Role Of Transient Receptor Potential Vanilloid 1 Channels Research Articles

Research Trend in The Inhibition of Transient Receptor Potential Vanilloid 1 (TRPV1): Bibliometric Analysis and Visualization

This study aimed to provide a comprehensive overview of the research trend in transient receptor potential vanilloid 1 (TRPV1) inhibition and modulation. A bibliometric analysis of peer-reviewed articles and reviews published from 2003 until 2022 in the Scopus database was conducted. A total of 7,470 publications were retrieved and distributed over 140 countries and published by 23,875 authors. The number of publications was increasing over the determined period, indicating a steady upward trend. Approximately 80% of the total extracted publications were research articles. The leading country in this research field is the United States of America. The top publishing journal was the British Journal of Pharmacology. The most frequent keywords included TRPV1, pain, and capsaicin. Analysis of authors-keywords pointed to the role of TRPV1 inhibition in numerous conditions including cancer, inflammation, oxidative stress, pruritus, osteoarthritis, migraine, the endocannabinoid system, nitric oxide, and endothelium relaxation. This study revealed most of the research was focused on the role of TRPV1 channels in pain. However, TRPV1 has been implicated in different pathological conditions. This implication should be translated into the development of therapeutic strategy, and efforts should be expanded into new clinical indications and novel drug discovery.

TRPV1 Exaggerates Cardiovascular Responses to Physical Exercise in Normotensive but Not in Hypertensive Rats

IntroductionThe transient receptor potential vanilloid‐1 (TRPV1) is an ion channel involved in several physiological responses, including arterial pressure regulation. This channel seems to have an important role in endothelium‐dependent and ‐independent vasodilation. In spontaneously hypertensive rats (SHRs), chronic treatment with a TRPV1 agonist decreases mean arterial pressure, which makes the TRPV1 a potential target for hypertension treatment. We have already shown that in normotensive rats, the acute blockage of TRPV1 channels leads to an exaggerated increase in mean arterial pressure and heart rate during physical exercise. Therefore, in this study we investigated whether the role of TRPV1 channels in cardiovascular responses during physical exercise is affected by arterial hypertension.MethodsMale Wistar normotensive and Wistar‐Kyoto SHRs (16–19 wk) were implanted with an intra‐arterial (ascending aorta) catheter to measure arterial pressure. The rats received an intra‐arterial injection of a TRPV1 antagonist N‐(4‐[6‐(4‐trifluoromethyl‐phenyl)‐pyrimidin‐4‐yloxy]‐benzothiazol‐2‐yl)‐acetamide (AMG 517, 60 μg/kg) or vehicle (20% ethanol in saline) and then were subjected to an incremental‐speed treadmill running at 24°C until fatigue. The pulsatile arterial pressure (which allowed the determination of mean, systolic and diastolic arterial pressures and the heart rate) was measured throughout the exercise period.ResultsIn both normotensive rats and SHR, the incremental exercise increased mean, systolic and diastolic arterial pressures and the heart rate (for mean arterial pressure, fatigue: Normotensive: 126 ± 3 mmHg; SHR: 165 ± 4 mmHg versus beginning of exercise: Normotensive: 108 ± 4 mmHg; SHR: 158 ± 5 mmHg). As expected, in the normotensive rats, the AMG 517 led to a greater exercise‐induced increases in the mean, systolic and diastolic arterial pressures and in the heart rate. In contrast, the TRPV1 antagonist had no effect on any of the cardiovascular variables evaluated in the SHRs (for mean arterial pressure, min 19: AMG 517: 161 ± 5 mmHg; Vehicle 164 ± 4 mmHg). The changes (values at fatigue minus values at the beginning of exercise) in the mean arterial pressure (Normotensive: 20.1 ± 1.8 mmHg versus SHR 10.5 ± 3.3 mmHg; p < 0.05) as well as in the heart rate (Normotensive: 196 ± 13 bpm versus SHR: 149 ± 9 bpm, p < 0.05) were greater in normotensive rats than in SHRs when the incremental exercise was performed after the TRPV1 antagonist injection.ConclusionsDespite inducing marked alterations in blood pressure regulation in the normotensive rats, the TRPV1 antagonist injection did not modify the cardiovascular responses to exercise in the SHRs, which suggests that the arterial hypertension affects the TRPV1‐mediated mechanism involved in arterial pressure regulation during exercise.Support or Funding InformationCAPES, CNPq and FAPEMIG.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Effects of neonatal treatment with the TRPV1 agonist, capsaicin, on adult rat brain and behaviour

Treatment of neonatal rats with the transient receptor potential vanilloid 1 (TRPV1) channel agonist, capsaicin, produces life-long loss of sensory neurons expressing TRPV1 channels. Previously it was shown that rats treated on day 2 of life with capsaicin had behavioural hyperactivity in a novel environment at 5–7 weeks of age and brain changes reminiscent of those found in subjects with schizophrenia. The objective of the present study was to investigate brain and behavioural responses of adult rats treated as neonates with capsaicin. It was found that the brain changes found at 5–7 weeks in rats treated as neonates with capsaicin persisted into adulthood (12 weeks) but were less in older rats (16–18 weeks). Increased prepulse inhibition (PPI) of acoustic startle was found in these rats at 8 and 12 weeks of age rather than the deficit commonly found in animal models of schizophrenia. Subjects with schizophrenia also have reduced flare responses to niacin and methylnicotinate proposed to be mediated by prostaglandin D2 (PGD2). Flare responses are accompanied by cutaneous plasma extravasation. It was found that the cutaneous plasma extravasation responses to methylnicotinate and PGD2 were reduced in capsaicin-treated rats. In conclusion, several neuroanatomical changes observed in capsaicin-treated rats, as well as the reduced cutaneous plasma extravasation responses, indicate that the role of TRPV1 channels in schizophrenia is worthy of investigation.

Neuroprotection induced by N-acetylcysteine against cytosolic glutathione depletion-induced Ca2+ influx in dorsal root ganglion neurons of mice: Role of TRPV1 channels

Glutathione (GSH) and N-acetylcysteine (NAC) are thiol-containing antioxidants, and also act through a direct reaction with free radicals. Transient receptor potential vanilloid 1 (TRPV1) is the principal transduction channel serving as a polymodal detector. Despite the importance of oxidative stress in pain sensitivity, its role in TRPV1 modulation is poorly understood. NAC may also have a regulator role on TRPV1 channel activity in the dorsal root ganglion (DRG) neuron. Therefore, we tested the effects of GSH and NAC on TRPV1 channel current, Ca2+ influx, oxidative stress and caspase activity in the DRG of mice.DRG neurons were freshly isolated from mice and the neurons were incubated for 6 and 24h with buthionine sulfoximine (BSO). Pretreatment of cultured DRG neurons with NAC, results in a protection against oxidative damages. This neuroprotection is associated with the attenuation of a Ca2+ influx triggered by oxidative agents such as H2O2, 5,5′-dithiobis-(2-nitrobenzoic acid) and GSH depletion via BSO. Here, we demonstrate the contribution of cytosolic factors (related to thiol group depletion) on the activation of TRPV1 channels in this mechanism. TRPV1 channels are activated by various agents including capsaicin (CAP), the pungent component of hot chili peppers, and are blocked by capsazepine. An oxidative environment also increased CAP-evoked TRPV1 currents in the neurons. When NAC and GSH were included in the patch pipette as well as extracellularly in the chamber, TRPV1 channels were not activated by CAP and H2O2. TRPV1 inhibitors, 2-aminoethyl diphenylborinate and N-(p-amylcinnamoyl)anthranilic acid strongly reduced BSO-induced oxidative toxicity and Ca2+ influx, in a manner similar to pretreatment with NAC and GSH. Caspase-3 and -9 activities of all groups were not changed by the agonists or antagonists.In conclusion, in our experimental model, TRPV1 channels are involved in the oxidative stress-induced neuronal death, and negative modulation of this channel activity by GSH and NAC pretreatment may account for their neuroprotective activity against oxidative stress.

TRPV1 Channels Regulate Cortical Excitability in Humans

Studies in rodents show that transient receptor potential vanilloid 1 (TRPV1) channels regulate glutamate release at central and peripheral synapses. In humans, a number of nonsynonymous single-nucleotide polymorphisms (SNPs) have been described in the TRPV1 gene, and some of them significantly alter the functionality of the channel. To address the possible role of TRPV1 channels in the regulation of synaptic transmission in humans, we studied how TRPV1 genetic polymorphisms affect cortical excitability measured with transcranial magnetic stimulation (TMS). Two SNPs of the TRPV1 gene were selected and genotyped (rs222747 and rs222749) in a sample of 77 healthy subjects. In previous cell expression studies, the "G" allele of rs222747 was found to enhance the activity of the channel, whereas rs222749 had no functional effect. Allelic variants in the rs222749 region were not associated with altered cortical response to single, paired, and repetitive TMS. In contrast, subjects homozygous for the G allele in rs222747 exhibited larger short-interval intracortical facilitation (a measure of glutamate transmission) explored through paired-pulse TMS of the primary motor cortex. Recruitment curves, short-interval intracortical inhibition, intracortical facilitation, and long-interval intracortical inhibition were unchanged. LTP- and LTD-like plasticity explored through intermittent or continuous theta-burst stimulation was also similar in the "G" and "non-G" subjects. To our knowledge, our results provide the first evidence that TRPV1 channels regulate cortical excitability to paired-pulse stimulation in humans.

Anion size modulates salt taste in rats

The purpose of this study was to investigate the influence of anion size and the contribution of the epithelial sodium channel (ENaC) and the transient receptor potential vanilloid-1 (TRPV1) channel on sodium-taste responses in rat chorda tympani (CT) neurons. We recorded multiunit responses from the severed CT nerve and single-cell responses from intact, narrowly tuned and broadly tuned, salt-sensitive neurons in the geniculate ganglion simultaneously with stimulus-evoked summated potentials to signal when the stimulus contacted the lingual epithelium. Artificial saliva served as the rinse and solvent for all stimuli (0.3 M NH(4)Cl, 0.5 M sucrose, 0.03-0.5 M NaCl, 0.01 M citric acid, 0.02 M quinine hydrochloride, 0.1 M KCl, and 0.03-0.5 M Na-gluconate). We used the pharmacological antagonist benzamil to assess NaCl responses mediated by ENaC, and SB-366791 and cetylpyridinium chloride to assess responses mediated by TRPV1. CT nerve responses were greater to NaCl than Na-gluconate at each concentration; this was attributed mostly to broadly tuned, acid-generalist neurons that responded with higher frequency and shorter latency to NaCl than Na-gluconate. In contrast, narrowly tuned NaCl-specialist neurons responded more similarly to the two salts, but with subtle differences in temporal pattern. Benzamil reduced CT nerve and single-cell responses only of narrowly tuned neurons to NaCl. Surprisingly, SB-366791 and cetylpyridinium chloride were without effect on CT nerve or single-cell NaCl responses. Collectively, our data demonstrate the critical role that apical ENaCs in fungiform papillae play in processing information about sodium by peripheral gustatory neurons; the role of TRPV1 channels is an enigma.