-
International Journal of Molecular... Feb 2022A large number of studies have focused on the role of substance P (SP) and the neurokinin-1 receptor (NK1R) in the pathogenesis of a variety of medical conditions. This... (Review)
Review
A large number of studies have focused on the role of substance P (SP) and the neurokinin-1 receptor (NK1R) in the pathogenesis of a variety of medical conditions. This review provides an overview of the role of the SP-NK1R pathway in the pathogenesis of musculoskeletal disorders and the evidence for its role as a therapeutic target for these disorders, which are major public health problems in most countries. To summarize, the brief involvement of SP may affect tendon healing in an acute injury setting. SP combined with an adequate conjugate can be a regenerative therapeutic option in osteoarthritis. The NK1R antagonist is a promising agent for tendinopathy, rheumatoid arthritis, and osteoarthritis. Research on the SP-NK1R pathway will be helpful for developing novel drugs for osteoporosis.
Topics: Humans; Musculoskeletal Diseases; Neurokinin-1 Receptor Antagonists; Osteoarthritis; Receptors, Neurokinin-1; Substance P
PubMed: 35269726
DOI: 10.3390/ijms23052583 -
The Lancet. Microbe Aug 2023The most prevalent symptoms of post-COVID-19 condition are pulmonary dysfunction, fatigue and muscle weakness, anxiety, anosmia, dysgeusia, headaches, difficulty in... (Review)
Review
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.
Topics: Humans; Substance P; COVID-19; Tachykinins; Neuropeptides; Receptors, Tachykinin
PubMed: 37327802
DOI: 10.1016/S2666-5247(23)00111-8 -
American Journal of Physiology.... Jul 2022Noxious stimuli on the colorectum cause colorectal contractions through activation of descending monoaminergic pathways projecting from the supraspinal defecation center...
Noxious stimuli on the colorectum cause colorectal contractions through activation of descending monoaminergic pathways projecting from the supraspinal defecation center to the spinal defecation center. Since it is known that substance P is involved in the response to peripheral noxious stimuli in the spinal cord, we investigated the effects of intrathecally administered substance P at L6-S1 levels on colorectal motility in rats that were anesthetized with α-chloralose and ketamine. Intrathecally administered substance P enhanced colorectal motility, even after transection of the thoracic spinal cord at the T4 level. Severing the pelvic nerves, but not the colonic nerves, abolished substance P enhanced colorectal motility. In the spinal cord at L6-S1 levels, expression of mRNA coding neurokinin (NK) 1-3 receptors was detected by RT-PCR. Immunohistological experiments revealed that preganglionic neurons of the pelvic nerves express NK1 receptors, whereas expression of NK2 receptors was not found. In addition, substance P-containing fibers densely innervated around the preganglionic neurons expressing NK1 receptors. An intrathecally administered NK1 receptor antagonist (spantide) attenuated capsaicin-induced colorectal contractions. These results suggest that the colokinetic action of substance P is mediated by the NK1 receptor in the spinal defecation center. Our findings indicate that substance P may function as a neurotransmitter in the spinal defecation center. We found that intrathecally administered substance P enhanced colorectal motility in anesthetized rats. Neurokinin (NK) 1 receptors, but not NK2 receptors, were detected in preganglionic neurons of the pelvic nerves. Blockade of NK1 receptors in the spinal cord attenuated the enhanced colorectal motility in response to intracolonic noxious stimuli. The findings indicate that substance P may function as a neurotransmitter in the spinal reflex pathway controlling defecation.
Topics: Animals; Colorectal Neoplasms; Defecation; Gastrointestinal Motility; Rats; Rats, Sprague-Dawley; Receptors, Neurokinin-1; Spinal Cord; Substance P
PubMed: 35470689
DOI: 10.1152/ajpgi.00342.2021 -
Pharmacology Research & Perspectives Aug 2022The tachykinin neuropeptide substance P (SP) is the canonical agonist peptide for the neurokinin 1 receptor (NK R). More recently, it has also been shown to activate the...
The tachykinin neuropeptide substance P (SP) is the canonical agonist peptide for the neurokinin 1 receptor (NK R). More recently, it has also been shown to activate the Mas-related G protein-coupled receptor X2 (MRGPRX2) receptor on mast cells (MCs), triggering degranulation and release of inflammatory mediators. SP undergoes rapid C-terminal truncation in vivo by a number of proteases to generate the metabolites SP(1-9)-COOH and in particular SP(1-7)-COOH. While the C terminus of SP is critical for NK R activation, studies have shown that the peptide polycationic N terminus is key for MRGPRX2 and mast cell activation. The study thus aimed to determine if the C-terminally truncated metabolites of SP, SP(1-9)-COOH, and SP(1-7)-COOH retained stimulatory activity at MRGPRX2. SP, SP(1-9)-COOH, and SP(1-7)-COOH were synthesized and tested on HEK293 cells expressing NK R or MRGPRX2, and LAD2 human mast cells, to determine the activity of SP and its metabolites in Ca mobilization, degranulation, and cytokine assays. As expected from prior studies, both C-terminally truncated SP metabolites had essentially no activity at NK R, even at very high concentrations. In contrast, the in vivo metabolite of SP, SP(1-9)-COOH retained ability to activate MRGPRX2 across all parameters tested, albeit with reduced potency compared to intact SP. SP(1-7)-COOH did not produce any significant MRGRPX2 activation. Our results suggest that the SP metabolite, SP(1-9)-COOH, may play a regulatory role through the activation of MRGPRX2. However, given the relatively low potency of both SP and SP(1-9)-COOH at MRGPRX2, additional work is needed to better understand the biological importance of this expanded SP/MRGPRX2 pathway.
Topics: Cell Degranulation; HEK293 Cells; Humans; Mast Cells; Nerve Tissue Proteins; Receptors, G-Protein-Coupled; Receptors, Neuropeptide; Substance P
PubMed: 35904495
DOI: 10.1002/prp2.990 -
Inflammation Feb 2023Staphylococcus aureus infections of bone tissue are associated with inflammatory bone loss. Resident bone cells, including osteoblasts and osteoclasts, can perceive S....
Staphylococcus aureus infections of bone tissue are associated with inflammatory bone loss. Resident bone cells, including osteoblasts and osteoclasts, can perceive S. aureus and produce an array of inflammatory and pro-osteoclastogenic mediators, thereby contributing to such damage. The neuropeptide substance P (SP) has been shown to exacerbate microbially induced inflammation at sites such as the gut and the brain and has previously been shown to affect bone cell differentiation and activity. Here we demonstrate that the interaction of SP with its high affinity receptor, neurokinin-1 receptor (NK-1R), expressed on murine osteoblasts and osteoclasts, augments the inflammatory responses of these cells to S. aureus challenge. Additionally, SP alters the production of pro- and anti-osteoclastogenic factors by bacterially challenged bone cells and their proteolytic functions in a manner that would be anticipated to exacerbate inflammatory bone loss at sites of infection. Furthermore, we have demonstrated that the clinically approved NK-1R antagonist, aprepitant, attenuates local inflammatory and pro-osteoclastogenic mediator expression in an in vivo mouse model of post-traumatic staphylococcal osteomyelitis. Taken together, these results indicate that SP/NK-1R interactions could play a significant role in the initiation and/or progression of damaging inflammation in S. aureus bone infections and suggest that the repurposing of currently approved NK-1R antagonists might represent a promising new adjunct therapy for such conditions.
Topics: Animals; Mice; Staphylococcus aureus; Substance P; Osteoclasts; Osteoblasts; Inflammation; Osteomyelitis; Neurokinin-1 Receptor Antagonists; Staphylococcal Infections
PubMed: 36040535
DOI: 10.1007/s10753-022-01731-z -
Frontiers in Cellular and Infection... 2022Detection and transduction of environmental signals, constitute a prerequisite for successful parasite invasion; i.e., transmission, survival, pathogenesis and disease... (Review)
Review
Detection and transduction of environmental signals, constitute a prerequisite for successful parasite invasion; i.e., transmission, survival, pathogenesis and disease manifestation and dissemination, with diverse molecules functioning as inter-cellular signaling ligands. Receptors [i.e., G protein-coupled receptors (GPCRs)] and their associated transduction mechanisms, well conserved through evolution, specialize in this function. However, canonical GPCR-related signal transduction systems have not been described in , although orthologs, with reduced domains and function, have been identified in Trypanosomatidae. These inter-cellular communication means seem to be essential for multicellular and unicellular organism's survival. GPCRs are flexible in their molecular architecture and may interact with the so-called receptor activity-modifying proteins (RAMPs), which modulate their function, changing GPCRs pharmacology, acting as chaperones and regulating signaling and/or trafficking in a receptor-dependent manner. In the skin, vasoactive- and neuro- peptides released in response to the noxious stimuli represented by the insect bite may trigger parasite physiological responses, for example, chemotaxis. For instance, in (.) , sensory [Substance P, SP, chemoattractant] and autonomic [Vasoactive Intestinal Peptide, VIP, and Neuropeptide Y, NPY, chemorepellent] neuropeptides at physiological levels stimulate effects on parasite taxis. VIP and NPY chemotactic effects are impaired by their corresponding receptor antagonists, suggesting that the stimulated responses might be mediated by putative GPCRs (with essential conserved receptor domains); the effect of SP is blocked by [(D-Pro 2, D-Trp7,9]-Substance P (10 M)] suggesting that it might be mediated by neurokinin-1 transmembrane receptors. Additionally, vasoactive molecules like Calcitonin Gene-Related Peptide [CGRP] and Adrenomedullin [AM], exert a chemorepellent effect and increase the expression of a 24 kDa band recognized in western blot analysis by (human-)-RAMP-2 antibodies. search oriented towards GPCRs-like receptors and signaling cascades detected a RAMP-2-aligned sequence corresponding to folylpolyglutamate synthase and a RAMP-3 aligned protein, a hypothetical protein with yet unknown function, suggesting that in , CGRP and AM activities may be modulated by RAMP- (-2) and (-3) homologs. The possible presence of proteins and molecules potentially involved in GPCRs cascades, i.e., RAMPs, signpost conservation of ancient signaling systems associated with responses, fundamental for cell survival, (i.e., taxis and migration) and may constitute an open field for description of pharmacophores against parasites.
Topics: Calcitonin Gene-Related Peptide; Cell Communication; Humans; Leishmania; Receptor Activity-Modifying Proteins; Receptors, G-Protein-Coupled; Substance P
PubMed: 35651757
DOI: 10.3389/fcimb.2022.812848 -
The Journal of Investigative Dermatology Aug 1981
Topics: Erythema; Humans; Substance P; Tachycardia; Vasodilation
PubMed: 6168709
DOI: 10.1111/1523-1747.ep12480167 -
Microcirculation (New York, N.Y. : 1994) Nov 2021We sought to define how sensory neurotransmitters substance P and calcitonin gene-related peptide (CGRP) affect membrane potential of vascular smooth muscle and...
OBJECTIVE
We sought to define how sensory neurotransmitters substance P and calcitonin gene-related peptide (CGRP) affect membrane potential of vascular smooth muscle and endothelium.
METHODS
Microelectrodes recorded membrane potential of smooth muscle from pressurized mouse mesenteric arteries (diameter, ~150 µm) and in endothelial tubes.
RESULTS
Resting potential was similar (~ -45 mV) for each cell layer. Substance P hyperpolarized smooth muscle and endothelium ~ -15 mV; smooth muscle hyperpolarization was abolished by endothelial disruption or NO synthase inhibition. Blocking K channels (apamin + charybdotoxin) attenuated hyperpolarization in both cell types. CGRP hyperpolarized endothelium and smooth muscle ~ -30 mV; smooth muscle hyperpolarization was independent of endothelium. Blocking K channels prevented hyperpolarization to CGRP in endothelium but not smooth muscle. Inhibiting K channels with glibenclamide or genetic deletion of K 6.1 attenuated hyperpolarization in smooth muscle but not endothelium. Pinacidil (K channel agonist) hyperpolarized smooth muscle more than endothelium (~ -35 vs. ~ -20 mV).
CONCLUSIONS
Calcitonin gene-related peptide elicits greater hyperpolarization than substance P. Substance P hyperpolarizes both cell layers through K channels and involves endothelium-derived NO in smooth muscle. Endothelial hyperpolarization to CGRP requires K channels, while K channels mediate hyperpolarization in smooth muscle. Differential K channel activation in smooth muscle and endothelium through sensory neurotransmission may selectively tune mesenteric blood flow.
Topics: Animals; Calcitonin Gene-Related Peptide; Endothelium; Endothelium, Vascular; Mesenteric Arteries; Mice; Muscle, Smooth, Vascular; Substance P
PubMed: 34633728
DOI: 10.1111/micc.12733 -
Gut Microbes 2023Abdominal pain is common in patients with gastrointestinal disorders, but its pathophysiology is unclear, in part due to poor understanding of basic mechanisms...
Abdominal pain is common in patients with gastrointestinal disorders, but its pathophysiology is unclear, in part due to poor understanding of basic mechanisms underlying visceral sensitivity. Accumulating evidence suggests that gut microbiota is an important determinant of visceral sensitivity. Clinical and basic research studies also show that sex plays a role in pain perception, although the precise pathways are not elucidated. We investigated pain responses in germ-free and conventionally raised mice of both sexes, and assessed visceral sensitivity to colorectal distension, neuronal excitability of dorsal root ganglia (DRG) neurons and the production of substance P and calcitonin gene-related peptide (CGRP) in response to capsaicin or a mixture of G-protein coupled receptor (GPCR) agonists. Germ-free mice displayed greater in vivo responses to colonic distention than conventional mice, with no differences between males and females. Pretreatment with intracolonic capsaicin or GPCR agonists increased responses in conventional, but not in germ-free mice. In DRG neurons, gut microbiota and sex had no effect on neuronal activation by capsaicin or GPCR agonists. While stimulated production of substance P by DRG neurons was similar in germ-free and conventional mice, with no additional effect of sex, the CGRP production was higher in germ-free mice, mainly in females. Absence of gut microbiota increases visceral sensitivity to colorectal distention in both male and female mice. This is, at least in part, due to increased production of CGRP by DRG neurons, which is mainly evident in female mice. However, central mechanisms are also likely involved in this process.
Topics: Animals; Female; Male; Mice; Calcitonin Gene-Related Peptide; Capsaicin; Colorectal Neoplasms; Gastrointestinal Microbiome; Substance P
PubMed: 36939195
DOI: 10.1080/19490976.2023.2188874 -
Journal of Internal Medicine Jan 2001A brief overview of recent developments in the substance P field is provided, in addition to a historical introduction. It is emphasized that there are multiple... (Review)
Review
A brief overview of recent developments in the substance P field is provided, in addition to a historical introduction. It is emphasized that there are multiple tachykinins and tachykinin receptors and that there are examples of coexistence of several tachykinin peptides and of several tachykinin receptors in single cells, and there is evidence for tachykininergic cotransmission. The distribution and functional significance of tachykinins in the gastrointestinal tract and in sensory neurones, and interactions with other peptides and transmitters, are reviewed. The recent production of knock-out mice for either substance P or the NK1 receptor is discussed, as well as the exciting concept of substance P receptor internalization. Finally, the development of specific substance P antagonists is summarized, and possible clinical implications discussed, and, in particular, a recent study which reports that a substance P antagonist shows clinical efficacy in depression.
Topics: Animals; Antidepressive Agents; Glutamic Acid; Guinea Pigs; History, 20th Century; Humans; Intestinal Mucosa; Mice; Mice, Knockout; Neurokinin-1 Receptor Antagonists; Neurons; Neuropeptides; Receptors, Neurokinin-1; Receptors, Tachykinin; Substance P; Tachykinins
PubMed: 11168782
DOI: 10.1046/j.0954-6820.2000.00773.x