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2022 ◽  
Vol 14 ◽  
Author(s):  
Yue Hu ◽  
Qing-Yue Fu ◽  
Dan-Ni Fu ◽  
Xue-Long Wang ◽  
Zhi-Hong Wang ◽  
...  

Itching is a common symptom of many skin or systemic diseases and has a negative impact on the quality of life. Zinc, one of the most important trace elements in an organism, plays an important role in the regulation of pain. Whether and how zinc regulates itching is largely unclear. Herein, we explored the role of Zn2+ in the regulation of acute and chronic itch in mice. It is found that intradermal injection (i.d.) of Zn2+ dose-dependently induced acute itch and transient receptor potential A1 (TRPA1) participated in Zn2+-induced acute itch in mice. Moreover, the pharmacological analysis showed the involvement of histamine, mast cells, opioid receptors, and capsaicin-sensitive C-fibers in Zn2+-induced acute itch in mice. Systemic administration of Zn2+ chelators, such as N,N,N′,N′-Tetrakis(2-pyridylmethyl)ethylenediamine (TPEN), pyrithione, and clioquinol were able to attenuate both acute itch and dry skin-induced chronic itch in mice. Quantitative polymerase chain reaction (Q-PCR) analysis showed that the messenger RNA (mRNA) expression levels of zinc transporters (ZIPs and ZnTs) significantly changed in the dorsal root ganglia (DRG) under dry skin-induced chronic itch condition in mice. Activation of extracellular signal-regulated kinase (ERK) pathway was induced in the DRG and skin by the administration of zinc or under dry skin condition, which was inhibited by systemic administration of Zn2+ chelators. Finally, we found that the expression of GPR39 (a zinc-sensing GPCR) was significantly upregulated in the dry skin mice model and involved in the pathogenesis of chronic itch. Together, these results indicated that the TRPA1/GPR39/ERK axis mediated the zinc-induced itch and, thus, targeting zinc signaling may be a promising strategy for anti-itch therapy.


2022 ◽  
Vol 12 ◽  
Author(s):  
Jacob C. A. Edvinsson ◽  
Kristian A. Haanes ◽  
Lars Edvinsson

The trigeminovascular system (TGV) comprise of the trigeminal ganglion with neurons and satellite glial cells, with sensory unmyelinated C-fibers and myelinated Aδ-fibers picking up information from different parts of the head and sending signals to the brainstem and the central nervous system. In this review we discuss aspects of signaling at the distal parts of the sensory fibers, the extrasynaptic signaling between C-fibers and Aδ-fibers, and the contact between the trigeminal fibers at the nerve root entry zone where they transit into the CNS. We also address the possible role of the neuropeptides calcitonin gene-related peptide (CGRP), the neurokinin family and pituitary adenylyl cyclase-activating polypeptide 38 (PACAP-38), all found in the TGV system together with their respective receptors. Elucidation of the expression and localization of neuropeptides and their receptors in the TGV system may provide novel ways to understand their roles in migraine pathophysiology and suggest novel ways for treatment of migraine patients.


2021 ◽  
Author(s):  
Ahmed NEGM ◽  
Katharina STOBBE ◽  
Lucile FLEURIOT ◽  
Delphine DEBAYLE ◽  
Emmanuel DEVAL ◽  
...  

Diet induced obesity is one of the major causes of obesity, which affects 13% of the world's adult population. Obesity is correlated to chronic pain regardless of other components of the metabolic syndrome. Our study focuses on investigating the effect of high-fat diet induced obesity on peripheral sensory neurons activity and pain perception, followed by deciphering the underlying cellular and molecular mechanisms that involve Acid-Sensing Ion Channel 3 (ASIC3). We show here that heat sensitive C-fibers from mice made obese by consumption of a high-fat diet exhibited an increased activity during baseline and upon heating. Obese mice showed long-lasting heat pain hypersensitivity once obesity was well established, while mechanical sensitivity was not affected. We found that the serum of obese mice was enriched in lysophosphatidylcholine (LPC) species (LPC16:0, LPC18:0 and LPC18:1), which activate ASIC3 channels and increased peripheral neuron excitability. Genetic deletion and in vivo pharmacological inhibition of ASIC3 protected and rescued mice from obesity-induced thermal hypersensitivity. Our results identify ASIC3 channels in DRG neurons and circulating LPC species that activate them as a mechanism contributing to heat pain hypersensitivity associated with high-fat diet induced obesity.


2021 ◽  
Vol 18 ◽  
Author(s):  
Mikhail I. Nemenov ◽  
Robinson J. Singleton ◽  
Louis S. Premkumar

: The cutaneous mechanisms that trigger spontaneous neuropathic pain in diabetic peripheral neuropathy (PDPN) are far from clear. Two types of nociceptors are found within the epidermal and dermal skin layers. Small-diameter lightly myelinated Aδ and unmyelinated C cutaneous mechano and heat sensitive (AMH and CMH) and C mechanoinsensitive (CMi) nociceptors transmit pain from the periphery to central nervous system. AMH and CMH fibers are mainly located in the epidermis and CMi fibers are distributed in the dermis. In DPN, dying back intra-epidermal AMH and CMH fibers leads to reduced pain sensitivity and the patients exhibit significantly increased pain thresholds to acute pain, when tested using traditional methods. The role of CMi fibers in painful neuropathies has not been fully explored. Microneurography has been the only tool to access CMi fibers and differentiate AMH, CMH and CMi fiber types. Due to the complexity, its use is impractical in clinical settings. In contrast, a newly developed diode laser fiber selective stimulation (DLss) technique allows to safely and selectively stimulate Aδ and C fibers in the superficial and deep skin layers. DLss data demonstrate that patients with painful DPN have increased Aδ fiber pain thresholds, while C-fiber thresholds are intact because in these patients CMi fibers are abnormally spontaneously active. It is also possible to determine the involvement of CMi fibers by measuring the area of DLss-induced neurogenic axon reflex flare. The differences in AMH, CMH and CMi fibers allow to identify patients with painful and painless neuropathy. In this review, we will discuss the role of CMi fibers in PDPN.


2021 ◽  
Author(s):  
Li-Yuan Liu

In Chinese traditional medicine (CTM), meridians are described as a set of linear and longitudinal pathways along body skin. Acupuncture at acupoints provoke signals that transmit along the pathway and arrive to focal organs, which can treat more than one hundred of diseases. The pathway has been proved by modern anatomical and physiological researches. Linear structure and activity: There exist a loop system along body skin, consisted of a complex of sympathetic-arrector pili muscles (AP muscles) and concentrated mast cells in the rats. Along certain skin pathway, abundant sympathetic endings distribute within the AP muscles, which are appeared as sympathetic-substance lines (SSL) by macro-autoradiography. Under the line, mast cells are densely distributed. After shaving rat’s hairs, the new hairs firstly grow along some lines and loops, called hair-loop-lines (HLL). Acupuncture or injection of α receptor agonist at an acupoint produce a pilomotor line and simulate strong acupuncture effect, accompanying with neurogenic inflammation along the line in the rats. These three lines are coincident each other. The pilomotor line can be blocked by local injecting of α receptor antagonist, by crosscutting off skin or by applying procaine along the line, or by peritoneal injecting of cromoglicate. All these suggest that the pilomotor line along the SSL is the pathway for transmitting acupuncture signals independently and then producing acupuncture effect. Mechanism of linear transmission: The local piloerection stimulates the nerve nets of sympathetic endings and low threshold mechanical sensitive C-fibers around the hair follicles, whose excitation transmit to adjacent hair follicles by cross innervation and provoke new piloerection and neurosecretion respectively by axon reflex. Excited peripherical endings of C-fibers release neuropeptides (SP and CGRP) that stimulate mast cell degranulation. The released histamine stimulates C-fibers to produce gentle itch and further release of neuropeptides from C-fibers. Moreover, histamine stimulates AP muscle contraction. Thus, a positive feedback loop along hair follicles—C-fibers—mast cells is initiated and the pilomotor is enhanced and transmitted, accompanying histamine-mediated inflammation and sensation. The diffusion of released NA and histamine to adjacent skin also play important role in the transmission. Both axon reflex and diffusing action are united to cooperation for chain transmission of acupuncture signals. Mechanism of acupuncture effect: The acupuncture effect does not unidirectionally increase or decrease, but oscillate periodically, with about 28 min per circle. It is assumed that acupuncture leads the whole-body function change undulately and every organ in the body finds their own balance point through vibration. Therefore, acupuncture is auto-regulation, bi-regulation and vibrating regulation. The vibration is assumed by periodically excited and inhibited afferent signals from pilomotor line that lead periodical oscillation of whole CNS and the following oscillation of whole-body function.As a sum, under the guidance of CTM, a novel and unknown linear system hidden along skin have been discovered, which play an important role in the horizontal and integrative regulation on whole-body function, as expected in the integrative physiology. Importantly, there is a new type of mechanical transmission of signal.


2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Şefik Evren Erdener ◽  
Zeynep Kaya ◽  
Turgay Dalkara

Abstract Background Pain is generally concomitant with an inflammatory reaction at the site where the nociceptive fibers are activated. Rodent studies suggest that a sterile meningeal inflammatory signaling cascade may play a role in migraine headache as well. Experimental studies also suggest that a parenchymal inflammatory signaling cascade may report the non-homeostatic conditions in brain to the meninges to induce headache. However, how these signaling mechanisms function in patients is unclear and debated. Our aim is to discuss the role of inflammatory signaling in migraine pathophysiology in light of recent developments. Body Rodent studies suggest that a sterile meningeal inflammatory reaction can be initiated by release of peptides from active trigeminocervical C-fibers and stimulation of resident macrophages and dendritic/mast cells. This inflammatory reaction might be needed for sustained stimulation and sensitization of meningeal nociceptors after initial activation along with ganglionic and central mechanisms. Most migraines likely have cerebral origin as suggested by prodromal neurologic symptoms. Based on rodent studies, a parenchymal inflammatory signaling cascade has been proposed as a potential mechanism linking cortical spreading depolarization (CSD) to meningeal nociception. A recent PET/MRI study using a sensitive inflammation marker showed the presence of meningeal inflammatory activity in migraine with aura patients over the occipital cortex generating the visual aura. These studies also suggest the presence of a parenchymal inflammatory activity, supporting the experimental findings. In rodents, parenchymal inflammatory signaling has also been shown to be activated by migraine triggers such as sleep deprivation without requiring a CSD because of the resultant transcriptional changes, predisposing to inadequate synaptic energy supply during intense excitatory transmission. Thus, it may be hypothesized that neuronal stress created by either CSD or synaptic activity-energy mismatch could both initiate a parenchymal inflammatory signaling cascade, propagating to the meninges, where it is converted to a lasting headache with or without aura. Conclusion Experimental studies in animals and emerging imaging findings from patients warrant further research to gain deeper insight to the complex role of inflammatory signaling in headache generation in migraine.


2021 ◽  
Vol 9 (5) ◽  
pp. 580-590
Author(s):  
Vaishnavi Sundar ◽  
◽  
Shalini Ramasamy ◽  
Sanjana Vimal ◽  
Anupam Dutta ◽  
...  

Substance P (SP) is a neuropeptide that has its place in the tachykinin family and helps in the transmission of neurogenic signals. SP is also a neuromodulator that plays a crucial part in pain during inflammatory processes. It is produced by the capsaicin-sensitive unmyelinated C fibers sensory neurons by the central and peripheral nervous systems. Substance P is known as a critical primary responder to most of the extreme stimuli, i.e., specifically those with the ability to destabilize the biological integrity. Hence, SP can be considered as an instantaneous system for defense, stress, healing, etc. SP is known to perform a vital role in neurogenic inflammation and the pathophysiology of acute pancreatitis. Out of these, neurogenic inflammation is responsible for acute interstitial pancreatitis as a result of oedema. SP binds itself to the G-protein coupled neurokinin-1 receptor and causes plasma leakage, cell proliferation, and invasion resulting in pancreatic cancer. SP along with comparable neuropeptides seems to be crucial targets with the capability of satisfying several unfulfilled medical requisites. This review article mainly focuses on compiling the available evidence to show that SP could be a novel therapeutic target for pancreatic diseases, and more exploration into the SP signaling pathways is the call of the hour.


2021 ◽  
Vol 2021 ◽  
pp. 1-10
Author(s):  
Simin Song ◽  
Yuan Xu ◽  
Jiang Liu ◽  
Yadi Jia ◽  
Xiaowei Lin ◽  
...  

Background. Manual acupuncture (MA) with different stimulus frequencies may give rise to varying acupuncture effects. However, the intensity-effect relationship and the underlying mechanisms of MA remain unclear. Objective. To compare the analgesic effects of different frequencies of twirling-rotating MA on rats with complete Freund’s adjuvant- (CFA-) induced pain and explore the underlying mechanism via peripheral sensory nerves. Methods. First, 36 healthy male Wistar rats were randomly divided into 6 groups: control group, 2 r/s MA group (twirling-rotating MA with the frequency of 2 revolutions per second), 4 r/s MA group (twirling-rotating MA with the frequency of 4 revolutions per second), CFA group, CFA + 2 r/s MA group, and CFA + 4 r/s MA group. Rats in three CFA groups received an intraplantar injection of CFA to establish a pain model, while the rats in other three groups received an intraplantar injection of saline. Rats in the 2 r/s MA group and 4 r/s MA group were treated with the corresponding frequencies of twirling-rotating MA on bilateral Zusanli (ST36) and Kunlun (BL60) for 7 days. The ipsilateral nociceptive thresholds (paw withdrawal latency; PWL) were tested to evaluate the analgesic effects. Second, 9 healthy male Wistar rats were randomly divided into 3 groups: control group, 2 r/s MA group, and 4 r/s MA group. The proportion of C-fiber neurons (calcitonin gene-related peptide- (CGRP-) positive neurons) and A-fiber neurons (neurofilament 200- (NF200-) positive neurons) in the dorsal root ganglia (DRG) activated by MA were quantitatively analyzed with the morphological immunofluorescence staining method. Third, 30 healthy male Wistar rats were randomly divided into 6 groups: control group, CFA group, CFA + 2 r/s MA group, CFA + 2 r/s MA + RTX group, CFA + 4 r/s MA group, and CFA  + 4 r/s MA + RTX group. Resiniferatoxin (RTX) was injected into the acupoints before acupuncture. PWL was evaluated to investigate the analgesic effect. Results. Both types of MA treatment increased the PWL of saline-injecting rats and pain model rats. Moreover, 4 r/s MA was superior to 2 r/s MA in increasing PWL. A higher quantity of excited C-fiber neurons was observed following 4 r/s MA than 2 r/s MA, while the reverse was observed in the activation of A-fiber neurons. Following the injection of RTX to inhibit the activation of C-fibers, the analgesic effect of 4 r/s MA reduced significantly but not of 2 r/s MA. Conclusion. Strong MA (4 r/s MA) has superior analgesic effects to gentle MA (2 r/s MA) on CFA model rats, which is associated with C-fiber activation.


Author(s):  
Marian Kollarik ◽  
Fei Ru ◽  
Nikoleta Pavelkova ◽  
John Mulcahy ◽  
John Hunter ◽  
...  

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