Calcitonin Gene-Related Peptide release and synergize with inflammatory conditions in mouse skin and peritoneum

2020 ◽  
Vol 295 (19) ◽  
pp. 6330-6343
Author(s):  
Anna K. Becker ◽  
Andrea Auditore ◽  
Monika Pischetsrieder ◽  
Karl Messlinger ◽  
Thomas Fleming ◽  
...  
Keyword(s):  
Peritoneal Dialysis ◽  
Transient Receptor Potential ◽  
Mouse Skin ◽  
Receptor Potential ◽  
Calcitonin Gene Related Peptide ◽  
Prostaglandin E ◽  
Related Peptide ◽  
Inflammatory Conditions ◽  
Calcitonin Gene ◽  
Transient Receptor

The plasmas of diabetic or uremic patients and of those receiving peritoneal dialysis treatment have increased levels of the glucose-derived dicarbonyl metabolites like methylglyoxal (MGO), glyoxal (GO), and 3-deoxyglucosone (3-DG). The elevated dicarbonyl levels can contribute to the development of painful neuropathies. Here, we used stimulated immunoreactive Calcitonin Gene–Related Peptide (iCGRP) release as a measure of nociceptor activation, and we found that each dicarbonyl metabolite induces a concentration-, TRPA1-, and Ca2+-dependent iCGRP release. MGO, GO, and 3-DG were about equally potent in the millimolar range. We hypothesized that another dicarbonyl, 3,4-dideoxyglucosone-3-ene (3,4-DGE), which is present in peritoneal dialysis (PD) solutions after heat sterilization, activates nociceptors. We also showed that at body temperatures 3,4-DGE is formed from 3-DG and that concentrations of 3,4-DGE in the micromolar range effectively induced iCGRP release from isolated murine skin. In a novel preparation of the isolated parietal peritoneum PD fluid or 3,4-DGE alone, at concentrations found in PD solutions, stimulated iCGRP release. We also tested whether inflammatory tissue conditions synergize with dicarbonyls to induce iCGRP release from isolated skin. Application of MGO together with bradykinin or prostaglandin E2 resulted in an overadditive effect on iCGRP release, whereas MGO applied at a pH of 5.2 resulted in reduced release, probably due to an MGO-mediated inhibition of transient receptor potential (TRP) V1 receptors. These results indicate that several reactive dicarbonyls activate nociceptors and potentiate inflammatory mediators. Our findings underline the roles of dicarbonyls and TRPA1 receptors in causing pain during diabetes or renal disease.

Ghrelin attenuated hyperalgesia induced by chronic nitroglycerin: CGRP and TRPV1 as targets for migraine management

Cephalalgia ◽  
2017 ◽  
Vol 38 (11) ◽  
pp. 1716-1730 ◽  
Author(s):  
Fereshteh Farajdokht ◽  
Gisou Mohaddes ◽  
Dariush Shanehbandi ◽  
Pouran Karimi ◽  
Shirin Babri
Keyword(s):  
Mrna Expression ◽  
Transient Receptor Potential ◽  
Receptor Potential ◽  
Calcitonin Gene Related Peptide ◽  
Transient Receptor Potential Vanilloid ◽  
Conditioned Place Aversion ◽  
Trigeminovascular System ◽  
Related Peptide ◽  
Calcitonin Gene ◽  
Transient Receptor

Background According to the neurovascular theory of migraine, activation of the trigeminovascular system contributes to the development of migraine. This study examined the effects of chronic intraperitoneal ghrelin (150 µg/kg) treatment on the development of chronic migraine induced by intermittent injection of nitroglycerin 10 mg/kg. Methods Baseline and post-drug (2 h following nitroglycerin injection) mechanical and thermal sensitivity were assessed by von Frey hair and tail immersion tests, respectively on days 1, 3, 5, 7, 9 and 11. Moreover, we investigated the effect of ghrelin treatment on nitroglycerin-induced aversive behavior by using a two-chamber conditioned place aversion paradigm. At the end of behavioral testing, on day 11, animals were sacrificed and plasma concentration of calcitonin gene-related peptide was measured using a rat-specific enzyme-linked immunosorbent assay kit. Also, real time polymerase chain reaction was used to quantify mRNA expression of calcitonin gene-related peptide and transient receptor potential vanilloid 1 in the trigeminal ganglion. Results Our results indicated that nitroglycerin activated the trigeminovascular system, which was reflected by mechanical and thermal hypersensitivity and elevation of mRNA expression of calcitonin gene-related peptide and transient receptor potential vanilloid-1, as migraine markers, and plasma calcitonin gene-related peptide levels. Moreover, chronic nitroglycerin injection induced conditioned place aversion and body weight loss. Nevertheless, ghrelin modulated nitroglycerin-triggered changes in transient receptor potential vanilloid-1 and calcitonin gene-related peptide expression, and mitigated nitroglycerin-induced hyperalgesia. Conclusion These results provide the first convincing evidence that ghrelin has a modulating effect on central sensitization induced by chronic intermittent nitroglycerin, and its antinociceptive effect may be related to a reduction of these factors in the trigeminal ganglion.

Die Beteiligung peripherer Rezeptoren und Neurotransmitter an den antihyperalgetischen Effekten der Akupunktur: ein aktuelles Review

2021 ◽  
Vol 02 (03) ◽  
pp. 191-192
Keyword(s):  
Transient Receptor Potential ◽  
Web Of Science ◽  
Receptor Potential ◽  
Calcitonin Gene Related Peptide ◽  
Corticotropin Releasing Factor ◽  
Transient Receptor Potential Vanilloid ◽  
Substanz P ◽  
Related Peptide ◽  
Calcitonin Gene ◽  
Transient Receptor

Der vorliegende Artikel analysiert die aktuellen präklinischen Studien zur Beteiligung peripherer Rezeptoren und Neuromediatoren an den antihyperalgetischen Effekten der Akupunktur. Die Datenbanken von PubMed, Scopus und Web of Science wurden mittels einer erweiterten Reviewmethode durchsucht. Anhand einer vordefinierten Suchstrategie wurden die präklinischen Artikel ausgewählt, welche die Rolle peripherer Rezeptoren und Neuromediatoren auf die schmerzkontrollierenden Effekte der Akupunktur bei Ratten und Mäusen untersuchten. Die Suche ergab 456 Artikel, von denen 29 die Einschlusskriterien der Studie erfüllten. Die ausgewählten Artikel behandelten folgende periphere Rezeptoren: Opioid- (n=9), Adenosin- (n=5), Cannabinoid- (n=5), Transient-Receptor-Potential-Vanilloid- (TRPV; n=3), Histamin- (n=2), adrenerge (n=1), muskarinerge (n=1), Corticotropin-releasing Factor (CRF)-(n=2), IL-1- (n=1) und Endothelinrezeptoren (n=1). Folgende Neuromediatoren korrelierten mit peripheren Effekten der Schmerzkontrolle: Opioidpeptide (n=4), Adenosin (n=3), Histamin (n=1), Substanz P (n=1), Calcitonin Gene-related Peptide (CGRP) (n=1), Anandamid (n=1), NO (n=1) sowie Noradrenalin (n=1).

scholarly journals CGRPα within the Trpv1-Cre population contributes to visceral nociception

2018 ◽  
Vol 314 (2) ◽  
pp. G188-G200 ◽  
Author(s):  
Nick J. Spencer ◽  
Elín I. Magnúsdóttir ◽  
Jon E. T. Jakobsson ◽  
Garreth Kestell ◽  
Bao Nan Chen ◽  
...  
Keyword(s):  
Acetic Acid ◽  
Transient Receptor Potential ◽  
Receptor Potential ◽  
Calcitonin Gene Related Peptide ◽  
Cation Channel ◽  
Related Peptide ◽  
Visceral Nociception ◽  
Calcitonin Gene ◽  
Transient Receptor

The role of calcitonin gene-related peptide (CGRP) in visceral and somatic nociception is incompletely understood. CGRPα is highly expressed in sensory neurons of dorsal root ganglia and particularly in neurons that also express the transient receptor potential cation channel subfamily V member 1 (Trpv1). Therefore, we investigated changes in visceral and somatic nociception following deletion of CGRPα from the Trpv1-Cre population using the Cre/lox system. In control mice, acetic acid injection (0.6%, ip) caused significant immobility (time stationary), an established indicator of visceral pain. In CGRPα-mCherrylx/lx;Trpv1-Cre mice, the duration of immobility was significantly less than controls, and the distance CGRPα-mCherrylx/lx;Trpv1-Cre mice traveled over 20 min following acetic acid was significantly greater than controls. However, following acetic acid injection, there was no difference between genotypes in the writhing reflex, number of abdominal licks, or forepaw wipes of the cheek. CGRPα-mCherrylx/lx;Trpv1-Cre mice developed more pronounced inflammation-induced heat hypersensitivity above baseline values compared with controls. However, analyses of noxious acute heat or cold transmission revealed no difference between genotypes. Also, odor avoidance test, odor preference test, and buried food test for olfaction revealed no differences between genotypes. Our findings suggest that CGRPα-mediated transmission within the Trpv1-Cre population plays a significant role in visceral nociceptive pathways underlying voluntary movement. Monitoring changes in movement over time is a sensitive parameter to identify differences in visceral nociception, compared with writhing reflexes, abdominal licks, or forepaw wipes of the cheek that were unaffected by deletion of CGRPα- from Trpv1-Cre population and likely utilize different mechanisms. NEW & NOTEWORTHY The neuropeptide calcitonin gene-related peptide (CGRP) is highly colocalized with transient receptor potential cation channel subfamily V member 1 (TRPV1)-expressing primary afferent neurons, but the functional role of CGRPα specifically in these neurons is unknown in pain processing from visceral and somatic afferents. We used cre-lox recombination to conditionally delete CGRPα from TRPV1-expressing neurons in mice. We show that CGRPα from within TRPV1-cre population plays an important role in visceral nociception but less so in somatic nociception.

Uterine Cervical Afferents in Thoracolumbar Dorsal Root Ganglia Express Transient Receptor Potential Vanilloid Type 1 Channel and Calcitonin Gene–related Peptide, but Not P2X3 Receptor and Somatostatin

2006 ◽  
Vol 104 (4) ◽  
pp. 651-657 ◽  
Author(s):  
Chuanyao Tong ◽  
Dawn Conklin ◽  
Brittany B. Clyne ◽  
Jennifer D. Stanislaus ◽  
James C. Eisenach
Keyword(s):  
Dorsal Root ◽  
Transient Receptor Potential ◽  
Receptor Potential ◽  
Calcitonin Gene Related Peptide ◽  
Transient Receptor Potential Vanilloid ◽  
P2x3 Receptor ◽  
Related Peptide ◽  
Calcitonin Gene ◽  
Transient Receptor

Background Little is known regarding the phenotype of afferents that innervate the uterine cervix. Chronic estrogen sensitizes uterine cervical afferents to mechanical distension, but whether this reflects changes in afferent neurotransmitter or excitatory ion channel expression is unknown. The authors used immunocytochemistry to characterize uterine cervical afferents and the effects of estrogen on them. Methods Fluorogold was injected into the uterine cervix of intact rats (n = 7) and those with ovariectomy alone (n = 9) or with estrogen supplementation (n = 8). Bilateral dorsal root ganglia at T12-L2 were removed and immunostained for transient receptor potential vanilloid type 1 (TRPV1), P2X3 receptor, calcitonin gene-related peptide, and somatostatin. The proportion of fluorogold-traced dorsal root ganglion neurons expressing each of these markers was compared with untraced neurons. Results Most fluorogold-traced cells were found at L1 (> 55%) and were of small diameter (24 microm). TRPV1 expression was similar between traced and untraced cells, except the estrogen treatment increased TRPV1 expression in traced cells. Calcitonin gene-related peptide expression was greater in traced than in untraced cells, with no effect of experimental treatment. No traced cells expressed the P2X3 receptor or somatostatin, although each of these was present in untraced cells. Conclusion Uterine cervical afferents in the hypogastric nerve express TRPV1, an important nociceptive channel, which may play a role in estrogen-induced sensitization of cervical afferents. High expression of calcitonin gene-related peptide suggests a sensory and efferent role for this peptide. In contrast to other viscera, these afferents do not express somatostatin or P2X3 receptor, indicating a unique phenotype of these C fibers.

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