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The most prevalent symptoms of post-COVID-19 condition are pulmonary dysfunction, fatigue and muscle weakness, anxiety, anosmia, dysgeusia, headaches, difficulty in concentrating, sexual dysfunction, and digestive disturbances. Hence, neurological dysfunction and autonomic impairments predominate in post-COVID-19 condition. Tachykinins including the most studied substance P are neuropeptides expressed throughout the nervous and immune systems, and contribute to many physiopathological processes in the nervous, immune, gastrointestinal, respiratory, urogenital, and dermal systems and participate in inflammation, nociception, and cell proliferation. Substance P is a key molecule in neuroimmune crosstalk; immune cells near the peripheral nerve endings can send signals to the brain with cytokines, which highlights the important role of tachykinins in neuroimmune communication. We reviewed the evidence that relates the symptoms of post-COVID-19 condition to the functions of tachykinins and propose a putative pathogenic mechanism. The antagonism of tachykinins receptors can be a potential treatment target., Competing Interests: Declaration of interests EPD holds an advisory and consultant role with Abbott Diagnostics and Imaware Diagnostics. All other authors declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

The anti-inflammatory effects of Aloe vera (AV), polysaccharide extract from AV, and extracts from the digestion and colonic fermentation of AV were evaluated using an immortal astrocyte cell line (U373 MG) that develops a neuro-inflammatory profile. Cell viability and inflammatory markers were assessed after stimulation with neuropeptide substance P (SP) that activates the pro-inflammatory MAPK (mitogen-activated protein kinase) pathway. Cell viability after SP treatment was over 50% at 10 mg/mL AV, polysaccharide extract from AV, extracts from the digestion: non-digestible fraction of AV non-digestible fraction of polysaccharide extract from AV and extracts from the colonic fermentation of AV, at 4 and 24 h. Moreover, cells exposed to SP and treated with these extracts showed lower protein-activated ERK1/ERK2 (extracellular signal-regulated kinases 1 and 2), p38 (MAPK protein p38), and NFκB (nuclear factor κB) levels with respect to the SP-stimulated control. Inflammation inhibition by extracts of polysaccharide extract from AV and extracts from the colonic fermentation of AV, at 24 h in the study of p38 was not as statistically significant in ERK1/ERK2 and NFκB. Nevertheless, there was a significant decrease (p < 0.05) in pro-inflammatory cytokine IL-6 levels in cells exposed to all samples. Samples with extracts from the colonic fermentation of AV, at 4 or 24 h showed the highest inhibitory effect on IL-6 production., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

The basal ganglia are a group of sub-cortical structures believed to play a critical role in action selection and sequencing. The striatum is the largest input structure of the basal ganglia and contains the neuropeptide substance P in abundance. Recent computational work has suggested that substance P could play a critical role in action sequence performance and acquisition, but this has not been tested experimentally before. The aim of the present study was to test how blocking substance P's main NK1-type receptors affected the sequential and temporal organization of spontaneous behavioral patterns. We did this in rats by focusing on the grooming chain, an innate and highly stereotyped ordered sequence. We performed an open field experiment in which the NK1 receptor antagonist L-733,060 was injected intraperitoneally in rats at two doses (2 and 4 mg/kg/ml), in a within-subject counterbalanced design. We used first order transition probabilities, Variable Length Markov Models, entropy metrics and T-pattern analysis to evaluate the effects of L-733,060 on sequential and temporal aspects of spontaneously ordered behavioral sequences. Our results suggest that blocking NK1 receptors made the transitions between the grooming chain elements significantly more variable, the transition structure of the grooming bouts simpler, and it increased the probability of transitioning from active to inactive states. Overall, this suggest that blocking substance P receptors led to a general break down in the fluency of spontaneous behavioral sequences, suggesting that substance P could be playing a key role in the implementation of sequential patterns., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

The chemokine fractalkine is synthesized as a membrane-bound protein, but studies have shown that serum levels of soluble fractalkine are elevated in inflammatory and autoimmune diseases. Patients with autoimmune diseases also have increased serum levels of neuropeptide substance P (SP). The shedding activity of the ADAM family is induced by peroxynitrite, but that of SP is unclear. Treatment of human macrophages with SP upregulated levels of membrane-bound fractalkine. Interestingly, small interfering RNA (siRNA) for DUOX2 further increased membrane-bound fractalkine but decreased soluble fractalkine compared with cells treated with SP alone. SP induced nitric oxide 2/inducible nitric oxide synthase (NOS2/iNOS) mRNA and increased levels of nitrotyrosine, a biomarker of peroxynitrite, whereas transfection with DUOX2 siRNA blunted upregulation of nitrotyrosine. Most importantly, N(ω)-nitro-L-arginine methyl ester (L-NAME, a nitric oxide synthase inhibitor) decreased protein levels of nitrotyrosine and concomitantly increased expression of membrane-bound fractalkine after exposure to SP. As for the signaling pathway of TGFβ1 (an inhibitor of iNOS mRNA expression), silencing of RNA for TAK-1 upregulated membrane-bound fractalkine, but silencing of RNA for the Smad family did not. Interfering RNA of transcription factor specificity protein 1 (Sp1) upregulated protein levels of TGFβ1/LAP. Most importantly, double transfection with siRNA for Sp1 and TRIM28/TIF1βor Fli-1 led to a significant increase in TGFβ1/LAP levels and a corresponding reduction of NOS2/iNOS, which inhibited the shedding of membrane-bound fractalkine. In conclusion, TRIM28/TIF1β and Fli-1 negatively regulate TGFβ1 expression to upregulate the generation of peroxynitrite, leading to increased shedding of membrane-bound fractalkine induced by SP., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

The striatum plays a central role in guiding numerous complex behaviors, ranging from motor control to action selection and reward learning. The diverse responsibilities of the striatum are reflected by the complexity of its organization. In this review, we will summarize what is currently known about the compartmental layout of the striatum, an organizational principle that is crucial for allowing the striatum to guide such a diverse array of behaviors. We will focus on the anatomical and functional properties of striosome (patch) and matrix compartments of the striatum, and how the engagement of these compartments is uniquely controlled by their afferents, intrinsic properties, and neuromodulation. We will give examples of how advances in technology have opened the door to functionally dissecting the striatum's compartmental design, and close by offering thoughts on the future and relevance for human disease., (© 2019 Wiley Periodicals, Inc.)

Tachykinins (TKs) include an evolutionarily conserved group of small bio-active peptides which possess a common carboxyl-terminal sequence, Phe-X-Gly-Leu-Met-NH2. TKs also have been shown to have implications in different steps of carcinogenesis, such as angiogenesis, mitogenesis, metastasis, and other growth-related events. The biological actions of substance P (SP), as the most important member of the TK family, are mainly mediated through a G protein-coupled receptor named neurokinin-1 receptor (NK1R). More recently, it has become clear that SP/NK1R system is involved in the initiation and activation of signaling pathways involved in cancer development and progression. Therefore, SP may contribute to triggering a variety of effector mechanisms including protein synthesis and a number of transcription factors that modulate the expression of genes involved in these processes. The overwhelming insights into the blockage of NK1R using specific antagonists could suggest a therapeutic approach in cancer therapy. In this review, we focus on evidence supporting an association between the signaling pathways of the SP/NK1R system and cancer cell proliferation and development.

Background: Low-level laser therapy (LLLT) is widely used in pain control in the field of physical medicine and rehabilitation and is effective for fibromyalgia pain. However, its analgesic mechanism remains unknown. A possible mechanism for the effect of LLLT on fibromyalgia pain is via the antinociceptive signaling of substance P in muscle nociceptors, although the neuropeptide has been known as a neurotransmitter to facilitate pain signals in the spinal cord., Objective: To establish an animal model of LLLT in chronic muscle pain and to determine the role of substance P in LLLT analgesia., Methods: We employed the acid-induced chronic muscle pain model, a fibromyalgia model proposed and developed by Sluka et al., and determined the optimal LLLT dosage., Results: LLLT with 685 nm at 8 J/cm2 was effective to reduce mechanical hyperalgesia in the chronic muscle pain model. The analgesic effect was abolished by pretreatment of NK1 receptor antagonist RP-67580. Likewise, LLLT showed no analgesic effect on Tac1-/- mice, in which the gene encoding substance P was deleted. Besides, pretreatment with the TRPV1 receptor antagonist capsazepine, but not the ASIC3 antagonist APETx2, blocked the LLLT analgesic effect., Conclusions: LLLT analgesia is mediated by the antinociceptive signaling of intramuscular substance P and is associated with TRPV1 activation in a mouse model of fibromyalgia or chronic muscle pain. The study results could provide new insight regarding the effect of LLLT in other types of chronic pain., (© 2019 American Academy of Pain Medicine. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

In psychiatric research, nuclear imaging complements MRI. A recent neuroimaging review of social anxiety disorder focused predominantly on MRI, omitting the contribution of nuclear imaging methods. Nuclear imaging investigations of neural activity are sparse but have generally yielded results consistent with studies performed using MRI. Evidence for disturbances in neurotransmitter systems in social anxiety disorder is limited but suggestive of both serotonergic and dopaminergic dysfunction. Research focusing on additional molecular targets using existing and novel tracers, combined with recent technologic innovations and trends in collaborative methodology, may shape future nuclear imaging endeavors in this field., (© 2018 by the Society of Nuclear Medicine and Molecular Imaging.)

Objective: This study aimed to investigate the role and mechanism of neuropeptide substance P (SP) in ST2 cell (bone mesenchymal stem cells of mice) osteogenic differentiation to provide a basis for the treatment of temporomandibular joint osteoarthritis., Methods: Third-generation ST2 cells were cultured with different concentrations of SP (0, 10⁻¹⁰, 10⁻⁸, 10⁻⁶, and 10⁻⁵ mol·L⁻¹). After 24, 48, and 72 h, cell proliferation was detected by CCK-8. The ST2 cells were cultured with 10⁻⁶ mol·L⁻¹ SP for 1, 3, 5, and 7 days. Subsequently, the expression of alkaline phosphatase (ALP), collagen typeⅠ(CollaⅠ), and osteocalcin (OCN) in the culture supernatant was tested by enzyme-linked immunosorbent assay (ELISA). ALP activity was detected by immunofluorescence staining. The ST2 cells were cultured with SP, Noggin (inhibitor of the bone morphogenetic protein signaling pathway), SP+Noggin, and 2% fetal bovine serum, respectively. Finally, the expression of ALP, CollaⅠ, and OCN in the culture supernatant was tested by ELISA., Results: CCK-8 showed that the effect of cell proliferation was most obvious when the SP concentration was 10⁻⁶ mol·L⁻¹ (P<0.01). The ELISA results demonstrated that ALP expression significantly increased at day 5 compared with that in the control group (P<0.01), whereas the expression of CollaⅠand OCN significantly increased at day 7 (P<0.05). Immunofluorescence results showed that ALP activity was strongest at day 5. The expression of ALP, CollaⅠ, and OCN decreased after Noggin addition (P<0.05)., Conclusions: SP can promote the proliferation and osteogenic differentiation of ST2 cells, and the bone morphogenetic protein signaling pathway may be involved in this process.

The hippocampus is a critical brain region for the formation of declarative memories. While social memory had long been attributed to be a function of the hippocampus, it is only of late that the area CA2 of the hippocampus was demarcated as essential for social memory formation. In addition to this distinct role, CA2 possesses unique molecular, structural and physiological characteristics compared to the other CA regions-CA1 and CA3, and the dentate gyrus (DG). CA2 pyramidal neurons are positioned at a location between CA1 and CA3, receiving inputs from CA3 and DG, in addition to forming a powerful disynaptic circuit with direct input from the entorhinal cortical layer II neurons. CA2 also receives direct inputs from the hypothalamic regions and displays a unique expression pattern for receptors for neuromodulators. The location, inputs, and molecular signatures of the area CA2 point to the possibility that CA2 serves as a modulatory gateway that processes information from the entorhinal cortex and CA3, before relaying them onto CA1, the major output of the hippocampus. This review discusses recent findings regarding plasticity and neuromodulation in the CA2 region of the hippocampus, and how this may have the potential to influence plasticity in connecting circuits, and thereby memory and behaviour.

Background and Purpose: Capsaicin-mediated modulation of taste nerve responses is thought to be produced indirectly by the actions of neuropeptides, for example, CGRP and substance P (SP), on taste cells implying they play a role in taste sensitivity. During the processing of gustatory information in taste buds, CGRP shapes peripheral taste signals via serotonergic signalling. The underlying assumption has been that SP exerts its effects on taste transmitter secretion in taste buds of mice., Experimental Approach: To test this assumption, we investigated the net effect of SP on taste-evoked ATP secretion from mouse taste buds, using functional calcium imaging with CHO cells expressing high-affinity transmitter receptors as cellular biosensors., Key Results: Our results showed that SP elicited PLC activation-dependent intracellular Ca 2+ transients in taste cells via neurokinin 1 receptors, most likely on glutamate-aspartate transporter-expressing Type I cells. Furthermore, SP caused Type I cells to secrete GABA., Conclusion and Implications: Combined with the recent findings that GABA depresses taste-evoked ATP secretion, the current results indicate that SP elicited secretion of GABA, which provided negative feedback onto Type II (receptor) cells to reduce taste-evoked ATP secretion. These findings are consistent with a role for SP as an inhibitory transmitter that shapes the peripheral taste signals, via GABAergic signalling, during the processing of gustatory information in taste buds. Notably, the results suggest that SP is intimately associated with GABA in mammalian taste signal processing and demonstrate an unanticipated route for sensory information flow within the taste bud., (© 2018 The British Pharmacological Society.)

Substance P (SP) and calcitonin gene-related peptide (CGRP) are the neuropeptides released from the sensory nerve endings. Neuropeptides play a role in bone and the relevant organs. It exerts functions in regulation of the bone metabolism, fracture healing and pain by a certain way. The biological properties and distributions of SP and CGRP are closely related to the pathogenesis and development of bone metabolism, fracture healing and pain.

In the beginning of the 1970s, only two chemical substances, acetylcholine and γ-aminobutyric acid (GABA), had been definitely established as neurotransmitters. Under such circumstances, I started my scientific career in Professor Masanori Otsuka's lab searching for the transmitter of primary sensory neurons. Until 1976, lines of evidence had accumulated indicating that the undecapeptide substance P could be released as a transmitter from primary afferent fibers into spinal synapses, although the substance P-mediated synaptic response had yet to be identified. Peripheral synapses could serve as a good model and thus, it was demonstrated in the prevertebral sympathetic ganglia by1985 that substance P released from axon collaterals of primary sensory neurons acts as the transmitter mediating non-cholinergic slow excitatory postsynaptic potential (EPSP). At that time, we also found that autonomic synapses were useful to uncover the transmitter role of the opioid peptide enkephalins, whose functions had been unknown since their discovery in 1975. Accordingly, enkephalins were found to serve a transmitter role in mediating presynaptic inhibition of cholinergic fast and non-cholinergic slow transmission in the prevertebral sympathetic ganglia. In 1990s, we attempted to devise a combined technique of brain slices and patch-clamp recordings. We applied it to study the regulatory mechanisms that operate around cerebellar GABAergic inhibitory synapses, because most of the studies then had centered on excitatory synapses and because inhibitory synapses are crucially involved in brain functions and disorders. Consequently, we discovered novel forms of heterosynaptic interactions, dual actions of a single transmitter, and receptor crosstalk, the details of which are described in this review.

Substance P (SP) is an 11-amino acid neuropeptide of the tachykinin family that preferentially activates the neurokinin-1 receptor (NK1R). First isolated 85 years ago and sequenced 40 years later, SP has been extensively studied. Early studies identified a role for SP and the NK1R in contraction of intestinal smooth muscle, central pain processing, and neurogenic inflammation. An FDA-approved NK1R antagonist, aprepitant, is used clinically for the treatment of chemotherapy-induced nausea, as the NK1R influences the activity of the brain stem emesis centers. More recently, SP and the NK1R have gained attention for their role in complex psychiatric processes including stress, anxiety, and depression. However, clinical development of NK1R antagonists for these indications has so far been unsuccessful. Several preclinical studies have also demonstrated a role of the NK1R in drug taking and drug seeking, especially as it relates to escalated consumption and stress-elicited seeking. This line of research developed in parallel with findings supporting a role of corticotropin-releasing factor (CRF) in stress-induced drug seeking. Over this time, CRF arguably gained more attention as a target for development of addiction pharmacotherapies. However, this effort has not resulted in a viable drug for use in human populations. Given promising clinical findings for the efficacy of NK1R antagonists on craving in alcoholics, along with recent data suggesting that a number of negative results from NK1R trials were likely due to insufficient receptor occupancy, the NK1R merits being revisited as a target for the development of novel pharmacotherapeutics for addiction., (© 2017 Elsevier Inc. All rights reserved.)

Neural input to the immune system can alter its ability to clear pathogens effectively. Patients suffering mild traumatic brain injury (mTBI) have shown reduced rates of pneumonia and a murine model replicated these findings, with better overall survival of TBI mice compared with sham-injured mice. To further investigate the mechanism of improved host response in TBI mice, this study developed and characterized a mild tail trauma model of similar severity to mild TBI. Both mild tail trauma and TBI induced similar systemic changes that normalized within 48 hours, including release of substance P. Examination of tissues showed that injuries are limited to the target tissue (ie, tail in tail trauma, brain in mTBI). Pneumonia challenge showed that mild TBI mice showed improved immune responses, characterized by the following: i) increased survival, ii) increased pulmonary neutrophil recruitment, iii) increased bacterial clearance, and iv) increased phagocytic cell killing of bacteria compared with tail trauma. Administration of a neurokinin-1-receptor antagonist to block substance P signaling eliminated the improved survival of mTBI mice. Neurokinin-1-receptor antagonism did not alter pneumonia mortality in tail trauma mice. These data show that immune benefits of trauma are specific to mTBI and that tail trauma is an appropriate control for future studies aimed at elucidating the mechanisms of improved innate immune responses in mTBI mice., (Copyright © 2016 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Mast cells (MCs) influence intercellular communication during inflammation by secreting cytoplasmic granules that contain diverse mediators. Here, we have demonstrated that MCs decode different activation stimuli into spatially and temporally distinct patterns of granule secretion. Certain signals, including substance P, the complement anaphylatoxins C3a and C5a, and endothelin 1, induced human MCs rapidly to secrete small and relatively spherical granule structures, a pattern consistent with the secretion of individual granules. Conversely, activating MCs with anti-IgE increased the time partition between signaling and secretion, which was associated with a period of sustained elevation of intracellular calcium and formation of larger and more heterogeneously shaped granule structures that underwent prolonged exteriorization. Pharmacological inhibition of IKK-β during IgE-dependent stimulation strongly reduced the time partition between signaling and secretion, inhibited SNAP23/STX4 complex formation, and switched the degranulation pattern into one that resembled degranulation induced by substance P. IgE-dependent and substance P-dependent activation in vivo also induced different patterns of mouse MC degranulation that were associated with distinct local and systemic pathophysiological responses. These findings show that cytoplasmic granule secretion from MCs that occurs in response to different activating stimuli can exhibit distinct dynamics and features that are associated with distinct patterns of MC-dependent inflammation.

This article provides an overview of the structure and function of substance P signalling system and its involvement in the cardiovascular regulation. Substance P is an undecapeptide originating from TAC1 gen and belonging to the tachykinin family. The biological actions of substance P are mainly mediated through neurokinin receptor 1 since substance P is the ligand with the highest affinity to neurokinin receptor 1. Substance P is widely distributed within the central and peripheral nervous systems as well as in the cardiovascular system. Substance P is involved in the regulation of heart frequency, blood pressure and in the stretching of vessels. Substance P plays an important role in ischemia and reperfusion and cardiovascular response to stress. Additionally, it has been also implicated in angiogenesis, pain transmission and inflammation. The substance P/neurokinin receptor 1 receptor system is involved in the molecular bases of many human pathological processes. Antagonists of neurokinin receptor 1 receptor could provide clinical solutions for a variety of diseases. Neurokinin receptor 1 antagonists are already used in the prevention of chemotherapy induced nausea and vomiting., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Endocrinology systems exert an important effect on vascular function and have direct actions on blood vessels. Estrogens provoke an increase in skin elasticity, epidermal hydration, skin thickness, reduce skin wrinkles and augment the content of collagen and the level of vascularisation. Therefore, there is an intricate cross-talk between skin conditions and stress. In stress, β2--adrenoreceptor (β2AR) pathway, cortisol, epinephrine and norepinephrine increase DNA damage and interfere with the regulation of the cell cycle, contributing to aging and skin diseases. Substance P is a neuropeptide released in the skin from the peripheral nerve and is related to stress and inflammation. SP provokes infiltration of inflammatory cells in the skin and induces a variety of cytokines/chemokines. Corticotropin-releasing hormone (CRH), produced by mast cells, is a neuropeptide also expressed in skin and responds to stress. CRH initiates diverse intracellular signaling pathways, including cAMP, protein kinase C, and mitogen-activated protein kinases (MAPK). Under stress, CRH, glucocorticoids, epinephrine and cytokines are generated. Moreover, the release of ACTH binds the receptor MC2-R and stimulates the generation of glucocorticoids such as corticosterone and cortisol, which interact with the transcription factors AP-1 and NF-kB. In skin keratinocytes, ACTH promotes the generation of pro-inflammatory cytokines, which enhances T-cell activity. Cortisol is immunosuppressive by inhibiting Th1 and Th2 cell response, antigen presentation, antibody and cytokine/chemokine production. However, glucocorticoids are certainly helpful in Th1-mediated autoimmune disorders. On the other hand, cytokines, such as TNF, IL-1 and IL-6, stimulate the generation of CRH and activate HPA axis in inflammatory states. Here, we describe for the first time a cross-talk between endocrinology and skin, including pro-inflammatory cytokines and neurogenic inflammatory pathways.

The distribution of microglia varies greatly throughout the brain. The substantia nigra (SN) contains the highest density of microglia among different brain regions. However, the mechanism underlying this uneven distribution remains unclear. Substance P (SP) is a potent proinflammatory neuropeptide with high concentrations in the SN. We recently demonstrated that SP can regulate nigral microglial activity. In the present study, we further investigated the involvement of SP in modulating nigral microglial density in postnatal developing mice. Nigral microglial density was quantified in wild-type (WT) and SP-deficient mice from postnatal day 1 (P1) to P30. SP was detected at high levels in the SN as early as P1 and microglial density did not peak until around P30 in WT mice. SP-deficient mice (TAC1(-/-)) had a significant reduction in nigral microglial density. No differences in the ability of microglia to proliferate were observed between TAC1(-/-) and WT mice, suggesting that SP may alter microglial density through chemotaxic recruitment. SP was confirmed to dose-dependently attract microglia using a trans-well culture system. Mechanistic studies revealed that both the SP receptor neurokinin-1 receptor (NK1R) and the superoxide-producing enzyme NADPH oxidase (NOX2) were necessary for SP-mediated chemotaxis in microglia. Furthermore, genetic ablation and pharmacological inhibition of NK1R or NOX2 attenuated SP-induced microglial migration. Finally, protein kinase Cδ (PKCδ) was recognized to couple SP/NK1R-mediated NOX2 activation. Altogether, we found that SP partly accounts for the increased density of microglia in the SN through chemotaxic recruitment via a novel NK1R-NOX2 axis-mediated pathway., (© 2015 Authors; published by Portland Press Limited.)

Substance P is endogenously released in the adult lamprey spinal cord and accelerates the burst frequency of fictive locomotion. This is achieved by multiple effects on interneurons and motoneurons, including an attenuation of calcium currents, potentiation of NMDA currents and reduction of the reciprocal inhibition. While substance P also depolarizes spinal cord neurons, the underlying mechanism has not been resolved. Here we show that effects of substance P on background K+ channels are the main source for this depolarization. Hyperpolarizing steps induced inward currents during whole-cell voltage clamp that were reduced by substance P. These background K+ channels are pH sensitive and are selectively blocked by anandamide and AVE1231. These blockers counteracted the effect of substance P on these channels and the resting membrane potential depolarization in spinal cord neurons. Thus, we have shown now that substance P inhibits background K+ channels that in turn induce depolarization, which is likely to contribute to the frequency increase observed with substance P during fictive locomotion.

The condition of the corneal epithelium is a critical determinant of corneal transparency and clear vision. The corneal epithelium serves as a barrier to protect the eye from external insults, with its smooth surface being essential for its optical properties. Disorders of the corneal epithelium include superficial punctate keratopathy, corneal erosion, and persistent epithelial defects (PEDs). The prompt resolution of these disorders is important for minimization of further damage to the cornea. Currently available treatment modalities for corneal epithelial disorders are based on protection of the ocular surface in order to allow natural healing to proceed. PEDs remain among the most difficult corneal conditions to treat, however. On the basis of characterization of the pathobiology of PEDs at the cell and molecular biological levels, we have strived to develop new modes of treatment for these defects. These treatments rely on two key concepts: provision of a substrate, such as the adhesive glycoprotein fibronectin, for the attachment and migration of corneal epithelial cells, and activation of these cells by biological agents such as the combination of substance P and insulin-like growth factor-1 (IGF-1). Central to both approaches is the role of the fibronectin-integrin system in corneal epithelial wound healing. Determination of the minimum amino acid sequences required for the promotion of corneal epithelial wound closure by fibronectin (PHSRN) and by substance P (FGLM-amide) plus IGF-1 (SSSR) has led to the development of peptide eyedrops for the treatment of PEDs that are free of adverse effects of the parent molecules., (Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Less than 10% of corneal allografts undergo rejection even though HLA matching is not performed. However, second corneal transplants experience a threefold increase in rejection, which is not due to prior sensitization to histocompatibility antigens shared by the first and second transplants since corneal grafts are selected at random without histocompatibility matching. Using a mouse model of penetrating keratoplasty, we found that 50% of the initial corneal transplants survived, yet 100% of the subsequent corneal allografts (unrelated to the first graft) placed in the opposite eye underwent rejection. The severing of corneal nerves that occurs during surgery induced substance P (SP) secretion in both eyes, which disabled T regulatory cells that are required for allograft survival. Administration of an SP antagonist restored immune privilege and promoted graft survival. Thus, corneal surgery produces a sympathetic response that permanently abolishes immune privilege of subsequent corneal allografts, even those placed in the opposite eye and expressing a completely different array of foreign histocompatibility antigens from the first corneal graft., (© Copyright 2015 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Objective: To review the published literature regarding the effects of anesthesia on cancer surgery to prevent tumor cell proliferation/migration or induce apoptosis., Background: Surgery is the main treatment for potentially curable solid tumors, but most cancer-related deaths in patients who have received previous surgical treatment are caused by metastatic disease. There is increasing evidence that anesthetic technique has the potential to affect long-term outcome after cancer surgery., Methods: This work reviews the English published literature that was obtained by performing a search of the PubMed database up to January 2014. We selected articles that provided evidence or reviewed the possible actions of anesthetics on cancer cells or the influence of anesthesia in recurrence/outcome., Results: Inhaled anesthetics induce immunosuppression and activate inflammatory cascade activation, whereas propofol has a protective action. Opioids might promote cancer recurrence and metastasis. In vitro and in vivo studies have demonstrated that local anesthetics inhibit proliferation and migration of cancer cells and induce apoptosis., Conclusions: Anesthesiologists should follow current best clinical practice and include all strategies that effectively decrease pain and attenuate stress. Regional anesthesia and multimodal analgesia, adding anti-inflammatory drugs, play an unquestionable role in the control of perioperative pain and may improve recurrence-free survival., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Background: Esophageal squamous cell carcinoma (ESCC) remains one of the most lethal malignant tumors, and currently there is no effective ways to manage the late stage disease. Therefore clarifying the mechanisms underlying the development of ESCC is of great importance to develop novel therapeutic agents. The present study focuses on the interaction between neurotransmitter substance P (SP) together with its receptor NK-1R and ESCC progression., Methods: The distribution of SP positive nerve fibers and expression of NK-1R were detected in ESCC tissue using immunohistochemistry. The effects of SP stimulation and blocking on the growth and migration of ESCC cells were measured by in vitro and in vivo assay., Results: A higher density of SP positive nerve fibers and elevated NK-1R expression on ESCC cells were observed. More importantly, the SP positive fiber density was correlated with tumor size and lymph node metastasis. SP promoted ESCC cell proliferation and migration by modulation of intracellular calcium levels., Conclusion: NK-1R activation by SP stimulation promotes growth and migration of ESCC cells., (Copyright © 2015 Elsevier B.V. All rights reserved.)

It is well established that L-type calcium channels (LTCCs) are expressed in astroglia. However, their functional role is still speculative, especially under pathologic conditions. We recently showed that the α1 subunit-like immunoreactivity of the CaV1.2 channel is strongly expressed in reactive astrocytes around beta-amyloid plaques in 11-month-old Alzheimer transgenic (tg) mice with the amyloid precursor protein London and Swedish mutations. The aim of the present study was to examine the cellular expression of all LTCC subunits around beta-amyloid plaques by in situ hybridization using (35)S-labeled oligonucleotides. Our data show that messenger RNAs (mRNAs) of the LTCC CaV1.2 α1 subunit as well as all auxiliary β and α2δ subunits, except α2δ-4, were expressed in the hippocampus of age-matched wild-type mice. It was unexpected to see, that cells directly located in the plaque core in the cortex expressed mRNAs for CaV1.2 α1, β2, β4, and α2δ-1, whereas no expression was detected in the halo. Furthermore, cells in the plaque core also expressed preprotachykinin-A mRNA, the precursor for substance P. By means of confocal microscopy, we demonstrated that collagen-IV-stained brain vessels in the cortex were associated with the plaque core and were immunoreactive for substance P. In cortical organotypic brain slices of adult Alzheimer mice, we could demonstrate that LTCC blockers increased angiogenesis, which was further potentiated by substance P. In conclusion, our data show that brain vessels associated with beta-amyloid plaques express substance P and an LTCC and may play a role in angiogenesis., (Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.)

The mechanism underlying the modulatory effect of substance P (SP) on GABA-activated response in rat dorsal root ganglion (DRG) neurons was investigated. In freshly dissociated rat DRG neurons, whole-cell patch-clamp technique was used to record GABA-activated current and sharp electrode intracellular recording technique was used to record GABA-induced membrane depolarization. Application of GABA (1-1000 μmol/L) induced an inward current in a concentration-dependent manner in 114 out of 127 DRG neurons (89.8 %) examined with whole-cell patch-clamp recordings. Bath application of GABA (1-1000 μmol/L) evoked a depolarizing response in 236 out of 257 (91.8%) DRG neurons examined with intracellular recordings. Application of SP (0.001-1 μmol/L) suppressed the GABA-activated inward current and membrane depolarization. The inhibitory effects were concentration-dependent and could be blocked by the selective neurokinin 1 (NK1) receptors antagonist spantide but not by L659187 and SR142801 (1 μmol/L, n=7), selective antagonists of NK2 and NK3. The inhibitory effect of SP was significantly reduced by the calcium chelator BAPTA-AM, phospholipase C (PLC) inhibitor U73122, and PKC inhibitor chelerythrine, respectively. The PKA inhibitor H-89 did not affect the SP effect. Remarkably, the inhibitory effect of SP on GABA-activated current was nearly completely removed by a selective PKCε inhibitor epilon-V1-2 but not by safingol and LY333531, selective inhibitors of PKCα and PKCβ. Our results suggest that NK1 receptor mediates SP-induced inhibition of GABA-activated current and membrane depolarization by activating intracellular PLC-Ca²⁺-PKCε cascade. SP might regulate the excitability of peripheral nociceptors through inhibition of the "pre-synaptic inhibition" evoked by GABA, which may explain its role in pain and neurogenic inflammation.

Substance P (SP) is an important mediator of pro-inflammatory mechanisms in the skin. It targets multiple cells such as keratinocytes, mast cells, and fibroblasts which are involved in the cutaneous generation of pruritus. This suggests that SP is an interesting target for therapy. In fact, in recent case reports and case series, SP antagonists demonstrated a significant antipruritic effect in acute and chronic pruritus such as drug-induced pruritus, paraneoplastic pruritus, prurigo nodularis, cutaneous T-cell lymphoma, and brachioradial pruritus.

Objective: To detect the effects of lumbar vertebrae Gucuofeng on the substance P content of hypothalamus and dorsal root ganglia in rat models., Methods: A hundred and twenty SPF level SD male rats with the weight of 350 to 450 g were randomly divided into rotary fixation group (RF group), simple fixation group (SF group) and sham-operation group (Sham group). The external link fixation system was implanted into the L4-L6 of rats in RF group and SF group; and in RF group, that the L5 spinous process was rotated to the right resulted in L4, L5, L6 spinous process not collinear; in SF group, the external link fixation system was simply implanted and not rotated. The rats of Sham group were not implanted the external link fixation system and only open and suture. The substance P content of hypothalamus and dorsal root ganglia were detected at 1, 4, 8, 12 weeks after operation., Results: Substance P content of hypothalamus in RF group and SF group was lower than Sham group at 1, 4, 8 weeks after operation (P<0.05). Substance P content of dorsal root ganglia was higher than Sham group at 1, 4, 8, 12 weeks after operation (P<0.05). There was no significant differences in the substance P content of hypothalamus among three groups at 12 weeks after operation (P>0.05)., Conclusion: Lumbar vertebrae Gucuofeng can inhibit the analgesic activity of substance P in hypothalamus and promote the synthesis and transmission of substance P in dorsal root ganglia, so as to cause or aggravate the pain.

Objective: To investigate the role of neurokinin-1 (NK1) receptor and non-N-methyl-D-aspartate (non-NMDA) receptor in modulating the cardiosomatic reflex in the spinal cord of rat., Methods: The effects of intrathecal injection of NK1 receptor agonist Sar-SP and antagonist CP-96345 and non-NMDA receptor agonist NMDA and antagonist 6, 7-dinitro-1,4-dihydro-quinoxaline-2,3-dione (DNQX) on the cardiosomatic reflex were observed in rats. The changes of the cardiosomatic reflex were monitored by observing the electromyogram (EMG) responses of the dorsal spinotrapezius muscle to intrapericardial bradykinin (BK) injection., Results: Intrathecal injection of Sar-SP significantly facilitated EMG responses to intrapericardial BK injection (P<0.05), which was completely blocked by intrathecal injection of NK1 antagonist CP-96345. Similarly, intrathecal injection of NMDA obviously facilitated the EMG responses (P<0.05), which was partially reversed by intrathecal injection of non-NMDA receptor antagonist DNQX. Intrathecal injection of Sar-SP along with NMDA significantly increased EMG as compared with single administration of Sar-SP or NMDA (P<0.05)., Conclusion: The spinal cord levels of NK1 receptor and non-NMDA receptor are involved in the modulation of the cardiosomatic reflex in rats.

It is currently widely accepted among clinicians that chronic tendinopathy is caused by a degenerative process devoid of inflammation. Current treatment strategies are focused on physical treatments, peritendinous or intratendinous injections of blood or blood products and interruption of painful stimuli. Results have been at best, moderately good and at worst a failure. The evidence for non-infammatory degenerative processes alone as the cause of tendinopathy is surprisingly weak. There is convincing evidence that the inflammatory response is a key component of chronic tendinopathy. Newer anti-inflammatory modalities may provide alternative potential opportunities in treating chronic tendinopathies and should be explored further., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Previous studies have implicated a myofibroblast-mast cell-neuropeptide axis of fibrosis in pathologic joint capsules from post-traumatic contractures. The hypothesis to be tested is that joint capsule cells (JC) from human elbows with post-traumatic contractures and their interactions with mast cells (MC) and neuropeptides in the microenvironment underlie the pathogenesis of contractures. The hypothesis was tested using an in vitro collagen gel contraction model. The JC were isolated from human elbow capsules and mixed with neutralized PureCol collagen I. The gels were treated in various ways, including addition of MC (HMC-1), the neuropeptide substance P (SP), an NK1 receptor (SP receptor) antagonist RP67580 and the mast cell stabilizer ketotifen fumarate (KF). The collagen gels were released from the wells and gel size (contraction) was measured optically at multiple time points. The JC contracted collagen gels in a dose-dependent manner. This was enhanced in the presence of MC and increased further with SP. Increasing concentrations of the SP receptor antagonist, RP67580 or the mast cell stabilizer, KF decreased the magnitude of contraction. These observations identify putative mechanistic components of a myofibroblast-mast cell-neuropeptide axis of fibrosis in the joint capsules in post-traumatic contractures and potential prophylactic or therapeutic interventions., (© 2014 Orthopaedic Research Society. Published by Wiley Periodicals, Inc.)

Objectives: Traumatic brain injury results in significant morbidity and mortality and is associated with infectious complications, particularly pneumonia. However, whether traumatic brain injury directly impacts the host response to pneumonia is unknown. The objective of this study was to determine the nature of the relationship between traumatic brain injury and the prevalence of pneumonia in trauma patients and investigate the mechanism of this relationship using a murine model of traumatic brain injury with pneumonia., Design: Data from the National Trauma Data Bank and a murine model of traumatic brain injury with postinjury pneumonia., Setting: Academic medical centers in Cincinnati, OH, and Boston, MA., Patients/subjects: Trauma patients in the National Trauma Data Bank with a hospital length of stay greater than 2 days, age of at least 18 years at admission, and a blunt mechanism of injury. Subjects were female ICR mice 8-10 weeks old., Interventions: Administration of a substance P receptor antagonist in mice., Measurements and Main Results: Pneumonia rates were measured in trauma patients before and after risk adjustment using propensity scoring. In addition, survival and pulmonary inflammation were measured in mice undergoing traumatic brain injury with or without pneumonia. After risk adjustment, we found that traumatic brain injury patients had significantly lower rates of pneumonia compared to blunt trauma patients without traumatic brain injury. A murine model of traumatic brain injury reproduced these clinical findings with mice subjected to traumatic brain injury demonstrating increased bacterial clearance and survival after induction of pneumonia. To determine the mechanisms responsible for this improvement, the substance P receptor was blocked in mice after traumatic brain injury. This treatment abrogated the traumatic brain injury-associated increases in bacterial clearance and survival., Conclusions: The data demonstrate that patients with traumatic brain injury have lower rates of pneumonia compared to non-head-injured trauma patients and suggest that the mechanism of this effect occurs through traumatic brain injury-induced release of substance P, which improves innate immunity to decrease pneumonia.

Mephedrone (4-methylmethcathinone) is a synthetic cathinone designer drug that alters pre-synaptic dopamine (DA) activity like many psychostimulants. However, little is known about the post-synaptic dopaminergic impacts of mephedrone. The neuropeptide neurotensin (NT) provides inhibitory feedback for basal ganglia and limbic DA pathways, and post-synaptic D1 -like and D2 -like receptor activity affects NT tissue levels. This study evaluated how mephedrone alters basal ganglia and limbic system NT content and the role of NT receptor activation in drug consumption behavior. Four 25 mg/kg injections of mephedrone increased NT content in basal ganglia (striatum, substantia nigra and globus pallidus) and the limbic regions (nucleus accumbens core), while a lower dosage (5 mg/kg/injection) only increased striatal NT content. Mephedrone-induced increases in basal ganglia NT levels were mediated by D1 -like receptors in the striatum and the substantia nigra by both D1 -like and D2 -like receptors in the globus pallidus. Mephedrone increased substance P content, another neuropeptide, in the globus pallidus, but not in the dorsal striatum or substantia nigra. Finally, the NT receptor agonist PD149163 blocked mephedrone self-administration, suggesting reduced NT release, as indicated by increased tissue levels, likely contributing to patterns of mephedrone consumption., (© 2014 International Society for Neurochemistry.)

The peptide substance P (SP) shows a widespread distribution in both the central and peripheral nervous systems, but it is also present in cells not belonging to the nervous system (immune cells, liver, lung, placenta, etc.). SP is located in all body fluids, such as blood, cerebrospinal fluid, breast milk, etc. i.e. it is ubiquitous in human body. After binding to the neurokinin-1 (NK-1) receptor, SP regulates many pathophysiological functions in the central nervous system, such as emotional behavior, stress, depression, anxiety, emesis, vomiting, migraine, alcohol addiction, seizures and neurodegeneration. SP has been also implicated in pain, inflammation, hepatitis, hepatotoxicity, cholestasis, pruritus, myocarditis, bronchiolitis, abortus, bacteria and viral infection (e.g., HIV infection) and it plays an important role in cancer (e.g., tumor cell proliferation, antiapoptotic effects in tumor cells, angiogenesis, migration of tumor cells for invasion, infiltration and metastasis). This means that the SP/NK-1 receptor system is involved in the molecular bases of many human pathologies. Thus, knowledge of this system is the key for a better understanding and hence a better management of many human diseases. In this review, we update the involvement of the SP/NK-1 receptor system in the physiopathology of the above-mentioned pathologies and we suggest valuable future therapeutic interventions involving the use of NK-1 receptor antagonists, particularly in the treatment of emesis, depression, cancer, neural degeneration, inflammatory bowel disease, viral infection and pruritus, in which that system is upregulated.

Microcrystals are responsible for some of the most common and complex arthropathies which are often accompanied by intense, severe pain and inflammatory reactions. The main pathogens are crystals of monosodium urate (MSU), responsible for the gout, calcium pyrophosphate (CPP), which deposits also in various clinical forms of arthopathies, and basic calcium phosphate associated with osteoarthritis. In this context, the microcrystal arthritis is characterized by multiple, acute attacks followed by chronic pain, disability, impaired quality of life, and increased mortality. Given their chronic nature, they represent an ever more urgent public health problem. MSU and CPP crystals are also able to activate nociceptors. The pain in mycrocrystalline arthritis (MCA) is an expression of the inflammatory process. In the course of these diseases there is an abundant release of inflammatory molecules, including prostaglandins 2 and kinins. Interleukin-1 represents the most important cytokine released during the crystal-induced inflammatory process. Therefore, clinically, pain is the most important component of MCA, which lead to functional impairment and disability in a large proportion of the population. It is fundamental to diagnose these diseases as early as possible, and to this aim, to identify appropriate and specific targets for a timely therapeutic intervention.

Substance P (SP) is commonly coexpressed with ACh in enteric motor neurons, and, according to the classical paradigm, both these neurotransmitters excite smooth muscle via parallel pathways. We hypothesized that, in addition, SP was responsible for maintaining the muscular responsiveness to ACh. We tested this hypothesis by using botulinum toxin (BoNT/A), a known blocker of vesicular release of neurotransmitters including ACh and neuropeptides. BoNT/A was injected into rat pyloric sphincter in different doses; as control we used boiled BoNT/A. At the desired time point, pylorus was dissected out and pyloric contractility was measured ex vivo in an organ bath and by measuring phosphorylation of myosin light chain 20 (MLC20). BoNT/A (10 IU) significantly reduced the response of pyloric muscle to exogenous ACh, an effect that was accompanied by reduced MLC20 phosphorylation in the muscle. Both effects were reversed by exogenous SP. CP-96345, a NK1 receptor antagonist, blocked the ability of exogenous SP to reverse the cholinergic hyporesponsiveness as well as the reduction in MLC20 phosphorylation induced by BoNT/A. In conclusion, we have identified a novel role for SP as a coneurotransmitter that appears to be important for the maintenance of muscular responsiveness to the principal excitatory neurotransmitter, ACh. These results also provide new insight into the effects of botulinum toxin on the enteric nervous system and gastrointestinal smooth muscle., (Copyright © 2014 the American Physiological Society.)

Traumatic injury as a trigger for the subsequent development of psoriatic arthritis (PsA) has been implicated by several case reports and case series. However, it is still unclear whether trauma is the inciting event or just an incidental finding. It is thought that the interplay of genetic, immunologic, and environmental factors, such as trauma, may trigger the development of PsA. At least two hypotheses of how trauma may be linked to the development of PsA have surfaced and involve a "deep Koebner effect," the concept of a synovio-entheseal complex and activation of the innate immune system by biomechanical factors. The role of neuropeptides such as substance P and vasoactive intestinal peptide has been highlighted in the synovium after trauma. Better understanding of this phenomenon would shed light into the pathophysiology of Psa and help the development of preventive and therapeutic strategies.

The anatomical understanding of the pain generators in osteoarthritis (OA) is incomplete and the teaching about these pain generators in medical school anatomy/histology courses is minimal. This review covers the nociceptive innervation of synovial joints for the purposes of teaching. Studies that discuss the presence of neuropeptides involved in pain, such as Substance P (SP) and calcitonin-gene-related peptide, are the focus of this review. Nociceptive free-nerve endings and SP staining nerves are found in the accessory ligaments, synovium, subchondral bone, menisci, and periosteum. The vasculature may also play a role in pain generation through vasospasm or ischemia, but this has yet to be proven. Joint denervation may relieve joint pain showing that it is indeed articular nerves that are carrying pain impulses but denervation does not identify the precise source of the pain. It remains unclear which of the anatomical loci of pain generation are primary in OA and if sources of pain vary in different patients and in different joints., (Copyright © 2012 Wiley Periodicals, Inc.)

Neuropeptide substance P (SP) has been implicated in inflammation, pain, depression and breast cancer cell (BCC) growth. Here, we examined the role of SP in trafficking of BCCs (human MDA-MB-231 and MDA-MB-231BrM2 cells) across the blood-brain barrier (BBB) and brain microvascular endothelial cells (BMECs) using in vitro and in vivo models. SP was secreted from BCCs and mediated adhesion and transmigration of BCCs across human BMECs (HBMECs) in vitro. SP induced activation of HBMECs, leading to secretion of Tumor Necrosis Factor alpha (TNF-α) and angiopoietin-2 (Ang-2) from HBMECs, resulting in changes in localization and distribution of tight junction (TJ) ZO-1 (tight junction protein zonula occludins-1) and claudin-5 structures as well as increased permeability of HBMECs. Using spontaneous breast cancer metastasis mouse model (syngeneic) of GFP-4T1-BrM5 mammary tumor cells administered into mammary fat pads of Balb/c mice, SP inhibitor spantide III inhibited in vivo changes in permeability of the BBB and BMEC-TJs ZO-1 and claudin-5 structures as well as decreased tumor cell colonization in brain. Thus, SP secreted from BCCs induces transmigration of BCCs across the BBB, leading to activation of BMECs and secretion of TNF-α and Ang-2, resulting in BBB impairment and colonization of tumor cells in brain. Therefore, therapies based on SP inhibition in combination with other therapies may prevent breaching of the BBB by BCCs and their colonization in brain., (© 2013 UICC.)

The transient receptor potential cation channel subfamily V member 1 (TRPV1) is known as a thermosensor and integrator of inflammation-induced hyperalgesia. TRPV1 is expressed in a subpopulation of primary afferent neurons that express several different neurotransmitters. The role of the TRPV1 channel in the development of hyperalgesia is established, but the role of the neurotransmitter glutamate, used partially by the same neuronal population and thus probably mediating the response, is still under investigation. We have used a Trpv1-Cre mouse line in which we either ablated Trpv1-Cre expressing neurons or induced vesicular glutamate transporter 2 (Vglut2) deficiency in Trpv1-Cre expressing neurons and investigated specific states of hyperalgesia after persistent inflammation. Furthermore, by pharmacologic inhibition of substance P (SP) or calcitonin gene-related peptide (CGRP) signaling in Vglut2-deficient mice, we also evaluated the contribution of SP or CGRP to inflammation-induced hyperalgesia, with or without the presence of vesicular glutamate transporter 2 (VGLUT2)-mediated glutamatergic transmission in Trpv1-Cre neurons. This examination, together with c-Fos analyses, showed that VGLUT2-mediated glutamatergic transmission in Trpv1-Cre afferents together with SP or CGRP is essential for the development of the heat hyperalgesia associated with persistent inflammation. Additionally, SP-, CGRP-, and VGLUT2-mediated transmission together were found to play a role in the development of mechanical hyperalgesia after persistent inflammation.

The tachykinin, substance P, is found primarily in sensory nerves. In the heart, substance P-containing nerve fibers are often found surrounding coronary vessels, making them ideally situated to sense changes in the myocardial environment. Recent studies in rodents have identified substance P as having dual roles in the heart, depending on disease etiology and/or timing. Thus far, these studies indicate that substance P may be protective acutely following ischemia-reperfusion, but damaging long-term in non-ischemic induced remodeling and heart failure. Sensory nerves may be at the apex of the cascade of events leading to heart failure, therefore, they make a promising potential therapeutic target that warrants increased investigation., (Copyright © 2013. Published by Elsevier Ireland Ltd.)

Neuropeptides play an important role in modulating seizures and epilepsy. Unlike neurotransmitters which operate on a millisecond time-scale, neuropeptides have longer half lives; this leads to modulation of neuronal and network activity over prolonged periods, so contributing to setting the seizure threshold. Most neuropeptides are stored in large dense vesicles and co-localize with inhibitory interneurons. They are released upon high frequency stimulation making them attractive targets for modulation of seizures, during which high frequency discharges occur. Numerous neuropeptides have been implicated in epilepsy; one, ACTH, is already used in clinical practice to suppress seizures. Here, we concentrate on neuropeptides that have a direct effect on seizures, and for which therapeutic interventions are being developed. We have thus reviewed the abundant reports that support a role for neuropeptide Y (NPY), galanin, ghrelin, somatostatin and dynorphin in suppressing seizures and epileptogenesis, and for tachykinins having pro-epileptic effects. Most in vitro and in vivo studies are performed in hippocampal tissue in which receptor expression is usually high, making translation to other brain areas less clear. We highlight recent therapeutic strategies to treat epilepsy with neuropeptides, which are based on viral vector technology, and outline how such interventions need to be refined in order to address human disease., (Copyright © 2013 Elsevier Ltd. All rights reserved.)