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Eugenol, a known vanilloid, was frequently used in dentistry as a local analgesic in addition, antibacterial and neuroprotective effects were also reported. Eugenol, capsaicin and many vanilloids are interacting with the transient receptor potential vanilloid 1 (TRPV1) in mammals and the TRPV1 is activated by noxious heat. The pharmacological manipulation of the TRPV1 has been shown to have therapeutic value. Caenorhabditis elegans (C. elegans) express TRPV orthologs (e.g. OCR-2, OSM-9) and it is a commonly used animal model system to study nociception as it displays a well-defined and reproducible nocifensive behavior. After exposure to vanilloid solutions, C. elegans wild type (N2) and mutants were placed on petri dishes divided in quadrants for heat stimulation. Thermal avoidance index was used to phenotype each tested C. elegans experimental groups. The results showed that eugenol, vanillin and zingerone can hamper nocifensive response of C. elegans to noxious heat (32-35 °C) following a sustained exposition. Also, the effect was reversed 6 h post exposition. Furthermore, eugenol and vanillin did not target specifically the OCR-2 or OSM-9 but zingerone did specifically target the OCR-2 similarly to capsaicin. Further structural and physicochemical analyses were performed. Key parameters for quantitative structure-property relationships (QSPR), quantitative structure-activity relationships (QSAR) and frontier orbital analyses suggest similarities and dissimilarities amongst the tested vanilloids and capsaicin in accordance with the relative anti-nociceptive effects observed.

Despite the apparent abundance of ligand-gated transient receptor potential vanilloid type 1 (TRPV1) and possible cross talk between the endocannabinoid and endovanilloid systems in the central nervous system (CNS), it is unclear what role TRPV1 receptor activation in CNS plays in neurobehavioral development. We previously reported that capsaicin or WIN55212-2 induces risk aversion in the plus-maze test, which was dependent on the gender and mouse strain used. In this study, pregnant BALBc mice were administered capsaicin (1.0 or 4.0 mg/kg, i.p.) during the second week of gestation. Developmental effects of prenatal exposure to capsaicin were assessed in neonates, and behavioral effects were assessed in adult offspring. Gender- and dose-specific variations in ultrasonic vocalizations, weight gain, righting reflex, and general activity of the pups were observed. Prenatal exposure to capsaicin altered plus-maze performance, especially with further exogenous capsaicin challenge. Furthermore, dose- and gender-specific effects were evident in the conditioned place preference/aversion paradigm following conditioning with capsaicin in adult animals. The capsaicin-induced aversion in the plus-maze test was enhanced by WIN55212-2 and blocked by pretreatment with vanilloid antagonist capsazepine or the CB(1) receptor antagonist rimonabant, demonstrating an interaction between the endocannabinoid and endovanilloid systems in CNS. Taken together, the interaction between the endocannabinoid and endovanilloid signaling systems can be exploited for therapeutic applications in health and disease.

Agents that block the efferent function of micturition reflex, such as antimuscarinics, are currently first-line therapy for overactive bladder (OAB) and neurogenic detrusor overactivity. Many urologists believe that the actual “efferent” pharmacologic management of OAB is not completely satisfactory. Consequently, research is trying to address issues of efficacy, tolerability, and convenience of new therapeutic strategies targeting the “afferent” function. This article discusses the rationale underlying the development of new drugs and the use of electrical modulation to manage lower urinary tract dysfunctions. It also offers insight into the mechanism of action, efficacy, side effects, and market status of several drugs that target the afferent branch of micturition reflex (vanilloids, botulinum toxin, tachykinin, nociceptin/orphanin FQ) and sacral neuromodulation.

Intravesical therapy with botulinum toxin type A (BTX-A) and vanilloids (capsaicin and resiniferatoxin) are actively investigated as potential treatments for lower urinary tract symptoms refractory to conventional therapy in patients with neurogenic detrusor overactivity. BTX-A cleaves soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) proteins in afferent and efferent nerve endings, impeding the fusion of synaptic vesicles with the neuronal membrane necessary for the release of neurotransmitters. Vanilloids desensitize the transient receptor potential vanilloid type 1 receptor and inactivate C-fibers. BTX-A intradetrusor injections are extremely effective for treating urinary incontinence, provide adequate protection of the upper urinary tract, and improve quality of life in patients with neurogenic detrusor overactivity. Therefore, BTX-A is currently the mainstay of intravesical therapy. However, despite promising results overall, the administration of these compounds, including BTX-A, remains an experimental procedure requiring further clinical studies.

Capsaicin, the pungent ingredient of hot chilli pepper, has been recently shown to induce apoptosis in several cell lines through a not well known mechanism. Here, we investigated the role of the vanilloid capsaicin in the death regulation of the human cancer androgen-resistant cell line PC-3. Capsaicin inhibited the growth of PC-3 with an IC(50) of 20 microM cells and induced cell apoptosis, as assessed by flow cytometry and nuclei staining with DAPI. Capsaicin induced apoptosis in prostate cells by a mechanism involving reactive oxygen species generation, dissipation of the mitochondrial inner transmembrane potential (DeltaPsi(m)) and activation of caspase 3. Capsaicin-induced apoptosis was not reduced by the antagonist capsazepine in a dose range from 0.1 microM to 20 microM, suggesting a receptor-independent mechanism. To study the in vivo effects of capsaicinoids, PC-3 cells were grown as xenografts in nude mice. Subcutaneous injection of either capsaicin or capsazepine (5 mg/kg body weight) in nude mice suppressed PC-3 tumor growth in all tumors investigated and induced apoptosis of tumor cells. Our data show a role for capsaicin against androgen-independent prostate cancer cells in vitro and in vivo and suggest that capsaicin is a promising anti-tumor agent in hormone-refractory prostate cancer, which shows resistance to many chemotherapeutic agents.

The shift in nutritional sciences from survival and safety to the promotion of well-being has led to systematic investigations on the biological activity of natural products of dietary origin, questioning the assumption that food plants contain little if any secondary metabolites apart those revealed by our senses and responsible for their colour, taste, and flavour. With 25% of the human population consuming chilli pepper every day, capsaicin is the most important pharmacological agent we get from our diet, and the study of its pungency set in motion a multidisciplinary investigation that ultimately led to the discovery of vanilloid receptors (TRPVs), a class of ion channels involved in thermo-, chemo-, and mechanosensation, and whose malfunctioning is implicated in neurogenic inflammation and a host of other pathological conditions. A series of studies centred on the modification of capsaicin will be described, focusing on a) the preparation of a library of unnatural natural capsaicinoids and the identification of leads with the lipophilic C-moiety amenable to structure-activity study, and b) the reversal of the biological activity of capsaicin from a TRPV1 agonist into an antagonist by modification of its vanillyl moiety.

Chemical compounds that contain the vanillyl moiety (4-hydroxy-3-methoxybenzyl) are collectively classified as vanilloids. Vanilloid phytochemicals can be found in a variety of sources, some of which are routinely consumed by humans throughout the world. The dietary and/or medicinal use of vanilloids may be effective in inhibiting or reversing carcinogenesis, which has sparked a considerable interest in these compounds as potential chemopreventive or chemotherapeutic agents. Certain vanilloids are also valuable as pharmacological tools for investigating neurobiology, and have been proven effective in alleviating neurogenic pain and inflammation. Recently several vanilloids have demonstrated the ability to induce apoptosis in various cell types. Vanilloids can interact with proteins and membranes to initiate pleiotropic effects, some of which are potentially cytotoxic. Certain vanilloids bind to cation channels on nociceptive sensory neurons to regulate Ca2+ uptake, which can promote neurotoxicity resulting in apoptosis and necrosis. Furthermore, some vanilloids appear to interfere with enzymatic processes in the plasma membrane and the mitochondria by functioning as coenzyme Q antagonist. This can promote reactive oxygen species production and/or the disruption of redox homeostasis resulting in apoptosis. This review will examine the cellular targets, cytotoxic effects, and the downstream effector mechanisms associated with vanilloid-induced apoptosis.

Capsaicin or vanilloid receptors (VRs) participate in the sensation of thermal and inflammatory pain. The cloned (VR1) and native VRs are non-selective cation channels directly activated by harmful heat, extracellular protons and vanilloid compounds. However, considerable attention has been focused on identifying other signalling pathways in VR activation; it is known that VR1 is also expressed in non-sensory tissue and may mediate inflammatory rather than acute thermal pain. Here we show that activation of protein kinase C (PKC) induces VR1 channel activity at room temperature in the absence of any other agonist. We also observed this effect in native VRs from sensory neurons, and phorbol esters induced a vanilloid-sensitive Ca2+ rise in these cells. Moreover, the pro-inflammatory peptide, bradykinin, and the putative endogenous ligand, anandamide, respectively induced and enhanced VR activity, in a PKC-dependent manner. These results suggest that PKC may link a range of stimuli to the activation of VRs.

Target-specific drugs, including natural products, offer promise for the amelioration of cancer and other human ailments with reduced side-effects. Capsaicin, the pungent ingredient present in chillies (Capsicum annuum L.), and capsazepine, a synthetic analogue of capsaicin (collectively referred to as vanilloids), are known to possess a variety of pharmacological and physiological properties. In our continuous effort to discover cancer chemopreventive agents from natural products, we investigated the effect of vanilloids on NFκB activation with stably transfected 293/NFκB-Luc human embryonic kidney cells induced by treatment with tumor necrosis factor (TNFα), and aromatase activity. Capsaicin and capsazepine blocked TNFα-induced NFκB activation in a dose-dependent manner with IC50 values of 13.5 and 8.5 μM, respectively. No cytotoxicity was observed at higher test concentration (20 μg/mL). In addition, these vanilloids inhibited aromatase activity with IC50 values of 0.68 and 4.21 μM, respectively. Computer aided molecular docking studies showed acceptable docking scores indicating good binding affinity of vanilloids with aromatase and NFκB. Based on these findings, aromatase and NFκB are suggested as valid targets for these compounds; additional investigation of chemopreventive or chemotherapeutic potential is required.

We have recently reported the specific binding of [3H]resiniferatoxin to sensory ganglion membranes; this binding appears to represent the postulated vanilloid (capsaicin) receptor. In the present report, we compare the structure/activity relations for binding to rat dorsal root ganglion membranes and for biological responses in the rat, using a series of vanilloids of the capsaicin (homovanilloyl-decylamide, homovanilloyl-dodecylamide, homovanilloyl-cyclododecylamide, homovanilloyl-hexadecylamide, homovanilloyl-piperidine and nonenoyl-homoveratrylamide) and resiniferatoxin (tinyatoxin, 12-deoxyphorbol 13-phenylacetate 20-homovanillate) classes. We find that all the tested biologically active vanilloids, but not the inactive structure analogs, compete for the [3H]resiniferatoxin binding sites in rat dorsal root ganglion membranes, and we conclude that the [3H]resiniferatoxin binding assay may provide an efficient approach for evaluating such compounds. We also provide evidence that the [3H]resiniferatoxin receptor is likely to recognize vanilloids which are inserted into the membranes; and that the apparent activity of capsaicinoids may be significantly influenced by factors other than equilibrium binding affinities.