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Ion Channels of Reward Pathway in Drug Abuse
Published in Tian-Le Xu, Long-Jun Wu, 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).
Molecular Mechanisms of Nociception
Published in Gary W. Jay, 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).
Investigating potential TRPV1 positive feedback to explain TRPV1 upregulation in airway disease states
Published in Drug Development and Industrial Pharmacy, 2021
Jesse Xu, Maliheh Ghadiri, Maree Svolos, Brent McParland, Daniela Traini, Hui Xin Ong, Paul M. Young
The release of substance P from airway epithelium cells because of TRPV1 activity is likely to act on airway smooth muscle to induce bronchoconstriction without neuronal input [57]. This was confirmed through the administration of capsaicin on ex vivo guinea pig airway tissue, which showed a contraction response in airway smooth muscle (Figure 5). The concentration required to elicit a 50% of maximal airway contraction (EC50) of 113.7 nM was determined for capsaicin, and this concentration was abated using TRPV1 antagonist, capsazepine by a 2.5-fold increase in EC50 (Table 1). This suggests that asthmatics may encounter worsening of airflow obstruction through airway constriction following exposure to capsaicin or any form of TRPV1 stimulation [58]. It was also found that capsazepine did not significantly inhibit the activity of capsaicin on bronchoconstriction in guinea pig trachea except in low concentrations (100 nM; Figure 5). As capsazepine is a competitive antagonist of TRPV1 channels, it is predicted that at higher concentrations of the agonist capsaicin, its activity had surmounted the affinity of capsazepine. A higher concentration of capsazepine will likely inhibit the contraction response of capsaicin at higher concentrations, however, issues of toxicity with capsazepine will also need to be considered. Consequently, it may be difficult to use the TRPV1 antagonist as a sole drug for antitussive or anti-inflammatory action due to uncertainty in its therapeutic window [44,59]. This is further shown in mixed effects of interleukin levels in airway epithelium following TRPV1 activation. In BEAS-2B cell lines, capsaicin at 10 µM concentration observed lowered levels in IL-6, and in Calu-3 cells, higher IL-8 levels were observed after 20 µM capsaicin exposure. These effects were not replicated for other concentrations of capsaicin and suggest that there is high variability in interleukin production following TRPV1 activation between cell lines.
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
However, TRPV1 channels were most investigated for their role in nociception in sensory neurons, several groups demonstrated that TRPV1 channels have broader effects on different tissues [40,41]. Therefore, understanding the role of TRPV1 channels in different pathologies and systems has utmost importance to use pharmacological tools for TRPV1 channels in diseases of the central nervous system. Recent studies demonstrated that TRPV1 plays a role in locomotion, emotion, and cognitive behaviors [10]. TRPV1 channels in brain regions such as dopaminergic neurons, thalamus, basal ganglia, hypothalamus, periaqueductal gray, cerebellar cortex, neurons in the locus coeruleus, and various layers of the cortex indicate the role of these channels in emotional responses. Genetic deletion of TRPV1 channels tended to have higher scores in several activity tests directly related to locomotor activity [19]. In our study, capsaicin suppressed and capsazepine exacerbated ouabain-induced locomotor activity. Furthermore, rearing numbers were also evaluated, and as seen in the locomotor activity, capsaicin inhibited ouabain-induced rearing. Although capsazepine increased the rearing numbers, that effect was prevented by co-treatment with capsaicin, which in line with our locomotor activity results. However, the effect of TRPV1 channels in depression is controversial [42,43]. Several reports demonstrated that TRPV1 channels mediate long-term depression and activation of these channels is responsible for depression and anxiety behavior [10]. In contrast, the effect of activation of TRPV1 channels with selective agonists showed antidepressant effects in a considerable number of papers [44]. In our study, ouabain-induced anhedonia and depression were prevented by TRPV1 agonism with capsaicin. Additionally, capsazepine administration exacerbated ouabain-induced depression. However, our results are contradictory with previous reports in which capsazepine showed the anxiolytic effect [45]. Nevertheless, we thought there might be two possible reasons for this discrepancy. First, impaired cellular ion homeostasis with ouabain might affect cellular mechanisms that mediate long-term potentiation and depression in the hippocampal neurons resulting in the altered depressive state. Second, Valvassori et al. demonstrated that ouabain-induced depressive state appears nine days after ouabain injection, which means the drug treatment period might not be enough to observe the effects of our treatments on the depressive state [6]. Therefore, we hypothesized that the difference we found possibly due to the treatment period.