vasoactive-intestinal-peptide and Neurogenic-Inflammation

Psoriasis is a chronic inflammatory disease with a multifactorial origin that affects the skin. It is characterized by keratinocyte hyperproliferation, which results in erythemato-squamous plaques. Just as the immune system plays a fundamental role in psoriasis physiopathology, the nervous system maintains the inflammatory process through the neuropeptides and neurotransmitters synthesis, as histamine, serotonin, calcitonin gene-related peptide, nerve growth factor, vasoactive intestinal peptide, substance P, adenosine, glucagon-like peptide, somatostatin and pituitary adenylate cyclase polypeptide. In patients with psoriasis, the systemic or in situ expression of these chemical mediators and their receptors are altered, which affects the clinical activity of patients due to its link to the immune system, provoking neurogenic inflammation. It is important to establish the role of the nervous system since it could represent a therapeutic alternative for psoriasis patients. The aim of this review is to offer a detailed review of the current literature about the neuropeptides and neurotransmitters involved in the physiopathology of psoriasis.

Topics: Animals; Calcitonin Gene-Related Peptide; Humans; Neurogenic Inflammation; Neuropeptides; Neurotransmitter Agents; Skin; Vasoactive Intestinal Peptide

Migraine is a primary headache disorder. Despite numerous studies conducted with the aim to understand the pathophysiology of migraine, several aspects are still unclear. The trigeminovascular system plays a key role. Neurogenic inflammation is presumed to be an important factor in migraine pathophysiology, mediated by the activation of primary neurons, leading to the release of various pro-inflammatory neuropeptides and neurotransmitters such as Calcitonin Gene-Related Peptide (CGRP), substance P (SP), and vasoactive intestinal peptide (VIP). Nitric oxide (NO), Pituitary adenylate cyclase-activating polypeptide (PACAP) and Glutamate (Glu) also play an important role in the modulation of inflammatory mechanisms.. To review the literature focusing on novel therapeutic targets in migraine, related to neurogenic inflammation.. A systematic literature search in the database of PUBMED was conducted regarding therapeutic strategies in migraine, focusing on substances and cytokines released during neurogenic inflammation, published until January 2017.. Ongoing phase III clinical studies with monoclonal antibodies against CGRP and CGRP receptors offer promising novel aspects for migraine treatment. Preclinical and clinical studies targeting SP and nitric oxide synthase (NOS) were all terminated with no significant results compared to placebo. New promising therapeutic goal could be PACAP and its receptor (PAC1), and kynurenic acid (KYNA) analogues.. Current migraine treatment offers pain relief only for a small proportion of migraine patients and might not be adequate for patients with cardiovascular comorbidity due to side effects. Better understanding of migraine pathophysiology might, therefore, lead to novel therapeutic lines both in migraine attack treatment and prophylaxis.

Topics: Animals; Calcitonin Gene-Related Peptide; Drug Discovery; Humans; Kynurenic Acid; Migraine Disorders; Molecular Targeted Therapy; Neurogenic Inflammation; Pituitary Adenylate Cyclase-Activating Polypeptide; Substance P; Vasoactive Intestinal Peptide

The enteric nervous system (ENS), referred to as the "second brain," comprises a vast number of neurons that form an elegant network throughout the gastrointestinal tract. Neuropeptides produced by the ENS play a crucial role in the regulation of inflammatory processes via cross talk with the enteric immune system. In addition, neuropeptides have paracrine effects on epithelial secretion, thus regulating epithelial barrier functions and thereby susceptibility to inflammation. Ultimately the inflammatory response damages the enteric neurons themselves, resulting in deregulations in circuitry and gut motility. In this review, we have emphasized the concept of neurogenic inflammation and the interaction between the enteric immune system and enteric nervous system, focusing on neuropeptide Y (NPY) and vasoactive intestinal peptide (VIP). The alterations in the expression of NPY and VIP in inflammation and their significant roles in immunomodulation are discussed. We highlight the mechanism of action of these neuropeptides on immune cells, focusing on the key receptors as well as the intracellular signaling pathways that are activated to regulate the release of cytokines. In addition, we also examine the direct and indirect mechanisms of neuropeptide regulation of epithelial tight junctions and permeability, which are a crucial determinant of susceptibility to inflammation. Finally, we also discuss the potential of emerging neuropeptide-based therapies that utilize peptide agonists, antagonists, siRNA, oligonucleotides, and lentiviral vectors.

Topics: Animals; Cytokines; Enteric Nervous System; Humans; Intestinal Mucosa; Neurogenic Inflammation; Neuropeptide Y; Vasoactive Intestinal Peptide

Dental pulp is a soft mesenchymal tissue densely innervated by afferent (sensory) fibers, sympathetic fibers, and parasympathetic fibers. This complexity in pulp innervation has motivated numerous investigations regarding how these 3 major neuronal systems regulate pulp physiology and pathology. Most of this research is focused on neuropeptides and their role in regulating pulpal blood flow and the development of neurogenic inflammation. These neuropeptides include substance P, calcitonin gene-related peptide, neurokinin A, neuropeptide Y, and vasoactive intestinal polypeptide among others. The purpose of this article is to review recent advances in neuropeptide research on dental pulp, including their role in pulp physiology, their release in response to common dental procedures, and their plasticity in response to extensive pulp and dentin injuries. Special attention will be given to neuropeptide interactions with pulp and immune cells via receptors, including studies regarding receptor identification, characterization, mechanisms of action, and their effects in the development of neurogenic inflammation leading to pulp necrosis. Their role in the growth and expansion of periapical lesions will also be discussed. Because centrally released neuropeptides are involved in the development of dental pain, the pain mechanisms of the pulpodentin complex and the effectiveness of present and future pharmacologic therapies for the control of dental pain will be reviewed, including receptor antagonists currently under research. Finally, potential clinical therapies will be proposed, particularly aimed to manipulate neuropeptide expression or blocking their receptors, to modulate a variety of biologic mechanisms, which preliminary results have shown optimistic results.

Topics: Alveolar Bone Loss; Animals; Calcitonin Gene-Related Peptide; Dental Pulp; Humans; Neurogenic Inflammation; Neurokinin A; Neurons, Afferent; Neuropeptide Y; Neuropeptides; Pulpitis; Substance P; Toothache; Vasoactive Intestinal Peptide

The nervous system contributes to the pathophysiology of peripheral inflammation and a neurogenic component has been implicated in many inflammatory disease, including oral diseases. Neurogenic inflammation should be regarded as a protective mechanism wich forms the first line of defense and protects tissue integrity. However, prolonged noxius stimulation may result in the inflammatory response. This review focuses on the evidence suggesting that neuropeptides have a pivotal role in the complex cascade of chemical activity associated with oral diseases. The pathophysiology is complex and neuropeptides are not solely responsible for the initiation and progression of the disease. However, since neuropeptides and inflammatory modulators are released together during the inflammatory response, it will be impossible to assign a specific role to each until work with selective antagonists is completed.

Topics: Animals; Disease Models, Animal; Disease Progression; Humans; Microcirculation; Mouth Diseases; Mouth Mucosa; Neurogenic Inflammation; Neuropeptides; Nociceptors; Pain; Rats; Substance P; Swine; Tongue; Vasoactive Intestinal Peptide

Pituitary adenylate cyclase-activating peptide-38 (PACAP38) and vasoactive intestinal peptide (VIP) belong to the same secretin-glucagon superfamily and are present in nerve fibers in dura and skin. Using a model of acute cutaneous pain we explored differences in pain perception and vasomotor responses between PACAP38 and VIP in 16 healthy volunteers in a double-blind, placebo-controlled, crossover study. All participants received intradermal injections of 200 pmol PACAP38, 200 pmol VIP and placebo into the volar forearm. Measurements included pain intensity on a visual analog scale (VAS), blood flow by laser Doppler flowmetry, visual flare and wheal. Pain intensities after PACAP38 and VIP were mild and limited to a short time of about 100 s after injection. The area under the VAS-time curve was larger following PACAP38 (P = 0.004) and VIP (P = 0.01) compared to placebo. We found no statistical difference in pain perception between PACAP38 and VIP. Skin blood flow increase, flare and wheal were larger after both PACAP38 (P = 0.011) and VIP (P = 0.001) compared to placebo. VIP induced a considerably larger increase in skin blood flow, flare and wheal than PACAP38 (P = 0.002). In conclusion, we found that peripheral nociceptive cutaneous responses elicited by PACAP38 and VIP are similar in healthy volunteers. This suggests that acute pain and vasomotor responses following intradermal injections of PACAP38 and VIP are primarily mediated by VPAC receptors.

Topics: Acute Disease; Administration, Cutaneous; Adult; Cross-Over Studies; Double-Blind Method; Female; Humans; Male; Middle Aged; Models, Neurological; Neurogenic Inflammation; Nociceptors; Pain; Pituitary Adenylate Cyclase-Activating Polypeptide; Vasoactive Intestinal Peptide; Young Adult

The mechanisms of naso-ocular interaction in allergic rhinoconjunctivitis are not well understood. Neurogenic inflammation affects both eyes and nose via the same neurogenic factors. The purpose of this study was to investigate the effects of neurogenic inflammation on conjunctival inflammation following nasal allergen provocation.. Sensitized rats were exposed to ovalbumin (OVA) via the nose. Parts of the nasal mucosa and conjunctivae were sliced and used for hematoxylin-eosin staining, immunohistochemical analysis, western blotting, and real-time polymerase chain reaction. The slides were observed under a light microscope, and the acquired images were analyzed. The levels of substance P (SP), vasoactive intestinal peptide (VIP), and nerve growth factor (NGF) were detected.. The levels of SP, VIP, and NGF were increased in both nasal mucosa and conjunctivae 1 h and 24 h after OVA administration (p < 0.05). Higher levels of SP, VIP, and NGF expression were observed in the nasal mucosa and conjunctivae 24 h after OVA administration (p < 0.05). Following damage of the nasal sensory nerves by capsaicin, the protein and mRNA levels of SP, VIP, and NGF were reduced.. In conclusion, the increased levels of VIP, SP, and NGF might be responsible for the ocular reaction following nasal challenge with allergen in rats.

Topics: Animals; Biomarkers; Conjunctiva; Conjunctivitis, Allergic; Nasal Mucosa; Nerve Growth Factor; Neurogenic Inflammation; Rats; Substance P; Vasoactive Intestinal Peptide

Vasoactive intestinal peptide (VIP) is one of the neuropeptides showing the strongest up-regulation in the nociceptive pathway after peripheral nerve injury and has been proposed to support neuropathic pain. Nevertheless, the story may be more complicated considering the known suppressive effects of the peptide on the immune reactivity of microglial cells, which have been heavily implicated in the onset and maintenance of pain after nerve injury. We here used mice deficient in VIP and the model of spared nerve injury, characterized by persistent tactile hypersensitivity. While tactile hypersensitivity developed similarly to wild type mice for the ipsilateral hindpaw, only transgenic mice showed a mirror-image tactile hypersensitivity in the contralateral hindpaw. This exacerbated neuropathic pain phenotype appeared to be mediated through a local mechanism acting at the level of the lumbar spinal cord as a distant nerve lesion in the front limb did not lead to hindpaw hypersensitivity in VIP-deficient mice. Innocuous tactile hindpaw stimulation was found to increase a neuronal activation marker in the bilateral superficial laminae of the lumbar dorsal horn of VIP-deficient, but not wild type mice, after SNI. A deeper study into the immune responsiveness to the nerve lesion also proved that VIP-deficient mice had a stronger early pro-inflammatory cytokine response and a more pronounced microglial reactivity compared to wild type controls. The latter was also observed at four weeks after spared nerve injury, a time at which bilateral tactile hypersensitivity persisted in VIP-deficient mice. These data suggest an action of VIP in neuropathic states that is more complicated than previously assumed. Future research is now needed for a deeper understanding of the relative contribution of receptors and fiber populations involved in the VIP-neuropathic pain link.

Topics: Animals; Calcium-Binding Proteins; Cytokines; Disease Models, Animal; Female; Functional Laterality; Gene Expression Regulation; Glial Fibrillary Acidic Protein; Hyperalgesia; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Microfilament Proteins; Neuralgia; Neurogenic Inflammation; Pain Measurement; Peripheral Nerve Injuries; Proto-Oncogene Proteins c-fos; Time Factors; Vasoactive Intestinal Peptide

Neurogenic inflammation is a local inflammatory response that is driven by the peripheral release of neuropeptides from small diameter afferents which occurs in many organs including joints. The knee joint has a rich endocannabinoid system which has been shown to decrease acute synovitis. The aim of this study was to investigate the influence of joint afferents on leukocyte-endothelial interactions within the synovial microcirculation of mice and determine the role of endocannabinoids on this inflammatory response. Electrical, antidromic stimulation of the saphenous nerve decreased leukocyte rolling at the lowest frequency tested (0.5Hz), while increasing leukocyte rolling at higher frequencies (2.0 and 5.0Hz). The leukocyte rolling effect of nerve stimulation was completely abolished by pre-treating the knee with the vasoactive intestinal peptide antagonist VIP

Topics: Animals; Endocannabinoids; Joints; Leukocytes; Male; Mice, Inbred C57BL; Neurogenic Inflammation; Receptors, Cannabinoid; Vasoactive Intestinal Peptide

Neuroinflammation driven by the vanilloid-type ion channel receptor transient receptor potential vanilloid type 1 (TRPV-1) is suspected to play a role in the pathophysiology of inflammatory bowel disease. Because inflammatory bowel disease is known to elevate the risk of colon cancer, we examined postulated roles for TRPV-1-driven neuroinflammation in promoting colitis-associated and spontaneous colon cancer development. Using a well-established model of colitis-associated cancer (CAC), we found that mice genetically deficient in TRPV-1 showed a higher incidence and number of tumors in the distal colon. In like manner, genetic deficiency of TRPV-1 in the APC(Min/+) model of spontaneous colon cancer accentuated the number of colonic adenomas formed. Mechanistic analyses in the CAC model revealed an increased infiltration of inflammatory cells into the tumors along with elevated expression of interleukin (IL)-6 and IL-11 and activation of the STAT3 and NF-κB signaling pathways. Notably, TPRV-1-deficient mice exhibited a defect in expression of the anti-inflammatory neuropeptides, vasoactive intestinal peptide (VIP), and pituitary adenylate cyclase-activating peptide (PACAP) which contributed to the generation of a local proinflammatory environment. Together, our findings argue that by limiting neuroinflammatory processes, TRPV-1 exerts a protective role that restricts the initiation and progression of colon cancer.

Topics: Animals; Colitis; Colonic Neoplasms; Cytokines; Genes, APC; Mice; Mice, Inbred C57BL; Mutation; Neurogenic Inflammation; NF-kappa B; Pituitary Adenylate Cyclase-Activating Polypeptide; RNA, Messenger; STAT3 Transcription Factor; TRPV Cation Channels; Vasoactive Intestinal Peptide

This immunohistochemical study sought to determine whether there are any differences in the peptidergic innervation of these pulps and whether dental caries is associated with changes in neuropeptide expression. Mandibular first permanent molars and second primary molars (n=120) were obtained from children requiring dental extractions under general anaesthesia. Extracted teeth were split longitudinally, placed in fixative, and categorized as intact, moderately carious or grossly carious. The coronal pulps were removed and 10-microm frozen sections were processed for indirect immunofluorescence. Double labelling employed combinations of the following antisera: (1) protein gene product 9.5, a general neuronal marker; (2) one of the neuropeptides calcitonin gene-related peptide (CGRP), substance P (SP), vasoactive intestinal polypeptide (VIP), neuropeptide Y (NPY), galanin (GAL), enkephalin (ENK) and somatostatin (SOM). Image analysis was then used to determine the percentage area of immunostaining for each label within different anatomical regions of the coronal pulp. Sparse or absent immunoreactivity for GAL, ENK and SOM made analysis impossible. Analysis of CGRP, SP and VIP revealed significant interdentition differences, with their expression being significantly greater in permanent teeth, but this was not the case for NPY, with primary and permanent teeth demonstrating a similar amount of label for this peptide. Both dentitions showed significant increases in CGRP, SP, VIP and NPY expression with caries progression. These findings could have biological and clinical importance in connection with nociception, inflammation and healing.

Topics: Analysis of Variance; Calcitonin Gene-Related Peptide; Child; Dental Caries; Dental Pulp; Dentition, Permanent; Disease Progression; Enkephalins; Fluorescent Antibody Technique, Indirect; Galanin; Humans; Molar; Neurogenic Inflammation; Neuropeptide Y; Neuropeptides; Somatostatin; Statistics, Nonparametric; Substance P; Tooth, Deciduous; Vasoactive Intestinal Peptide