SP-like nerve fibers are distributed in various bone tissues of the human body, including long bones, joints and teeth, and most of the metabolically active parts such as the periosteum and epiphyseal growth plate are distributed, and the cortex and bone marrow are relatively small at the backbone 4 , SP is also found in chondrocytes, subchondral bone, and cartilage membranes SP is known to be involved in many physiological and pathophysiological processes including vasodilation, extravasation, smooth muscle contraction 12 , pain transmission 13 , neurogenic inflammation 14 , angiogenesis and bone turnover 15 , Cartilage, which contains no blood vessels, nerves, or lymphatics, has long been considered inert tissue in the body.

However, an increasing number of studies have shown that cartilage is also regulated by sensory nerves, and sensory neuropeptides can be involved in the regulation of cartilage physiological and pathological metabolism by affecting the proliferation, differentiation, and secretion of chondrocytes 17 — Although SP and its receptors are widely distributed in the locomotor system, its effects on bone and cartilage metabolism are not well-understood.

In the present review, we focus on the effects of SP on bone and cartilage metabolism in some physiological and pathological states. The balance between osteoclastic bone resorption and osteogenic bone formation processes in bone metabolism is the key to maintaining normal bone mass Osteoclasts and osteoblasts are derived from bone marrow macrophages and bone marrow stromal cells BMSCs , respectively Neuropeptides regulate the functions of osteoclasts and osteoblasts by binding to receptors, and participate in bone growth, repair and reconstruction.

Nk-R1 is expressed by osteoblasts and osteoclast precursors 22 Figure 1. Figure 1. Schema of the effects of released SP on the osteoclasts and osteoblasts. Osteoblastic progenitors are derived from mesenchymal stem cells MSCs 23 and require Runx2 also known as Cbfa1, runt-related transcription factor2 transcription factors to develop into a mature osteoblastic lineage. They are characterized by an osteoblastic morphology, accompanied by an increase in alkaline phosphatase ALP activity and the production of type I collagen and osteocalcin However, the effect of SP on bone formation remains unclear.

Interestingly, Goto et al. Wang et al. SP can improve the bone formation activity of late osteoblasts by acting on Nk-R1 Shih et al. Paradoxically, SP slightly stimulated thymidine incorporation and strongly inhibited calcium accumulation in bone noduli, which was associated with a small decrease in ALP activity Although the results of such studies are inconsistent, it is certain that the formation of osteoblasts is influenced by SP. Further research is needed to clarify how SP regulates bone differentiation, what mechanisms are involved in bone formation, and which neurokinin receptors SP activates in osteoblasts and osteocytes.

Tanja et al. Takaaki et al. They showed that SP released from peripheral sensory nerve endings is one of the risk factors for the development of arthritis. It induces synovial hyperplasia and hypertrophy, up-regulates RANKL expression and down-regulates the expression of OPG in synovial fibroblastic cells, which results in osteoclastogenesis.

SP-like nerve fibers are closely related to the reconstruction of orthodontic periodontal tissue. In patients with severe root resorption of orthodontic teeth, SP can increase the production of pro-inflammatory cytokines and osteoclast formation in pulp fibroblasts Bone loss in capsaicin-treated animals was associated with a decrease in the rate of bone formation and an increase in the number of osteoclasts and the function of osteoclasts Given the above evidence, it is paradoxical that excessive release of SP leads to increased bone absorption, and that extensive reduction of SP in bones also leads to osteoporosis.

SP may maintain a balance between bone resorption and bone formation and mediate bone resorption depending on whether its level is greater or less than a specific range, suggesting that different amounts of SP affect bone metabolism through different mechanisms. Caye-Thomasen et al. Mori et al. Some scholars have observed that cutting off the sympathetic nerve can promote an increase in peripheral SP and bone absorption 41 , The reason may be that after the sympathetic nerve is cut off, the intake of nerve growth factor in the bone tissues it innervates will be reduced, so the sensory nerve will increase the intake of nerve growth factor, which will further promote the synthesis and peripheral release of SP in the sensory neurons.

These findings clearly indicate the effects of SP in accelerating osteoclastic bone resorption. Osteocytes are the main cell in mature bone tissue, equivalent to human adulthood. Nk-R1 has been reported to exist on monocytes, pre-osteoblast cells, osteoblasts, and osteoclasts.

Some findings clearly indicate the accelerated effect of SP on osteoclastic bone resorption. And the effect of SP on bone formation is still unclear. Osteoporosis is a critical risk factor for fragility fractures, causing substantial morbidity, and mortality, especially in postmenopausal women and the elderly A large number of neuropeptides regulating bone metabolism may represent a regulatory pathway for the pathogenesis of osteoporosis.

Liu et al. Interestingly, spinal cord injury SCI in experimental rats resulted in an osteoporotic phenotype in the proximal tibia, due to enhanced osteoclast uptake, which was associated with a substantial increase in SP immunoreactive nerve fibers, consistent with in vitro observations of SP enhancing osteoclast activity BMD and bone microstructure were significantly reduced at 3 weeks after mechanical stimulation of SCI. Firstly, metabolic function changes, such as impaired renal function, hyperlipidemia, and insulin resistance, which may be related to the pathogenesis of OP after SCI.

The second is the reduced mechanical loading, the third explanation responsible for this process in the nerve injury itself Chen et al. SP increased the amount of trabecular bone and reduced trabecular bone separation. Histological analysis showed that the gelatin microspheres containing SP effectively promoted osteogenesis, regardless of the concentration.

Zheng et al. Biomechanical analysis showed that blockade of SP signaling can reduce the maximum stress and maximum load of L3 vertebrae and tibiae. In mice treated with L, there was an increase in the number of osteoclasts, a decrease in the number of osteoblasts and an increase in the osteoid volume in the secondary spongiosa, thereby inhibiting the recruitment of BMSCs to the bone reconstruction site.

Kingery et al. Based on the evidence above, it is possible that the pathogenesis of osteoporosis is associated with the regulation of SP.

SP signaling certainly plays an important role in the maintenance of bone mass. SP is considered to be a regulator of angiogenesis that is important for bone repair and remodeling. Ding et al. The fracture healing ability of young mice with OVX-induced bone loss was significantly worse than that in control mice, and SP in the fracture site was significantly decreased at all time points.

It was also found that angiogenesis was impaired in OVX mice. The results suggest that neural regulation may play a role in osteoporotic fracture healing and that SP plays an important role during fracture healing, particularly in the early stages. These data contribute to the evidence that SP may play an important role in osteoporotic fracture healing. This research suggested that SP is essential in the process of cartilage ossification during fracture healing.

Furthermore, absence of SP reduces pain sensitivity and the mechanical stability of the bone after fracture in general.

Guo et al. Although the effects of SP on osteoblasts and osteoclasts remain controversial, SP plays a critical role in maintaining the balance between bone resorption and bone formation by regulating osteoblasts and osteoclasts during fracture healing 53 , Based on the correlation between neuropeptides and fracture healing, the authors hypothesized that SP is secreted into the surrounding bone tissue in a certain way.

The amount of this neuropeptide changes during fracture healing, and SP binds to receptors on the cell membrane, activating intracellular signaling pathways, which in turn affect fracture healing and later bone remodeling. SP is a neuroinflammatory mediator produced by sensory nerve fibers and local inflammatory cells, such as macrophages, lymphocytes, and dendritic cells 53 , SP plays an important role in the skeletal degeneration and damage induced by chronic inflammation 4.

Abnormal expression of SP and Nk-R1 in inflammatory diseases provides evidence for SP's involvement in the inflammatory response. Knocking out the Nk-R1 gene and applying an Nk-R1 antagonist in animal models of inflammatory diseases have significant anti-inflammatory effects.

SP plays an important role in the development of arthritis as evidenced by a positive correlation between the size and severity of joint destructive changes Rheumatoid arthritis RA is a systemic autoimmune disease associated with chronic inflammation of connective tissue. Recent evidence suggests that SP and its receptors are involved in joint inflammation and are involved in the pathophysiology of RA SP stimulated RA synovial cells to release prostaglandin E2 and collagenase, which in turn increased the proliferation of RA synovial cells This suggests that SP plays a role in the development of cartilage destruction and bone damage in arthritis.

Experiments with chronic arthritis in rats have shown that sustained inflammatory stimulation can increase SP release in the spinal cord horn Chronic inflammation is a common symptom in OA osteoarthritis and RA. A study by Barbara et al. SP seems to be extremely important for cartilage health because it participates in mechanical transduction through Nk-R1 62 — Millward-Sadler et al. Blockade of SP signaling by a chemical antagonist of Nk-R1 inhibited chondrocyte responses to mechanical stimulation.

Karaha et al. However, SP expression in articular chondrocytes, cartilage matrix, and synovial membrane cells was significantly higher in a high-exercise group, suggesting that SP plays a role in regulating the physiological microenvironment of the cartilage, metabolism, and joint function. Opolka et al. The first NK-1R antagonists were developed in the early s, but most were not effective as analgesics and anti-depressants as they could not efficiently cross the blood-brain barrier.

An exception to this rule was LY, which was shown to block rodent licking behavior in the late stages of persistent nociceptive activation with inhibition of ex vivo substance P binding to both peripheral and central NK-1R Iyengar et al. Subsequently, an analysis of the pharmacokinetics of the non-peptide NK-1R antagonist ezlopitant in dogs revealed the presence of this compound and its two pharmacologically active metabolite compounds in cerebrospinal fluid following intravenous or oral administration, indicating its ability to cross the blood brain barrier Reed-Hagen et al.

Similarly, the NK-1R antagonist casopitant, when radioactively labeled, has been demonstrated to be rapidly absorbed into the bloodstream and can subsequently be found within the brain Ruhlmann and Herrstedt, This antagonist has completed phase II and III clinical trials and has similar success to aprepitant in the treatment of chemotherapy-induced nausea and vomiting Ruhlmann and Herrstedt, , but this drug has not yet received United States Food and Drug Administration approval.

The ability of NK-1R antagonists to cross the blood-brain barrier means that these agents have the potential for use in the treatment in wide range of CNS disorders. Indeed, aprepitant and its pro-drug fosaprepitant are currently employed as post-chemotherapy anti-emetic agents Aapro et al. Likewise, casopitant has completed phase II and phase III trials and has similar success to aprepitant in the treatment of chemotherapy-induced nausea and vomiting Ruhlmann and Herrstedt, In addition to use as an anti-emetic, there has been promising research that aprepitant and other NK-1R antagonists may have efficacy against other CNS disorders including depression.

The NK-1R antagonist MK has been shown to effectively suppress depressive behavior in guinea pigs, and both MK and casopitant successfully completed phase II clinical trials to treat depression Kramer et al. This hope stems from the promising effects of NK-1R antagonists capable of crossing the blood-brain barrier in animal models of such disorders Table 1. For example, the NK-1R antagonist SR has shown efficacy as a co-therapy with other anti-inflammatory agents in ameliorating myelin oligodendrocyte glycoprotein-induced EAE, a mouse model of MS Reinke et al.

Similarly, CP , has also been demonstrated to reduce EAE severity, and this effect was associated with stabilization of the blood brain barrier as well as reduced T-helper type 1 immunity Nessler et al.

For example, since direct hippocampal substance P administration elicits seizures in mice and an NK-1R antagonist has been shown to prevent seizure activity in a rodent model of helminth brain infection Robinson et al. Furthermore, our own studies have shown that pharmacological targeting of NK-1R with the antagonist L, can not only prevent the development of damaging inflammation due to streptococcal CNS infection when administered prophylactically, but can also reverse infection-associated gliosis and demyelination when delivered therapeutically without increasing CNS bacterial burden Chauhan et al.

While further studies are clearly needed to define the specific mechanisms underlying the ability of substance P to augment CNS inflammation and its role in pathogen clearance, the available data raise the intriguing possibility that currently approved NK-1R antagonists, such as aprepitant, could be repurposed for use as a co-therapy to limit neuroinflammatory damage associated with infectious agents and certain neurodegenerative conditions.

The use of such agents might have considerable advantages over other anti-inflammatory agents such as corticosteroids, non-steroidal anti-inflammatory drugs, prostaglandin inhibitors, and P2X7 antagonists, by limiting excessive inflammation without broadly attenuating host immune responses that may be required to resolve infection.

Continued research on the ability of NK-1R antagonists to alleviate these health conditions may therefore yield new treatment options for patients with CNS infections, and perhaps other inflammatory neurological disorders. Infectious and sterile CNS disorders are often associated with overwhelming and damaging inflammation due to the immune responses of resident CNS cells and infiltrating leukocytes.

Currently, neuroinflammatory diseases such as meningitis are treated with corticosteroids in combination with antibacterial, antiviral, or antifungal agents Aberdein and Singer, ; Hoffman and Weber, Corticosteroids have both anti-inflammatory and immunosuppressive properties and treatment with these agents has been shown to reduce the risk of hearing loss and mortality due to meningitis. However, the immunosuppressive properties of corticosteroids may interfere with the ability of the body to clear infections, especially if the antibiotics used are not effective or antiviral medications are not available Fitch and van de Beek, Furthermore, corticosteroid treatment can lead to adverse effects including the development of ulcers, myopathy, and bone loss, or central effects including sleep disorders and mood swings.

As such, there is a current need for new treatment options to limit neuroinflammation associated with infection of the CNS and neurodegenerative conditions.

Substance P is produced at high levels in the CNS, and its target receptor NK-1R is expressed by resident CNS cells including microglial and astrocytes, and by immune cells that can infiltrate the CNS such as macrophages and lymphocytes. Importantly, this tachykinin functions both as a neurotransmitter and an immunomodulator, and substance P is recognized to exacerbate inflammatory responses at peripheral sites including the skin, lung and gastrointestinal and urogenital tracts. Our own studies indicate that therapeutic intervention with NK-1R antagonists can limit neuroinflammation, reactive gliosis and demyelination in a mouse model of streptococcal meningitis Chauhan et al.

This data therefore supports the use of NK-1R receptor antagonists in the treatment of such neuroinflammatory disorders. Figure 1. Substance P-mediated exacerbation of neuroinflammatory damage following central nervous system CNS infection. Local inflammation promotes the recruitment of leukocytes to the site of infection that will, in turn, recognize microbial components and produce more pro-inflammatory and neurotoxic mediators.

Importantly, inflammatory cytokines can also augment the expression of PRR and NK-1R by glia and leukocytes, and can elevate local production of substance P. This positive feedback loop would be anticipated to increase the sensitivity of host cells to pathogen components and sensitize leukocytes and glia to this neuropeptide, thereby exacerbating inflammatory damage.

Intervention with pharmaceutical NK-1R inhibitors capable of penetrating the blood-brain barrier would prevent substance P mediated exacerbation of glial and leukocyte inflammatory responses, and interrupt such a feedback loop. The latest generation of NK-1R antagonists can be delivered orally and can readily cross the blood-brain barrier. Importantly, these antagonists exert central effects and the NK-1R antagonist, aprepitant, is approved for use as an anti-emetic agent in patients receiving chemotherapy.

As such, the repurposing of currently available NK-1R antagonists may yield alternative co-therapy options for CNS inflammation associated with extracellular bacteria and parasites, and perhaps MS, with more specificity and reduced adverse effects. All authors have contributed significantly to the preparation of this review article. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Aapro, M. Aprepitant and fosaprepitant: a year review of efficacy and safety. Oncologist 20, — Abbadie, C. Spinal cord substance P receptor immunoreactivity increases in both inflammatory and nerve injury models of persistent pain. Neuroscience 70, — Aberdein, J.

Clinical review: a systematic review of corticosteroid use in infections. Care Agro, A. Inhibition of murine intestinal inflammation by anti-substance P antibody. PubMed Abstract Google Scholar. Andoh, T. Brain Res. Arsenescu, R. IL induction of mRNA encoding substance P in murine macrophages from the spleen and sites of inflammation. Baker, S. Cloning of a C-terminally truncated NK-1 receptor from guinea-pig nervous system.

Beaujouan, J. NK-1 receptors are the only class of tachykinin receptors found on mouse cortical astrocytes. Peptides 12, — Beinborn, M. U S A , — Benarroch, E. Depletion of ventromedullary NK-1 receptor-immunoreactive neurons in multiple system atrophy. Brain , — Human positron emission tomography studies of brain neurokinin 1 receptor occupancy by aprepitant.

Psychiatry 55, — Bernstein, C. Bettelli, E. Reciprocal developmental pathways for the generation of pathogenic effector T H 17 and regulatory T cells. Nature , — Bill, A. Substance P: release on trigeminal nerve stimulation, effects in the eye. Acta Physiol. Blum, A. Interleukin 12 and antigen independently induce substance P receptor expression in T cells in murine schistosomiasis mansoni.

Bost, K. Quantification of macrophage-derived substance P receptor mRNA using competitive polymerase chain reaction. Tachykinin-mediated modulation of the immune response. Tachykinin-modulated anti-viral responses. Substance P: a late-acting B lymphocyte differentiation cofactor. Bradesi, S. Role of spinal microglia in visceral hyperalgesia and NK1R up-regulation in a rat model of chronic stress. Gastroenterology , Brown, G.

Inflammatory neurodegeneration and mechanisms of microglial killing of neurons. Caberlotto, L. Neurokinin 1 receptor and relative abundance of the short and long isoforms in the human brain. Calvo, C. Substance P enhances IL-2 expression in activated human T cells. Castagliuolo, I. Neurokinin-1 NK-1 receptor is required in Clostridium difficile- induced enteritis. Chauhan, V. Vesicular stomatitis virus infects resident cells of the central nervous system and induces replication-dependent inflammatory responses.

Virology , — Prophylactic and therapeutic targeting of the neurokinin-1 receptor limits neuroinflammation in a murine model of pneumococcal meningitis. NOD2 plays an important role in the inflammatory responses of microglia and astrocytes to bacterial CNS pathogens.

Glia 57, — Neurogenic exacerbation of microglial and astrocyte responses to Neisseria meningitidis and Borrelia burgdorferi. Chen, L. Drug Targets 5, — Chernova, I. Corrigan, F. Inflammation in acute CNS injury: a focus on the role of substance P. Covas, M. Disturbed immunoregulatory properties of the neuropeptide substance P on lymphocyte proliferation in HIV infection.

Croitoru, K. Selective modulation of the natural killer activity of murine intestinal intraepithelial leucocytes by the neuropeptide substance P. Immunology 71, — Cuello, A. Detection of substance P in the central nervous system by a monoclonal antibody. U S A 76, — The distribution of substance P immunoreactive fibers in the rat central nervous system. Organization of substance P primary sensory neurons: ultrastructural and physiological correlates.

Cunningham, S. DeFea, K. Cell Biol. Di Fabio, R. Identification, biological characterization and pharmacophoric analysis of a new potent and selective NK1 receptor antagonist clinical candidate. Douglas, S. AIDS Res. Retroviruses 24, — Neurokinin-1 receptor expression and function in human macrophages and brain: perspective on the role in HIV neuropathogenesis.

N Y Acad. Elevated substance P levels in HIV-infected men. AIDS 15, — Neurokinin-1 receptor: functional significance in the immune system in reference to selected infections and inflammation. Doyle, C. Substance P receptor neurokinin-1 -expressing neurons in lamina I of the spinal cord encode for the intensity of noxious stimulation: a c-Fos study in rat. Neuroscience 89, 17— Ebner, K. The role of substance P in stress and anxiety responses. Amino Acids 31, — Elsawa, S.

Reduced CTL response and increased viral burden in substance P receptor-deficient mice infected with murine gamma-herpesvirus Fitch, M. Drug Insight: steroids in CNS infectious diseases—new indications for an old therapy. Fong, T. Differential activation of intracellular effector by two isoforms of human neurokinin-1 receptor. Garcia-Recio, S. Biological and pharmacological aspects of the NK1-receptor. Garza, A. Substance P signaling contributes to granuloma formation in Taenia crassiceps infection, a murine model of cysticercosis.

Gerard, N. Human substance P receptor NK-1 : organization of the gene, chromosome localization and functional expression of cDNA clones. Biochemistry 30, — Gillespie, E. Truncated neurokinin-1 receptor is increased in colonic epithelial cells from patients with colitis-associated cancer.

Goode, T. Neurokinin-1 receptor NK-1R expression is induced in human colonic epithelial cells by proinflammatory cytokines and mediates proliferation in response to substance P. Guo, C. Glia 48, — Harrison, S. Gene symbol: Tac1 Homo sapiens , Mus musculus , Rattus norvegicus 1. Physiological and pathological functions Although the existence of substance P has been known for more than eighty years, the bulk of physiological and pathological roles of SP have been uncovered only in the past 20 years.

Pain One of the earliest physiological functions of substance P is described in its role in nociception. Vomiting The vomiting center in the medulla controls the vomiting reflex. Inflammation Substance P has also been linked with the pathogenesis of inflammatory disorders. Other functions of substance P Mood disorders, anxiety, stress Substance P was suggested to have anxiogenic properties. Neurogenesis Substance P promotes the proliferation of adult rat neural progenitor cells.

Respiratory rhythm 6. Substance P increases respiratory rhythm and tidal volume. Vasodilation 50 Dermatitis 26 2. Pancreatic Information i. Substance P in acute pancreatitis The role of substance P in acute pancreatitis and associated lung injury has been extensively studied. Substance P in chronic pancreatitis Surprisingly there has been little work evaluating the role of substance P in chronic pancreatitis.

Substance P in pancreatic acinar cells Gene and peptide expression of substance P has been detected in isolated pancreatic acinar cells. Effects of substance P on pancreatic exocrine secretion Substance P has also been shown to regulate pancreatic secretion. Tools for study of Substance P a. The mice were healthy and fertile. These mice were protected against caerulein-induced acute pancreatitis.

These mice were protected against caerulein-induced acute pancreatitis 3 NEP knockout mice. These mice showed potentiated effects of substance P.

It has been used in several acute pancreatitis studies with success 28, 38, L, Compound ID: It has been used in acute pancreatitis with success. It was shown to suppress pancreatitis pain in L-arginine induced pancreatitis.

It was shown to block the inhibitory effect of substance P on exocrine secretion CP99, Compound ID: It was shown to suppress nociceptive behavior in dibutyltin dichloride induced acute pancreatitis It was shown to stimulate pancreatic plasma extravasation via NK1R activation Exogenous substance P is available from Bachem.

Antibodies There are several commercially available SP antibodies. Substance P-associated increase of intra-articular temperature and pain threshold in the arthritic TMJ.

J Orofac Pain 12 2 , The combination of neurokinin-1 and galanin receptor antagonists ameliorates caerulein-induced acute pancreatitis in mice. Peptides 31 2 , Role of substance P and the neurokinin 1 receptor in acute pancreatitis and pancreatitis-associated lung injury.

Preprotachykinin-A gene deletion protects mice against acute pancreatitis and associated lung injury. Substance P serum levels are increased in major depression: preliminary results. Biol Psychiatry , Neurotransmitters in the CNS control of breathing. Respir Physiol. Neurogenic amplification of immune complex inflammation. Science , Changes in peptidergic innervation in chronic pancreatitis. Pancreas 7 2 , Primary afferent tachykinins are required to experience moderate to intense pain.

Nature , Tachykinin substance-P gene expression in Leydig cells of the human and mouse testis. Endocrinology 5 , Fibromyalgia: an overview. Aprepitant: a review of its use in the prevention of chemotherapy-induced nausea and vomiting. Drugs 64 7 , Neutral endopeptidase determines the severity of pancreatitis-associated lung injury. J Surg Res 1 , Expression of interleukin 8 IL-8 and substance P in human chronic pancreatitis. Gut 47 3 , Cutaneous stimuli releasing immunoreactive substance P in the dorsal horn of the cat.

Brain Res , Noxious heating of the skin releases immunoreactive substance P in the substantia gelatinosa of the cat: a study with antibody microprobes. The role of substance P in stress and anxiety responses. Amino Acids 31 3 , Expression of substance P and neurokininreceptor in laryngeal cancer: linking chronic inflammation to cancer promotion and progression.

Histopathology 54 2 , J Physiol. Substance P and NK-1R expression in oral precancerous epithelium. Oncol Rep 22 6 , Substance P mediates inflammatory oedema in acute pancreatitis via activation of the neurokinin-1 receptor in rats and mice.

Br J Pharmacol 3 , Aggregation and concentration-dependent sorting of exocrine regulated secretory proteins. Biochem Biophys Res Commun. Neurokinin-1 receptor antagonist treatment protects mice against lung injury in polymicrobial sepsis. J Leukoc Biol 82 3 , Substance P inhibits bicarbonate secretion from guinea pig pancreatic ducts by modulating an anion exchanger.

Am J Physiol Cell Physiol. Human monocytes and macrophages express substance P and neurokinin-1 receptor. J Immunol 11 ,