The rationale for the topical application of capsaicin and other vanilloids in the treatment of pain is that such compounds selectively excite and subsequently desensitize nociceptive neurons. This desensitization is triggered by the activation of vanilloid receptors (TRPV1), which leads to an elevation in intracellular free Ca2+ levels. Depending on the vanilloid concentration and duration of exposure, the Ca2+ influx via TRPV1 desensitizes the channels themselves, which may represent not only a feedback mechanism protecting the cell from toxic Ca2+ overload, but also likely contributes to the analgesic effects of capsaicin. This review summarizes the current state of knowledge concerning the mechanisms that underlie the acute capsaicin-induced Ca2+-dependent desensitization of TRPV1 channels and explores to what extent they may contribute to capsaicin-induced analgesia. In view of the polymodal nature of TRPV1, we illustrate how the channels behave in their desensitized state when activated by other stimuli such as noxious heat or depolarizing voltages. We also show that the desensitized channel can be strongly reactivated by capsaicin at concentrations higher than those previously used to desensitize it. We provide a possible explanation for a high incidence of adverse effects of topical capsaicin and point to a need for more accurate clinical criteria for employing it as a reliable remedy., L. Vyklický, K. Nováková-Toušová, J. Benedikt, A. Samad, F. Touška, V. Vlachová., and Obsahuje bibliografii a bibliografické odkazy
Membrane currents induced by capsaicin (CAPS) in cultured sensory neurons from 1- to 2-day-old rats were studied. Responses to CAPS (lO^M) exceeding 1 nA at -50 mV were found in smaller, usually bipolar or tripolar neurons in which GABA (30 yuM) induced small or no response. Large, unipolar neurons, which exhibited large responses to GABA, were completely insensitive to CAPS (10//M). In contrast to GABA, responses to CAPS exhibited a slow rise and slow decay and a marked tachyphylaxis after repeated CAPS applications at high concentrations which made it difficult to study the concentration-response relationship. In partially run-down neurons, which exhibited quasi stable responses, the slope of the ascending phase was concentration-dependent with an apparent association rate constant Ki 9x104 [M-1s-1]. The time constant of the decay was 3.5 s, and was concentration-independent. However, in 5 neurones the EC50 measured from the first series of CAPS applications at increasing concentrations was 0.31 ±0.5ptA with a Hill coefficient 1.66±0.35. The responses to CAPS reversed at +10.4±2.5 mV suggesting that the current is carried nonselectively by monovalent cations and Ca2+. The channel conductance of CAPS-gated channels at -50 mV calculated from the mean membrane current and variance of the current noise in outside-out patches or measured directly was 28 pS (n=5). It is suggested that the CAPS-gated channels are either controlled by receptors with a very high affinity or that the channels are controlled by membrane-bound protein(s) which do not depend in their function on the supply of GTP or other intracellular metabolites.
Capsazepine is a competitive antagonist of capsaicin, a TRPV1 agonist responsible for the spicy taste of pepper. TRPV1 agonists and antagonists are known to affect mammalian body temperature, but their action on thermoregulation in insects is poorly known. In this study we evaluated the effect of capsazepine on the thermal preference of the American cockroach, Periplaneta americana using a thermal gradient. Our results revealed that capsazepine in submicromolar concentrations induces a preference for higher ambient temperatures when compared to the control insects. To assess whether capsazepine may act also as an antagonist of capsaicin in insects, we determined this insects' thermal behaviour when capsazepine was applied before capsaicin. The hypothermic response to capsaicin was clearly blocked by pre-treatment with capsazepine only in female American cockroaches. Our results indicate the involvement of structures functionally similar to TRPV1 in insect thermosensation., Justyna Maliszewska, Eugenia Tęgowska., and Obsahuje bibliografii
The role of afferent sensory neurones in gastric mucosal protection is discussed. The principal effects of substance P and capsaicin on gastric motility and mucosal blood flow are taken in correlation with gastric mucosal injury. It seems likely that the protective effect of sensory neuropeptides is dependent on gastric mucosal blood flow and is mediated through the nitric oxide-generating system and partly the prostaglandins. The interaction between these two systems and the primordial effect of one of them on gastric mucosal blood flow and mucosal integrity after neuropeptide release is still not clear.
Extracts of Helleborus roots were traditionally used in the Balkan area for their analgesic action. We report that the pure natural product MCS-18 isolated from this source is a potent, specific and reversible antagonist of the capsaicin receptor, TRPV1, expressed in rat dorsal root ganglion (DRG) neurons. TRPV1 is a nonselective cation channel expressed in a subset of cutaneous and visceral sensory nerve endings and activated by noxious heat, acidity and fatty acid metabolites of arachidonic acid, with a decisive role in inflammatory heat hyperalgesia. MCS-18 inhibited the increase in intracellular calcium concentration evoked in DRG neurons by capsaicin (300 nM) and low pH (5.5) but not by heat (43 ºC). The substance had no effect on the responses mediated by acid-sensing ion channels (ASICs) or the irritant receptor TRPA1. Whole-cell patch-clamp was used to confirm the inhibition of capsaicin-induced currents by MCS-18 which was dose-dependent. The mechanism of inhibition does not require an intact cell, as capsaicin-induced currents were also inhibited in the excised outside-out configuration. The antagonism of the capsaicin and proton action on native TRPV1 by MCS-18 may be of interest for pain therapy., C. Neacsu ... [et al.]., and Obsahuje bibliografii a bibliografické odkazy
Transient receptor potential vanilloid 1 (TRPV1) receptor is a nonselective cation channel activated by capsaicin, a pungent substance from chili peppers. It is considered to act as an integrator of various physical and chemical nociceptive stimuli, as it can be gated by noxious heat (>43ºC), low pH (protons) and also by recently described endogenous lipids. The structure and function of TRPV1 receptors was vigorously studied, especially since its cloning in 1997. However, most of the research was pointed towards the role of TRPV1 receptors in the peripheral tissues. Mounting evidence now suggests that TRPV1 receptors on the central branches of dorsal root ganglion neurons in the spinal cord may play an important role in modulation of pain and nociceptive transmission. The aim of this short review was to summarize the knowledge about TRPV1 receptors in the spinal cord dorsal horn, preferentially from morphological and electrophysiological studies on spinal cord slices and from in vivo experiments., D. Špicarová, J. Paleček., and Obsahuje bibliografii a bibliografické odkazy
The structure, expression and function of the transient receptor potential vanilloid 1 (TRPV1) receptor were intensively studied since the cloning in 1997 and TRPV1 receptors are now considered to act as transducers and molecular integrators of nociceptive stimuli in the periphery. In contrast, spinal TRPV1 receptors were studied less extensively and their role in pain modulation is still not fully understood. This short review is a follow up on our previous summary in this area ( Spicarova and Palecek 2008). The aim was to review preferentially the most recent findings concerning the role of the spinal TRPV1 receptors, published within the last five years. The update is given on the expression and function of the spinal TRPV1 receptors, their activation by endogenous agonists, interaction between the endocannabinoid and endovanillod system and possible role of the spinal TRPV1 receptors in pathological pain states. There is now mounting evidence that TRPV1 receptors may be an important element in modulation of nociceptive information at the spinal cord level and represent an interesting target for analgesic therapy., D. Spicarova, V. Nerandzic, J. Palecek., and Obsahuje bibliografii a bibliografické odkazy