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Acute central nervous system (CNS) injury, encompassing traumatic brain injury (TBI) and stroke, accounts for a significant burden of morbidity and mortality worldwide, largely attributable to the development of cerebral oedema and elevated intracranial pressure (ICP). Despite this, clinical treatments are limited and new therapies are urgently required to improve patient outcomes and survival. Originally characterised in peripheral tissues, such as the skin and lungs as a neurally-elicited inflammatory process that contributes to increased microvascular permeability and tissue swelling, neurogenic inflammation has now been described in acute injury to the brain where it may play a key role in the secondary injury cascades that evolve following both TBI and stroke. In particular, release of the neuropeptides substance P (SP) and calcitonin gene-related peptide (CGRP) appear to be critically involved. In particular, increased SP expression is observed in perivascular tissue following acute CNS injury, with the magnitude of SP release being related to both the frequency and degree of the insult. SP release is associated with profound blood-brain barrier disruption and the subsequent development of vasogenic oedema, as well as neuronal injury and poor functional outcomes. Inhibition of SP through use of a neurokinin 1 (NK1) antagonist is highly beneficial following both TBI and ischaemic stroke in pre-clinical models. The role of CGRP is more unclear, especially with respect to TBI, with both elevations and reductions in CGRP levels reported following trauma. However, a beneficial role has been delineated in stroke, given its potent vasodilatory effects. Thus, modulating neuropeptides represents a novel therapeutic target in the treatment of cerebral oedema following acute CNS injury.

The cold-induced vascular response, consisting of vasoconstriction followed by vasodilatation, is critical for protecting the cutaneous tissues against cold injury. Whilst this physiological reflex response is historic knowledge, the mechanisms involved are unclear. Here by using a murine model of local environmental cold exposure, we show that TRPA1 acts as a primary vascular cold sensor, as determined through TRPA1 pharmacological antagonism or gene deletion. The initial cold-induced vasoconstriction is mediated via TRPA1-dependent superoxide production that stimulates α 2C -adrenoceptors and Rho-kinase-mediated MLC phosphorylation, downstream of TRPA1 activation. The subsequent restorative blood flow component is also dependent on TRPA1 activation being mediated by sensory nerve-derived dilator neuropeptides CGRP and substance P, and also nNOS-derived NO. The results allow a new understanding of the importance of TRPA1 in cold exposure and provide impetus for further research into developing therapeutic agents aimed at the local protection of the skin in disease and adverse climates. Blood flow in the skin of mammals changes in response to cold, but the mechanisms driving this response are unclear. Aubdool et al . show that the non-selective cation channel, TRPA1, is a vascular cold sensor and required for the vascular protective response to local cold exposure.

Substance P (SP), an important neuropeptide, has a crucial role in the progression of several cancers, including prostate cancer, through interacting with the neurokinin-1 receptor (NK1R). Oxidative stress is also involved in the onset and progression of prostate cancer. However, no studies have been performed on the cross-talk between the SP/NK1R system and cellular redox balance in prostate cancer, and how it is involved in tumorogenesis. We aimed to investigate the effect of the SP/NK1R system and the blockage of NK1R with its specific antagonist (aprepitant) on the cellular redox status of the prostate cancer cell line (PC3 and LNCaP). We performed the resazurin assay to evaluate the toxicity of the aprepitant on the PC3 and LNCaP cell lines. The intracellular reactive oxygen species (ROS) level was measured after SP and aprepitant treatment. The alterations of expression and activity of two crucial cellular oxidoreductases, glutaredoxin, and thioredoxin were evaluated by qRT-PCR and commercial kits (ZellBio GmbH), respectively. Our results revealed that SP increased ROS production and decreased the expression and activity of glutaredoxin and thioredoxin. On the other hand, treatment of cells with aprepitant showed reverse results. In conclusion, we found that the SP/NK1R system could promote prostate cancer progression by inducing oxidative stress. In addition, the inhibition of NK1R by aprepitant modulated the effect of the SP/NK1R system on the cellular redox system. Aprepitant might therefore be introduced as a candidate for the treatment of prostate cancer; however, more studies are required to confirm the validation of this hypothesis.

The neuropeptides Substance P and CGRPα have long been thought important for pain sensation. Both peptides and their receptors are expressed at high levels in pain-responsive neurons from the periphery to the brain making them attractive therapeutic targets. However, drugs targeting these pathways individually did not relieve pain in clinical trials. Since Substance P and CGRPα are extensively co-expressed, we hypothesized that their simultaneous inhibition would be required for effective analgesia. We therefore generated Tac1 and Calca double knockout (DKO) mice and assessed their behavior using a wide range of pain-relevant assays. As expected, Substance P and CGRPα peptides were undetectable throughout the nervous system of DKO mice. To our surprise, these animals displayed largely intact responses to mechanical, thermal, chemical, and visceral pain stimuli, as well as itch. Moreover, chronic inflammatory pain and neurogenic inflammation were unaffected by loss of the two peptides. Finally, neuropathic pain evoked by nerve injury or chemotherapy treatment was also preserved in peptide-deficient mice. Thus, our results demonstrate that even in combination, Substance P and CGRPα are not required for the transmission of acute and chronic pain.

Mice lacking two neuropeptides thought to be essential for processing pain show no change in how they respond to a wide range of harmful stimuli.Mice lacking two neuropeptides thought to be essential for processing pain show no change in how they respond to a wide range of harmful stimuli.

New factors in wound healing are sorely needed. Here Youngsook Son and colleagues identify substance P, a small neuropeptide, as one such factor that seems to work by mobilizing stromal-like cells to the site of wounding, accelerating the healing process ( pages 367–369 ). Tissue injury may create a specific microenvironment for inducing the systemic participation of stromal-like cells in the repair process. Here we show that substance P is an injury-inducible factor that acts early in the wound healing process to induce CD29 + stromal-like cell mobilization. Likewise, mobilization of such cells also occurs in uninjured mice, rats and rabbits if substance P is intravenously injected. Upon further characterization these substance P–mobilized CD29 + cells were found to be similar to stromal cells from a number of connective tissues, including bone marrow (that is, bone marrow stromal cells, or BMSCs). Both substance P injection and transfusion of autologously derived substance P–mobilized CD29 + cells from uninjured rabbits accelerated wound healing in an alkali burn model. Also, epithelial engraftment of the transfused cells into the injured tissue occurred during the wound healing. Finally, using human BMSCs as a test population, we show that substance P stimulates transmigration, cell proliferation, activation of the extracellular signal–related kinases (Erk) 1 and 2 and nuclear translocation of β-catenin in vitro . This finding highlights a previously undescribed function of substance P as a systemically acting messenger of injury and a mobilizer of CD29 + stromal-like cells to participate in wound healing.

Electroacupuncture (EA) is considered to have potential antidiabetic effects; however, the role of the pancreatic intrinsic nervous system (PINS) in EA-induced amelioration of type 2 diabetes (T2DM) remains unclear. Therefore, we investigated whether EA at ST25 exerts any beneficial effects on insulin resistance (IR), inflammation severity, and pancreatic β cell function via the PINS in a rat model of a high-fat diet-streptozotocin (HFD/STZ)-induced diabetes. To this end, Sprague Dawley rats were fed with HFD to induce IR, followed by STZ (35 mg/kg, i.p.) injection to establish the T2DM model. After hyperglycemia was confirmed as fasting glucose level > 16.7 mmol/L, the rats were treated with EA (2 mA, 2/15 Hz) for the next 28 days. Model rats showed increased serum glucose, insulin, IR, and TNF- α levels with a concomitant decrease in β cell function. Microscopy examination of the pancreas revealed pathological changes in islets, which reverted to near-normal levels after EA at ST25. EA improved islet cell morphology by increasing islet area and reducing vacuolation. EA at ST25 decreased transient receptor potential vanilloid 1 (TRPV1) and increased substance P (SP) and calcitonin gene-related peptide (CGRP) expression. Subsequently, insulin secretion decreased and impaired pancreatic endocrine function was restored through the TRPV1 channel (SP/CGRP)-insulin circuit. EA increased choline acetyltransferase and neuropeptide Y expression and controlled inflammation. It also enhanced the cocaine and amphetamine-regulated transcript prepropeptide expression and promoted glucagon-like peptide-1 secretion. Additionally, the electrophysiological activity of PINS during acupuncture (2.71 ± 1.72 Hz) was significantly increased compared to the pre-acupuncture frequency (0.32 ± 0.37 Hz, P < 0.05). Thus, our study demonstrated the beneficial effect of EA on β cell dysfunction via the PINS in rat models of HFD-STZ-induced T2DM.

Inflammation is a natural response to tissue injury. Uncontrolled inflammatory response leads to inflammatory disease. Acute pancreatitis is one of the main reasons for hospitalization amongst gastrointestinal disorders worldwide. It has been demonstrated that endogenous hydrogen sulfide (H2S), a gasotransmitter and substance P, a neuropeptide, are involved in the inflammatory process in acute pancreatitis. Cell adhesion molecules (CAM) are key players in inflammatory disease. Immunoglobulin (Ig) gene superfamily, selectins, and integrins are involved at different steps of leukocyte migration from blood to the site of injury. When the endothelial cells get activated, the CAMs are upregulated which leads to them interacting with leukocytes. This review summarizes our current understanding of the roles H2S, substance P and adhesion molecules play in acute pancreatitis.

We evaluated the changes in substance P (SP)-expressing trigeminal neurons (TNs) innervating the cornea following ocular surface inflammation. Ocular surface inflammation was induced in Sprague–Dawley rats using 0.1% benzalkonium chloride (BAK). The corneal staining score, corneal epithelial apoptosis, conjunctival goblet cells, and density of corneal subbasal nerve plexus (SNP) were assessed, and the mRNA levels of SP, interleukin (IL)-1β, IL-6, and tumour necrosis factor-α were measured in corneas and ipsilateral trigeminal ganglia (TG). SP-immunoreactivity (IR) was measured in corneal intraepithelial nerves and TNs. The cell size of corneal TNs in the TG was calculated. All parameters were observed immediately (BAK group), at 1 week (1 w group), and 2 months (2 m group) after 2 weeks of BAK application. BAK caused an increase in the corneal staining score and the number of apoptotic cells, loss of conjunctival goblet cells, reduced density of corneal SNP, and upregulated expression of SP and inflammatory cytokines in both the cornea and TG in the BAK group but those changes were not observed in the 2 m group. On the other hand, SP-IR% and mean cell size of corneal TNs increased significantly in the BAK, 1 w, and 2 m groups, compared to the control. Our data suggest that following ocular surface inflammation, large-sized corneal TNs which normally do not express SP, expressed it and this phenotype switching lasted even after the inflammation disappeared. Long-lasting phenotypic switch, as well as changes in the expression level of certain molecules should be addressed in future studies on the mechanism of corneal neuropathic pain.

The role of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) has been highlighted in mechanisms underlying inflammatory and neuropathic pain processes. The present study was designed to investigate whether NF-κB signaling is associated with pain-related neuropeptide expression in patients with chronic back pain related to degenerative disc disease (DDD). Intervertebral disc (IVD) tissues were collected from forty DDD patients undergoing disc replacement or fusion surgery, and from eighteen postmortem (PM) control subjects. RELA, NFKB1, CGRP, TAC1, TRPV1, and MMP-3 gene expression were analyzed by RT-qPCR, while NF-κB subunit RelA and NF-κB1–DNA binding in nuclear extracts and calcitonin gene related peptide (CGRP), substance P (SP), and transient receptor potential, subfamily V, member 1 (TRPV1) protein levels in cytosolic extracts of tissues were assessed by enzyme-linked immunosorbent assay (ELISA). An upregulated NF-κB1–DNA binding, and higher CGRP and TRPV1 protein levels were observed in DDD patients compared to PM controls. In DDD patients, NF-κB1–DNA binding was positively correlated with nuclear RelA levels. Moreover, NF-κB1–DNA binding was positively associated with TRPV1 and MMP-3 gene and SP and TRPV1 protein expression in DDD patients. Our results indicate that the expression of SP and TRPV1 in IVD tissues was associated with NF-κB activation. Moreover, NF-κB may be involved in the generation or maintenance of peripheral pain mechanisms by the regulation of pain-related neuropeptide expression in DDD patients.