TRPV1 Receptors Research Articles

Antinociceptive, antineuropathic, and antimigraine-like activities ofFritillariaimperialis L. rich in verticinone on rats: Mechanisms of action

Ethnopharmacological relevanceFritillaria imperialis L. (Fabaceae), commonly known as “Laleh vazhgon”, ethnomedicinally utilized in Iranian traditional medicine to treat joint pain, chronic daily headaches, and back pain. Aim of the studyTo investigate the antinociceptive, anti-neuropathic, and anti-migraine activities of Fritillaria imperialis bulbs essential oil (FIEO) as well as to uncover the potential mechanisms of action involved. Materials and methodsThe antinociceptive activity of FIEO and its main constituent, Verticinone (Vt), was assessed using the formalin-induced paw licking assay. The potential mechanisms of antinociception were investigated through various antagonists. Additionally, their antineuropathic activity was examined using the cervical spinal cord contusion (CCS) technique and the possible role of Stat3 was evaluated using Western blot analysis. The nitroglycerin-induced model (NTG) was also employed for the evaluation of migraine. ResultsFIEO demonstrated significant antinociceptive activity in both phases of the formalin-induced test. However, the FIEO activity was more pronounced effect observed in the second phase. Modulators of the NO-cGMP-K+ channel pathway significantly reversed the antinociceptive activity of FIEO (P < 0.05). Additionally, antagonists of TRPV1, PPARα, dopamine D1, GABAA, and δ-opioid receptors also significantly reversed the antinociceptive effects of FIEO (P < 0.05). In a separate study, both FIEO and Vt were found to attenuate hyperalgesia and mechanical allodynia (P < 0.01) when evaluated using the CCS-induced pain model. Furthermore, FIEO may alleviate migraine behaviors, likely related to the regulation of NO and CGRP levels. ConclusionFIEO exerts an antineuropathic effect through the phosphorylation of Stat3. Furthermore, the antinociceptive activity is partially modulated via the NO-cGMP-K+ channel pathway, as well as the activation of TRPV, PPAR, opioid, and GABA receptors. Vt may be involved in the antinociceptive, antineuropathic, and antimigraine activities induced by FIEO.

Anxiolytic Properties of the TRPV1 Receptor Antagonist in a Dark/Light Chamber Test on ICR Mice

Anxiolytic Properties of the TRPV1 Receptor Antagonist in a Dark/Light Chamber Test on ICR Mice

Novel apocynin regulates TRPV1 activity in the trigeminal system and controls pain in a temporomandibular joint neurogenic model

ObjectiveHerein, we investigate the potential analgesic effect of a newly synthesized chalcone-derived apocynin in a neurogenic pain model. MethodsMolecular docking was used to foretell the apocynin binding features and dynamics with the TRPV1 channel, and the activity was tested in vitro, using transfected HEK 293T cells with the rat TRPV1 receptor. The analgesic effect of apocynin was investigated using a capsaicin-induced pain model. The expression of TRPV1, TRPA1, TRPM8, and MAPKs was assessed by electrophoresis, and immunosorbent assays were performed to quantify the neurotransmitters Substance P, Glutamate, and CGRP. A survival assay using Galleria mellonella was carried out to determine the toxicity. ResultsWe observed that apocynin exhibits greater thermodynamic stability. Upon apocynin ligand binding, it changes the electrostatic potential for a predominantly electronegative state in the interior and neutral in its external vanilloid pocket. Treatment of apocynin induces antinociceptive effects against the noxious challenge of capsaicin. Histologically, apocynin decreased the number of TRPV1+ immunopositive cells. Electrophoresis showed reduced phosphorylation of p44/42 (ERK1/2) and decreased protein levels of substance P, and CGRP. In the survival assay, apocynin showed low toxicity. ConclusionsIn conclusion, we provide proof-of-principles that the newly synthesized apocynin compound effectively prevented nociception in a neurogenic model of orofacial pain.

Cannabinoid hyperemesis syndrome: genetic susceptibility to toxic exposure.

Cannabinoid hyperemesis syndrome presents as a complex of symptoms and signs encompassing nausea, vomiting, abdominal pain, and hot water bathing behavior, most typically in a heavy cannabis user. Its presentation is frequently associated with hypothalamic-pituitary-adrenal axis activation with stress and weight loss. Recent investigation has identified five statistically significant mutations in patients distinct from those of frequent cannabis users who lack the symptoms, affecting the TRPV1 receptor, two dopamine genes, the cytochrome P450 2C9 enzyme that metabolizes tetrahydrocannabinol, and the adenosine triphosphate-binding cassette transporter. The syndrome is associated with escalating intake of high potency cannabis, or alternatively, other agonists of the cannabinoid-1 receptor including synthetic cannabinoids. Some patients develop environmental triggers in scents or foods that suggest classical conditioned responses. Various alternative "causes" are addressed and refuted in the text, including exposure to pesticides, neem oil or azadirachtin. Nosological confusion of cannabinoid hyperemesis syndrome has arisen with cyclic vomiting syndrome, whose presentation and pathophysiology are clearly distinct. The possible utilization of non-intoxicating antiemetic cannabis components in cannabis for treatment of cannabinoid hyperemesis syndrome is addressed, along with future research suggestions in relation to its genetic foundation and possible metabolomic signatures.

Роль ванілоїдного рецептора типу 1 та глутаматних рецепторів у синаптичній активності нейронів пластинки X спинного мозку щурів

This study is aimed at understanding the mechanisms of nociceptive signaling in lamina X of the spinal cord, which are involved in the regulation of pain sensations. First, tetrodotoxin, which blocks action potentials, was applied to the system, which made it possible to isolate miniature synaptic activity (mEPSCs). After that, they added pidal, an agonist of TRPV1 receptors, which caused a significant increase in the frequency and amplitude of mEPSCs. Against the background of tetrodotoxin, the effect of capsaicin was biphasic: at first, the frequency of events increased sharply, after which it gradually decreased, but the amplitude increased. A control, without tetrodotoxin, application of capsaicin also caused an increase in synaptic activity, but this effect was not biphasic. Additional blockade of NMDA receptors (AP-5) partially reduced capsaicin-induced activity, while an AMPA receptor blocker (CNQX) almost completely abolished it, suggesting a critical role of glutamate receptors in maintaining this activity. The obtained results emphasize the importance of TRPV1 receptors in central sensitization and the possibility of its regulation, which opens new ways of modulation of chronic pain.

Thermosensitive hyaluronic acid-manganese-capsaicin complex nanogel improving NKG2D/CAR-T melanoma treatment through adjusting tumor microenvironment

Intratumorally injection of CAR-T cells to treat melanoma can reduce the incidence of systemic side effects and ensure an adequate concentration of CAR-T cells. However, few targeting ligands and hostile tumor microenvironment (TME) inhibit the CAR-T cells' survival and infiltration. An in situ hyaluronic acid‑manganese-capsaicin complex nanogel (HA-Mn-CAP Gel) was designed by forming complex nanogel based on the main skeleton material of hyaluronic acid (HA). It targeted CD44 and TRPV1 receptors through HA and CAP, concentrated and released Mn at melanoma, subsequently relieving the hypoxia in the tumor and increasing the expression of CAR-T cells' specific ligands. Cell experiments showed that HA-Mn-CAP Gel significantly enhanced the expression of representative NKG2D ligands (MICA/B and ULBP2/5/6) >2.7 times on A375 melanoma cells. Sequential administration of HA-Mn-CAP Gel and NKG2D/CAR-T increased the tumor inhibition rate about 1.5 times that of the NKG2D/CAR-T group in melanoma-bearing NSG mice. The results of immunohistochemistry and immunofluorescence assays showed that the combined HA-Mn-CAP Gel and NKG2D/CAR-T significantly increased the proliferation and infiltration of T cells, especially for CD8+ cells. Therefore, the new promising strategy of increasing the target ligand expression and adjusting TME before administering CAR-T cells is suitable for treating solid tumors.

Is It Possible to Regenerate the Underactive Detrusor? Part 1 Molecular and Stem Cell Therapies Targeting the Urinary Bladder and Neural Axis ICI-RS 2024.

Detrusor muscle weakness is commonly noted on urodynamics in patients with refractory voiding difficulty. No approved therapies have been proven to augment the strength of a detrusor voiding contraction. This subject was discussed by a think-tank at the International Consultation on Incontinence- Research Society (ICI-RS) meeting held in Bristol, June 2024. The discussions of the think-tank are being published in two parts. This first part discusses molecular and stem cell therapies targeting the urinary bladder and the neural axis. Senescence of the urothelium and extracellular ATP acting through P2X3 receptors might be important in detrusor underactivity. Several molecules such as parasympathomimetics, acotiamide, ASP8302, neurokinin-2 agonists have been explored but none has shown unequivocal clinical benefit. Different stem cell therapy approaches have been used, chiefly in neurogenic dysfunction, with some studies showing benefit. Molecular targets for the neural axis have included TRPV-4, Bombesin, and serotoninergic receptors and TAC-302 which induces neurite growth. Several options are currently being pursued in the search for an elusive molecular or stem cell option for enhancing the power of the detrusor muscle. These encompass a wide range of approaches that target each aspect of the contraction mechanism including the urothelium of bladder and urethra, myocyte, and neural pathways. While none of these have shown unequivocal clinical utility, some appear promising. Lessons from other fields of medicine might prove instructive. Not necessary. Not a clinical trial.

Antinociceptive and antineuropathic effects of Trifolium resupinatum L. on formalin-induced nociception and cervical spinal cord hemi-contusion: Underlying Mechanisms

Ethnopharmacological relevanceTrifolium resupinatum L. (Fabaceae), known as Persian clover, ethnomedicinally used in Persian folk medicine to treat peritoneal inflammation, rheumatism, and back pain. Aim of the studyTo investigate the antineuropathic and antinociceptive activities of Trifolium resupinatum leaves essential oil (TREO) in male Wistar rats, as well as to explore the potential mechanisms of action. Materials and methodsThe antinociceptive activity of TREO and its main constituents, quercetin (Qc) was assessed using the formalin-induced paw licking test. Moreover, the potential mechanisms of antinociception were evaluated through various competitive and non-competitive antagonisms. Additionally, the antineuropathic potential was investigated using the cervical spinal cord hemi-contusion (CCS) model, and the role of phosphorylated Stat-3 was analyzed using Western blotting. ResultsTREO exerted significant antinociceptive activity (P < 0.01) in both phases of the formalin-induced test; however, its effects were more pronounced in the second phase. Modulators of the NO-cGMP-K+ channel pathway significantly reversed the antinociceptive activity of TREO (P < 0.05). Additionally, antagonists of TRPV1 and TRPV2, as well as CB1 and GABAA receptors, significantly reversed the antinociceptive effects of TREO (P < 0.05). In another study, both TREO and Qc significantly attenuated hyperalgesia and mechanical allodynia (P < 0.01) when evaluated using the CCS-induced nociception model. Notably, TREO also reduced the expression levels of interleukin-1 beta, interleukin-2, and tumor necrosis factor alpha in CCS-induced rats (P < 0.05). ConclusionTREO and Qc exhibit both antinociceptive and anti-neuropathic activities. The antinociceptive effects are partially mediated through the NO-cGMP-K+ channel pathways, along with the activation of TRPV, GABA, and cannabinoid receptors. Furthermore, the anti-neuropathic activity of TREO may be partially regulated through the inhibition of cytokines.

Therapeutic Potential of Capsaicin in Various Neurodegenerative Diseases with Special Focus on Nrf2 Signaling.

Neurodegenerative disease is mainly characterized by the accumulation of misfolded proteins, contributing to mitochondrial impairments, increased production of proinflammatory cytokines and reactive oxygen species, and neuroinflammation resulting in synaptic loss and neuronal loss. These pathophysiological factors are a serious concern in the treatment of neurodegenerative diseases. Based on the symptoms of various neurodegenerative diseases, different treatments are available, but they have serious side effects and fail in clinical trials, too. Therefore, treatments for neurodegenerative diseases are still a challenge at present. Thus, it is important to study an alternative option. Capsaicin is a naturally occurring alkaloid found in capsicum. Besides the TRPV1 receptor activator in nociception, capsaicin showed a protective effect in brain-related disorders. Capsaicin also reduces the aggregation of misfolded proteins, improves mitochondrial function, and decreases ROS generation. Its antioxidant role is due to increased expression of an nrf2-mediated signaling pathway. Nrf2 is a nuclear erythroid 2-related factor, a transcription factor, which has a crucial role in maintaining the normal function of mitochondria and the cellular defense system against oxidative stress. Intriguingly, Nrf2 mediated pathway improved the upregulation of antioxidant genes and inhibition of microglial-induced inflammation, improved mitochondrial resilience and functions, leading to decreased ROS in neurodegenerative conditions, suggesting that Nrf2 activation could be a better therapeutic approach to target pathophysiology of neurodegenerative disease. Therefore, the present review has evaluated the potential role of capsaicin as a pharmacological agent for the treatment and management of various neurodegenerative diseases via the Nrf2-mediated signaling pathway.

Coumarins rather than alkylamides evoke the numbing orosensation of pomelo peel

Liangpingyou, a well-known Chinese pomelo (Citrus grandis L.) variety, elicits a unique and uncharacterized numbing aftertaste. To understand the molecular bases and characteristics of the pomelo-induced numbing sensation, we first determined that hydroxyl sanshools, the major Sichuan pepper chemosensates, were not responsible via silylation-GC–MS analysis. Pomelo peel juice was then subjected to solid-phase extraction to form 4 fractions, and key sensory-active substances were screened via taste dilution analysis. Three simple coumarins, meranzin hydrate, isomeranzin, and marmin, were identified to induce numbing, which has not been previously reported. Sensory studies via extensively modified half-tongue tests and verification steps revealed recognition thresholds within 0.49–1.78, 0.32–1.56, and 0.43–1.46 μmol/L for numbness, pungency, and astringency, respectively. The temporal dominance trends showed the following taste notes: Meranzin hydrate–numbing dominated, isomeranzin–numbing and pungent, and marmin–astringent and numbing. Molecular docking analysis suggested that coumarins target the receptors TRPV1, TPRA1, and KCNK3

Responses to Herbal Compounds in Brain Cancer Cells: two Cell-Calcium Assays and a Molecular Docking Computation Study

Herbal plant secondary metabolites such as curcumin, resveratrol, and capsaicin are becoming increasingly popular as natural remedies. These herbal compounds are also known to act on the calcium signaling pathways, and therefore cell calcium assays can be used to study the relative interactions of these compounds with cellular receptors pertaining to natural remedies. To investigate this, Fluo-4, a fluorophore that specifically binds to Ca2+, was used to detect the increase in calcium signaling in human glioblastoma cells treated with curcumin, resveratrol, and capsaicin. The human cells used are U87 MG cells which expresses TRPV1, a pain receptor on the cell membrane. The increases of the fluorescence intensity in the cells treated with the three herbal compounds were measured using a bulk microplate assay, which generates data in a high throughput, and a microfluidic single-cell assay, which allows for the observation of the cell calcium changes in real-time. It was found that all three compounds would increase the intracellular Ca2+ concentrations on the two assays, with curcumin generating the highest increase, which confirms the greatest responses elicited by this herbal compound from the cell. Furthermore, the data obtained by a molecular docking computation study, which has been used to determine the binding affinities of the three compounds with the TRPV1 receptor, corroborate with the experimental finding of the highest cellular response due to curcumin.

Capsaicin Improves Systemic Inflammation, Atherosclerosis, and Macrophage-Derived Foam Cells by Stimulating PPAR Gamma and TRPV1 Receptors.

Capsaicin, a bioactive compound found in peppers, is recognized for its anti-inflammatory, antioxidant, and anti-lipidemic properties. This study aimed to evaluate the effects of capsaicin on atherosclerosis progression. Apolipoprotein E knockout mice and their C57BL/6 controls were utilized to assess blood lipid profile, inflammatory status, and atherosclerotic lesions. We also examined the influence of capsaicin on cholesterol influx and efflux, and the role of TRPV1 and PPARγ signaling pathways in bone marrow-derived macrophages. Capsaicin treatment reduced weight gain, visceral adiposity, blood triglycerides, and total and non-HDL cholesterol. These improvements were associated with a reduction in atherosclerotic lesions in the aorta and carotid. Capsaicin also improved hepatic oxidative and inflammatory status. Systemic inflammation was also reduced, as indicated by reduced leukocyte rolling and adhesion on the mesenteric plexus. Capsaicin decreased foam cell formation by reducing cholesterol influx through scavenger receptor A and increasing cholesterol efflux via ATP-binding cassette transporter A1, an effect primarily linked to TRPV1 activation. These findings underscore the potential of capsaicin as a promising agent for atherosclerosis prevention, highlighting its comprehensive role in modulating lipid metabolism, foam cell formation, and inflammatory responses.

Capsaicin: Emerging Pharmacological and Therapeutic Insights.

Capsaicin, the most prominent pungent compound of chilli peppers, has been used in traditional medicine systems for centuries; it already has a number of established clinical and industrial applications. Capsaicin is known to act through the TRPV1 receptor, which exists in various tissues; capsaicin is hepatically metabolised, having a half-life correlated with the method of application. Research on various applications of capsaicin in different formulations is still ongoing. Thus, local capsaicin applications have a pronounced anti-inflammatory effect, while systemic applications have a multitude of different effects because their increased lipophilic character ensures their augmented bioavailability. Furthermore, various teams have documented capsaicin's anti-cancer effects, proven both in vivo and in vitro designs. A notable constraint in the therapeutic effects of capsaicin is its increased toxicity, especially in sensitive tissues. Regarding the traditional applications of capsaicin, apart from all the effects recorded as medicinal effects, the application of capsaicin in acupuncture points has been demonstrated to be effective and the combination of acupuncture and capsaicin warrants further research. Finally, capsaicin has demonstrated antimicrobial effects, which can supplement its anti-inflammatory and anti-carcinogenic actions.

Exploring the taste presentation and receptor perception mechanism of salty peptides from Stropharia rugosoannulata based on molecular dynamics and thermodynamics simulation

The taste presentation and receptor perception mechanism of the salty peptide of Stropharia rugosoannulata were predicted and verified using peptide omics and molecular interaction techniques. The combination of aspartic acid (D) and glutamic acid (E), or peptide fragments composed of arginine (R), constitute the characteristic taste structural basis of salty peptides of S. rugosoannulata. The taste intensity of the salty peptide positively correlates with its concentration within a specific concentration range (0.25–1.0 mg/mL). The receptor more easily recognizes the first amino acid residue at the N-terminal of salty peptides and the aspartic acid residue in the peptides. GLU513, ASP707, and VAL508 are the critical amino acid residues for the receptor to recognize salty peptides. TRPV1 is specifically the receptor for recognizing salty peptides. Hydrogen bonds and electrostatic interactions are the main driving forces for the interactions between salty peptides and TRPV1 receptors. KSWDDFFTR has the most potent binding capacity with the receptor and has tremendous potential for application in sodium salt substitution. This study confirmed the taste receptor that specifically recognizes salty peptides, analyzed the receptor-peptide binding interaction, and provided a new idea for understanding the taste receptor perception of salty peptides.

Design and experimental validation of a new radiolabeled analog of N-(3-hydroxy-4-methoxy-phenyl-methyl) ferrocene-carboxamide (VFC) targeting the TRPV1 receptor

The TRPV1 receptor has been recognized to play a role in cancer development, being overexpressed in prostate, breast, lung, and colon cancers. Since TRPV1 activation promotes cancer cell proliferation, invasion, and migration, TRPV1 antagonists may show potential as anti-cancer agents. Capsaicin and capsaicinoids are phytochemicals derived from homovanillic acid found in abundance in chili peppers and responsible for its pungent properties. Capsaicin acts as a potent agonist of TRPV1 with recognized antineoplastic properties. Here, we employ computational approaches including molecular modeling and docking to refine the 3D structure of human TRPV1 and assess its interaction with the newly synthesized N-(3-hydroxy-4-methoxyphenylmethyl)ferrocenecarboxamide (VFC) and its cyclopentadienyl tricarbonyl rhenium and technetium analogs. Radiolabeling of VFC with 99mTc was achieved by double ligand exchange to afford 99mTc-VFC in high radiochemical purity and yield. Biodistribution studies in mice demonstrated preferential accumulation of 99mTc-VFC in the bladder, liver, kidney, and lung. These findings may contribute to developing efficient TRPV1-targeted radiotracers for molecular imaging of tumors by SPECT.

Maintaining calcium homeostasis as a strategy to alleviate nephrotoxicity caused by evodiamine

Evodiamine (EVO), the main active alkaloid in Evodia rutaecarpa, was shown to exert various pharmacological activities, especially anti-tumor. Currently, it is considered a potential anti-cancer drug due to its excellent anti-tumor activity, which unfortunately has adverse reactions, such as the risk of liver and kidney injury, when Evodia rutaecarpa containing EVO is used clinically. In the present study, we aim to clarify the potential toxic target organs and toxicity mechanism of EVO, an active monomer in Evodia rutaecarpa, and to develop mitigation strategies for its toxicity mechanism. Transcriptome analysis and related experiments showed that the PI3K/Akt pathway induced by calcium overload was an important step in EVO-induced apoptosis of renal cells. Specifically, intracellular calcium ions were increased, and mitochondrial calcium ions were decreased. In addition, EVO-induced calcium overload was associated with TRPV1 receptor activation. In vivo TRPV1 antagonist and calcium chelator effects were observed to significantly reduce body weight loss and renal damage in mice due to EVO toxicity. The potential nephrotoxicity of EVO was further confirmed by an in vivo test. In conclusion, TRPV1-mediated calcium overload-induced apoptosis is one of the mechanisms contributing to the nephrotoxicity of EVO due to its toxicity, whereas maintaining body calcium homeostasis is an effective measure to reduce toxicity. These studies suggest that the clinical use of EVO-containing herbal medicines should pay due attention to the changes in renal function of patients as well as the off-target effects of the drugs.

Topically applied novel TRPV1 receptor antagonist, ACD440 Gel, reduces evoked pain in healthy volunteers, a randomized, double-blind, placebo-controlled, crossover study.

The TRPV1 receptor is a key molecule in pain generation. Previous development of oral TRPV1-antagonists was halted due to systemic heat insensitivity and body temperature alterations. The present Phase 1b study investigated the efficacy, safety and plasma exposure of a topically administered TRPV1-antagonist (ACD440 Gel) in healthy subjects. The study comprised two parts. In part 1, 24 healthy subjects were included in this randomized double-blind, placebo-controlled, crossover trial. ACD440 Gel or Placebo was applied once daily and wiped off after 1 h, for 5 consecutive days. Assessments were done in normal skin, skin optimized for penetration (by stripping and occlusive gel application) and UVB-irradiated skin. Pain induced by thermo-nociceptive CO2 laser impulses generated laser-evoked potentials (LEPs), with readouts of peak-to-peak (PtP) amplitude in vertex-EEG and pain assessments by VAS (0-100). Endpoints include effects at 1 hour post-dose, AUC(Days 1-5) and AUC(0-24, Day 4). In UVB-irradiated skin, also pain on pinprick and skin redness were assessed. Part 2 explored the plasma pharmacokinetics of ACD440. ACD440 Gel reduced LEP PtP amplitude and VAS pain, p < 0.001, in all skin conditions, versus placebo. In UVB-irradiated skin, pinprick pain was also reduced, p = 0.047. Effects were significant after 1 h, maintaining for at least 9 h. There were no adverse events or drug-induced erythema. Plasma exposures of ACD440 were too low to establish an elimination half-life of ACD400. Topical ACD440 Gel demonstrated a significant analgesic effect on LEP, VAS score and pinprick pain, with low systemic exposures, supporting further clinical development. This study demonstrates that the topical administration of a TRPV1-antagonist, ACD440 Gel, has potential as a new treatment for painful conditions affecting the skin, such as chronic peripheral neuropathic pain, without any local or systemic side effects.

Cutaneous Application of Capsaicin Cream Reduces Clinical Signs of Experimental Colitis and Repairs Intestinal Barrier Integrity by Modulating the Gut Microbiota and Tight Junction Proteins.

Capsaicin, a pungent compound in chili peppers, is described as having potent anti-inflammatory, antioxidant, and antimicrobial properties. It is also described as a potential modulator of the immune system and intestinal microbiota. Oral or rectal administration of capsaicin has been studied to treat or prevent colitis. However, those vias are often not well accepted due to the burning sensation that capsaicin can cause. Our objective was to evaluate whether the application of capsaicin skin creams (0.075%) would be effective in improving inflammation and epithelial barrier function as well as the composition of the gut microbiota in a model of mild colitis induced by dextran sulfate sodium (1.5%). The results showed that the cutaneous application of capsaicin reversed weight loss and decreased colon shortening and diarrhea, all typical signs of colitis. There was also an improvement in the intestinal epithelial barrier, preserving proteins from tight junctions. We also evaluated the biodistribution of 99mtechnetium-radiolabeled capsaicin (99mTc-CAPS) applied to the back skin of the animals. We found significant concentrations of 99 mTc-Cap in the colon and small intestine after 2 and 4 h of administration. In addition, there was an increased expression of capsaicin receptor TRPV1 in the colon. Moreover, animals with colitis receiving cutaneous capsaicin presented a better short-chain fatty acid profile and increased levels of SIgA, suggesting increased microbiota diversity. In conclusion, our work opens avenues for further studies to better understand capsaicin's potential benefits and mechanisms in addressing colitis through cutaneous application.

Effects of oral administration of nonselective Trk inhibitor on bladder overactivity in rodent models of prostatic inflammation.

Our research focused on the assessment of the impact of systemic inhibition of Trk receptors, which bind to nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF), on bladder hypersensitivity in two distinct rodent models of prostatic inflammation (PI). Male Sprague-Dawley rats were divided into three groups (n = 6 each): the control group (no PI, vehicle administration), the untreated group (PI, vehicle administration), and the treated group (PI, nonselective Trk inhibitor, GNF 5837, administration). PI in rats was induced by a intraprostatic injection of 5% formalin. Posttreatment, we carried out conscious cystometry and a range of histological and molecular analyses. Moreover, the study additionally evaluated the effects of a nonselective Trk inhibitor on bladder overactivity in a mouse model of PI, which was induced by prostate epithelium-specific conditional deletion of E-cadherin. The rat model of PI showed upregulations of NGF and BDNF in both bladder and prostate tissues in association with bladder overactivity and inflammation in the ventral lobes of the prostate. GNF 5837 treatment effectively mitigated these PI-induced changes, along with reductions in TrkA, TrkB, TrkC, and TRPV1 mRNA expressions in L6-S1 dorsal root ganglia. Also, in the mouse PI model, GNF 5837 treatment similarly improved bladder overactivity. The findings of our study suggest that Trk receptor inhibition, which reduced bladder hypersensitivity and inflammatory responses in the prostate, along with a decrease in overexpression of Trk and TRPV1 receptors in sensory pathways, could be an effective treatment strategy for male lower urinary tract symptoms associated with PI and bladder overactivity.

Effective suppression of Ih and INa caused by capsazepine, known to be a blocker of TRPV1 receptor

A synthetic inhibitor of capsaicin-induced TRPV1 channel activation is called capsazepine (CPZ). In this study, we aimed to explore the effects of CPZ on hyperpolarization-activated cationic current (Ih) and voltage-gated Na + current (INa) in pituitary tumor (GH3) cells. Through patch-clamp recordings, we found that CPZ concentration-dependently inhibited Ih amplitude and slowed its activation time course. The IC50 and KD values were 3.1 and 3.16 μM, respectively. CPZ also shifted the steady-state activation curve of Ih towards a more hyperpolarized potential. However, there was no change in the gating charge of the curve. A modified Markovian model predicted the CPZ-induced decrease in the voltage-dependent hysteresis of Ih. CPZ suppressed INa in GH3 cells, without altering its activation or inactivation time course. Additionally, exposure to CPZ reduced spontaneous firing. These findings suggest that CPZ’s inhibitory effects on Ih and INa are direct and not dependent on vanilloid receptor binding. This could provide light on an unidentified ionic mechanism influencing the membrane excitability of neurons and endocrine or neuroendocrine cells in vivo.