Ion Channels of Reward Pathway in Drug Abuse
Tian-Le Xu, Long-Jun Wu in Nonclassical Ion Channels in the Nervous System, 2021
A study has shown that knockout of Trpv1 led to higher alcohol addiction susceptibility in mice (Blednov and Harris 2009), which suggests a possible role of TRPV1 in drug addiction. Besides alcohol, another study on methamphetamine addiction found that the expression of Trpv1 mRNA increased specifically in the frontal cortex but not in the striatum or the hippocampus of mice up to a week after three consecutive methamphetamine injections (Tian et al. 2010). Interestingly, mice showing methamphetamine-induced conditioned place preference exhibited Trpv1 mRNA and protein expression increase in NAc (Tian et al. 2018), which might indicate different patterns of TRPV1 activation in the reward pathway. Furthermore, inhibition of TRPV1 with capsazepine resulted in an inhibition of addiction-related behaviors, and similar results were also reported on cocaine- and morphine-induced conditioned place preference or self-administration (Hong et al. 2017; You et al. 2019; Ma et al. 2018).
Proinflammatory Peptides in Relation to Other Inflammatory Mediators
Sami I. Said in Proinflammatory and Antiinflammatory Peptides, 2020
Low-pH media are often encountered in the body, either in physiological (gastric juice, or urine) or pathophysiological (sites of injury or inflammation, venous blood from infarcted cardiac tissue) conditions. Protons, depending on their concentration in the medium, may initiate either protective inflammatory responses or, if the pH is markedly low and not buffered efficiently, may lead to tissue damage and cell death. Low-pH media (pH 6.5–5) may also excite capsaicin-sensitive sensory neurons and activate their secretory function, thereby causing neurogenic inflammation (4). Protons can be regarded as a typical example of agents that may stimulate sensory neurons via direct or indirect mechanisms. Exposure to low-pH media of slices of rat or guinea pig tissues was found to evoke a Ca2+-dependent release of CGRP (5,6), as well as inward current to cations in dorsal root ganglion (7) or trigeminal ganglion neurons in culture (8). These effects are blocked by capsazepine, a compound that antagonizes the effect of capsaicin (9,10), presumably by inhibiting the capsaicin-activated “receptor” (11), and by ruthenium red, an inorganic dye which blocks Ca2+ influx through the capsaicin-activated receptor/channel (12). These observations suggested the hypothesis that protons produce excitation of sensory nerves directly, by stimulation of the channel/receptor activated by capsaicin. The fact that capsazepine abolished the cough response to citric in guinea pigs supports the hypothesis that protons could also activate the capsaicin “receptor” on sensory nerves also in invivo conditions (13).
Molecular Mechanisms of Nociception
Gary W. Jay in Chronic Pain, 2007
Small molecule agonists of TRPV1 [capsaicin and resiniferatoxin (RTX)] are used for a number of clinical syndromes in animal studies, including intractable neuropathic pain, spinal detrusor hyperreflexia, and bladder hypersensitivity. Vanilloid receptor 1 (VR1) antagonists have yet to reach the clinic. Capsazepine is the classic TRPV1 antagonist but it demonstrates poor pharmacokinetics and significant species selectivity issues in the laboratory (47).
A new era for the design of TRPV1 antagonists and agonists with the use of structural information and molecular docking of capsaicin-like compounds
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2022
Julio Caballero
Capsaicin-like TRPV1 ligands have a well-defined pharmacophore, composed by a consecutive disposition of three chemical features: head, neck, and tail groups (Figure 1). Capsaicin-like TRPV1 ligands bind to a large pocket formed by transmembrane domains, where they adopt a “tail-up, head-down” configuration, placing the head close to the S4–S5 linker36. Head, neck, and tail, also designed as A-, B-, and C-regions, can be easily identified in capsaicin, where the vanilloid (4-hydroxy-3-methoxyphenyl) group is in the A-region, amide is in the B-region, and the lipophilic chain of the 8-methyl-6-nonenoic acid is in the C-region. It is possible to identify these pharmacophoric features in TRPV1 agonists and antagonists. For instance, the agonist MDR-652 contains the 3-fluoro-4-(hydroxymethyl)phenyl in the A-region, urea in the B-region, and 2-(tert-butyl)-4–(3-chlorophenyl)thiazole in the C-region. On the other hand, the antagonist capsazepine contains the 2,3,4,5-Tetrahydro-1H-2-benzazepine-7,8-diol in the A-region, thiourea in the B-region, and 4-chlorophenyl)ethyl in the C-region. Figure 2 shows examples of TRPV1 agonists and antagonists, where the pharmacophoric features are represented.
Role of TRPV1 channels on glycogen synthase kinase-3β and oxidative stress in ouabain-induced bipolar disease
Published in Journal of Receptors and Signal Transduction, 2022
Osman Kukula, Mustafa Nusret Çiçekli, Sinan Şafak, Caner Günaydın
Elevated plus maze test was also performed to investigate the effect of drug treatments on depression (Figure 2(B)). Ouabain (48.3 ± 4.08) significantly decreased the number of open arm entries compared to the control (78.4 ± 5.52, p < 0.001, Figure 2(B)). Although capsaicin at the doses of 0.5 (36.1 ± 14.5) and 1 mg/kg (63 ± 15.2) did not change the number of open arm entries, it attenuated the ouabain-induced decrease in the open arm entries at the dose of 2 mg/kg (71.1 ± 6.89, p = 0.038, Figure 2(B)). However, capsazepine at 1.25 (32.2 ± 14.7) and 2.5 mg/kg (33.6 ± 3.06) doses did not significantly affect the number of open arm entries compared to the ouabain group (p > 0.05, Figure 2(B)). However, capsazepine at the dose of 5 mg/kg (20.4 ± 7.29) decreased the number of entries to open arms (p < 0.001, Figure 2(B)). Additionally, lithium prevented the ouabain-induced decrease in the number of open arm entries (82.6 ± 10.8, p < 0.001, Figure 2(B)).
Calcium-dependent, non-apoptotic, large plasma membrane bleb formation in physiologically stimulated mast cells and basophils
Published in Journal of Extracellular Vesicles, 2019
C. Jansen, C Tobita, E. U. Umemoto, J. Starkus, N. M. Rysavy, L. M. N. Shimoda, C. Sung, A.J. Stokes, H Turner
General chemicals were from VWR (West Chester, PA, USA) and Sigma Aldrich (St. Louis, MO, USA). Phorbol myristate acetate (PMA) and ionomycin were from Calbiochem (Gibbstown, NJ, USA). IgE anti-di-nitro phenol (anti-DNP) is from Sigma and KLH-DNP was from Calbiochem. Bee venom was from HollisterStier (Spokane, WA, USA). To mitigate batch-to-batch variation in venom, three independent batches were selected on the basis of similar potency for induction of histamine release in control experiments, mixed, aliquoted and used for the duration of the studies presented here. Mastoparan and mellitin were from Sigma Aldrich. Arachidonic acid was from Enzo (Farmingdale, NY, USA). 2-Aminoethoxydiphenyl borate (2-APB) was from Calbiochem (LaJolla, CA, USA). Capsaicin and capsazepine were from Sigma Aldrich.
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