αCGRP is essential for algesic exocytotic mobilization of TRPV1 channels in peptidergic nociceptors (original) (raw)
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The role of endogenous molecules in modulating pain through TRPV1
The Journal of Physiology, 2013
• TRPV1 (transient receptor potential vanilloid 1) channels are found throughout the body in epithelial cells and in peripheral and central terminals in neurons. They exert a variety of functions ranging from inflammation, to nociception and pain. • TRPV1 is a molecular integrator in that it can be activated by different endogenous stimuli.
Neuropharmacology, 2013
Pha1b toxin is a peptide purified from the venom of the armed spider Phoneutria nigriventer, with markedly antinociceptive action in models of acute and persistent pain in rats. Similarly to ziconotide, its analgesic action is related to inhibition of high voltage activated calcium channels with more selectivity for N-type. In this study we evaluated the effect of Pha1b when injected peripherally or intrathecally in a rat model of spontaneous pain induced by capsaicin. We also investigated the effect of Pha1b on Ca 2þ transients in cultured dorsal root ganglia (DRG) neurons and HEK293 cells expressing the TRPV1 receptor. Intraplantar or intrathecal administered Pha1b reduced both nocifensive behavior and mechanical hypersensitivity induced by capsaicin similarly to that observed with SB366791, a specific TRPV1 antagonist. Peripheral nifedipine and mibefradil did also decrease nociceptive behavior induced by intraplantar capsaicin. In contrast, u-conotoxin MVIIA (a selective N-type Ca 2þ channel blocker) was effective only when administered intrathecally. Pha1b, MVIIA and SB366791 inhibited, with similar potency, the capsaicin-induced Ca 2þ transients in DRG neurons. The simultaneous administration of Pha1b and SB366791 inhibited the capsaicin-induced Ca 2þ transients that were additive suggesting that they act through different targets. Moreover, Pha1b did not inhibit capsaicin-activated currents in patchclamp recordings of HEK293 cells that expressed TRPV1 receptors. Our results show that Pha1b may be effective as a therapeutic strategy for pain and this effect is not related to the inhibition of TRPV1 receptors.
Cell Calcium, 2008
Multimodal stimuli like heat, cold, bacterial or mechanical events are able to elicit pain, which is necessary to guarantee survival. However, the control of pain is of major clinical importance. The perception and transduction of pain is differentially modulated in the peripheral and central nervous system (CNS): while peripheral structures modulate these signals, the perception of pain occurs in the CNS. In recent years major advances have been made in the understanding of the processes which are involved in pain sensation. For the peripheral pain reception, the importance of specific pain receptors of the transition receptor pore (TRP)-family (e.g. the TRPV-1 receptor) has been analyzed. These receptors/channels are localized at the cell membrane of nociceptive neurones as well as in membranes of intracellular calcium stores like the endoplasmic reticulum. While the associated channel conducts different ions, a major proportion is calcium. Therefore, this review focuses on (1) the modulations of intracellular calcium ([Ca 2+ ] i) initiated by the activation of pain receptors and (2) the consequences of [Ca 2+ ] i changes for the processing of pain signals at the peripheral side. The possible interference of TRPV-1 induced [Ca 2+ ] i modulations to the function of other membrane receptors and channels, like voltage gated calcium, sodium or potassium channels, or co-expressed CB1-receptors will be discussed. The latter interactions are of specific interest since the analgetic properties of endo-and exo-cannabinoids are mediated by CB1 receptors and their activation significantly modulates the calcium induced release of pain related transmitters. Furthermore, multiple cross links between different pain modulating intracellular pathways and their dependence on [Ca 2+ ] i modulations will be illuminated. Overall, this review will summarize new insights resulting in the understanding of the prominent influence of [Ca 2+ ] i for processes which are involved in pain sensation.
The importance of TRPV1-sensitisation factors for the development of neuropathic pain
Molecular and Cellular Neuroscience, 2015
Transient receptor potential vanilloid type 1 (TRPV1), classically associated with transduction of hightemperature and low-pH pain, underlies pain hypersensitivity in neuropathic pain. The molecular regulation of TRPV1 channel activity is not yet fully understood. Therefore, we investigated factors regulating sensitisation of this receptor during development of neuropathic pain in a rat model of chronic construction injury (CCI) in the dorsal root ganglia (DRG).
Pflügers Archiv - European Journal of Physiology, 2005
Neurogenic inflammation is produced by overstimulation of peripheral nociceptor terminals by injury or inflammation of tissues. Excessive activity of sensory neurons produces vasodilation, plasma extravasation and hypersensitivity. Mechanistically, neurogenic inflammation is due to the release of substances from primary sensory nerve terminals that act directly or indirectly at the peripheral terminals, either activating or sensitizing nociceptors, endothelial cells and immunocytes. Notably, small-diameter sensory neurons that are sensitive to capsaicin play a key role in the generation of neurogenic inflammation. The cloning of the vanilloid receptor 1 (TRPV1) has been a breakthrough that has propelled our understanding of the molecular mechanisms involved in neurogenic inflammation. TRPV1 pivotally contributes to the integration of various stimuli and modulates nociceptor excitability, thus making it a true gateway for pain transduction. In addition, TRPV1 is the endpoint target of intracellular signalling pathways triggered by inflammatory mediators. Phosphorylation-induced potentiation of TRPV1 channel activity, along with an incremented TRPV1 surface expression are major events underlying the nociceptor activation and sensitization that leads to thermal hyperalgesia. The important contribution of TRPV1 receptor to the onset and maintenance of neurogenic inflammation has validated it as a therapeutic target for inflammatory pain management. As a result, the development of specific TRPV1 antagonists is a central focus of current drug discovery programs.
Nociceptors Lacking TRPV1 and TRPV2 Have Normal Heat Responses
The Journal of Neuroscience, 2004
Vanilloid receptor 1 (TRPV1) has been proposed to be the principal heat-responsive channel for nociceptive neurons. The skin of both rat and mouse receives major projections from primary sensory afferents that bind the plant lectin isolectin B4 (IB4). The majority of IB4-positive neurons are known to be heat-responsive nociceptors. Previous studies suggested that, unlike rat, mouse IB4-positive cutaneous afferents did not express TRPV1 immunoreactivity. Here, multiple antisera were used to confirm that mouse and rat have different distributions of TRPV1 and that TRPV1 immunoreactivity is absent in heat-sensitive nociceptors. Intracellular recording in TRPV1-/-mice was then used to confirm that TRPV1 was not required for detecting noxious heat. TRPV1-/-mice had more heat-sensitive neurons, and these neurons had normal temperature thresholds and response properties. Moreover, in TRPV1-/-mice, 82% of heat-responsive neurons did not express immunoreactivity for TRPV2, another putative n...
Thermal nociception and TRPV1 function are attenuated in mice lacking the nucleotide receptor P2Y2
PAIN, 2008
Recent studies indicate that ATP and UTP act at G protein-coupled (P2Y) nucleotide receptors to excite nociceptive sensory neurons; nucleotides also potentiate signaling through the pro-nociceptive capsaicin receptor, TRPV1. We demonstrate here that P2Y 2 is the principal UTP receptor in somatosensory neurons: P2Y 2 is highly expressed in dorsal root ganglia and P2Y 2 (−/−) mice showed profound deficits in UTP-evoked calcium transients and potentiation of capsaicin responses. P2Y 2 (−/−) mice were also deficient in the detection of painful heat: baseline thermal response latencies were increased and mutant mice failed to develop thermal hypersensitivity in response to inflammatory injury (injection of complete Freund's adjuvant into the hindpaw). P2Y 2 was the only Gq-coupled P2Y receptor examined that showed an increase in DRG mRNA levels in response to inflammation. Surprisingly, TRPV1 function was also attenuated in P2Y 2 (−/−) mice, as measured by the frequency and magnitude of capsaicin responses in vitro and behavioral responses to capsaicin administration in vivo. However, TRPV1 mRNA levels and immunoreactivity were not reduced, and behavioral sensitivity to capsaicin could be largely restored in P2Y 2 (−/−) mice by pretreatment with bradykinin, suggesting that normal function of TRPV1 requires ongoing modulation by G proteincoupled receptors. These results indicate that nucleotide signaling through P2Y 2 plays a key role in thermal nociception.
Role of TRPV1 receptors in descending modulation of pain
Molecular and Cellular Endocrinology, 2008
Transient receptor potential vanilloid type 1 (TRPV1) receptor is a ligand-gated non selective cation channel activated by heat (>43°), low pH and endogenous lipid molecules such as anandamide, Narachydonoyl-dopamine, N-acyl-dopamines and products of lipoxygenases (12-and 15-(S)-HPETE) termed endovanilloids. Apart from peripheral primary afferent neurons and dorsal root ganglia, TRPV1 receptor is expressed throughout the brain. Recent evidence show that TRPV1 receptor stimulation by endocannabinoids or by capsaicin within the periaqueductal grey (PAG) leads to analgesia and this effect is associated with glutamate increase and the activation of OFF cell population in the rostral ventromedial medulla (RVM). Activation of the antinociceptive descending pathway via TPRV1 receptor stimulation in the PAG may be a novel strategy for producing analgesia. This review will summarize the more recent insights into the role of TRPV1 receptor within the antinociceptive descending pathway and its possible exploitation as a target for novel pain-killer agents.
Experimental Brain Research, 2009
The capsaicin receptor TRPV1 is a polymodal sensory transducer molecule in the pain pathway. TRPV1 integrates noxious heat, tissue acidosis and chemical stimuli which are all known to cause pain. Studies on TRPV1-deWcient mice suggest that TRPV1 is essential for acid sensing by nociceptors and for thermal hyperalgesia in inXammation of the skin, but not for transducing noxious heat. After TRPV1, other TRPV channels were cloned with polymodal properties and sensitivity to noxious heat, named TRPV2, TRPV3 and TRPV4. While TRPV3 and TRPV4 are predominantly warm sensors, TRPV2's threshold is in the noxious range (>52°C). However, mice deWcient of TRPV2 and TRPV1 or TRPV3 or TRPV4 show no major impairment of noxious heat sensing. Ruthenium red, a water soluble polycationic dye, was found to block the pore of the capsaicin-operated cation channel TRPV1 thus interfering with all polymodal ways of TRPV1 activation. Antagonistic eVects of the dye were subsequently described on many other TRP-channels, especially on the heat-sensitive ones of the vanilloid family, TRPV2, TRPV3 and TRPV4. In this study, we used the rat skin-nerve preparation to deWne the possible actions of ruthenium red on the proton, capsaicin and noxious heat activation of native polymodal nociceptors. Ruthenium red was found to suppress only the capsaicin-induced excitation and desensitization of these nerve endings. On the contrary, the proton and heatinduced discharge responses of the single Wbres were not inXuenced. Additionally, we found that the dye concentration dependently increases the excitability of the neurons resulting in ongoing activity and burstlike discharge. These diVerential results are discussed in the light of recent Wndings from transgenic mouse models, and they point once more to major (pharmacological) diVerences between cellular models of nociception, including spinal ganglion neuron and transfected cell lines, and the real native nerve endings.