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Michael J. Iadarola - One of the best experts on this subject based on the ideXlab platform.
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the vanilloid agonist Resiniferatoxin for interventional based pain control
Current Topics in Medicinal Chemistry, 2011Co-Authors: Michael J. Iadarola, Andrew J MannesAbstract:The idea of selectively targeting nociceptive transmission at the level of the peripheral nervous system is attractive from multiple perspectives, particularly the potential lack of non-specific (non-targeted) CNS side effects. Out of the multiple TRP channels involved in nociception, TRPV1 is a strong candidate based on its biophysical conductance properties and its expression in inflammation-sensitive dorsal root ganglion neurons and their axons and central and peripheral nerve terminals. While TRPV1 antagonists have undergone extensive medicinal chemical and pharmacological investigation, for TRPV1 agonists nature has provided an optimized compound in RTX. RTX is not suitable for systemic administration, but it is highly adaptable to a variety of pain problems when used by local administration. This can include routes as diverse as subcutaneous, intraganglionic or intrathecal (CSF space around the spinal cord). The present review focuses on the molecular and preclinical animal experiments that form the underpinnings of our clinical trial of intrathecal RTX for pain in advanced cancer. As such this represents a new approach to pain control that emerges from a long line of research on capsaicin and other vanilloids, their physiological actions, and the molecular biology of the capsaicin receptor TRPV1.
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disruption of the transient receptor potential vanilloid 1 can affect survival bacterial clearance and cytokine gene expression during murine sepsis
Anesthesiology, 2011Co-Authors: Virginia Guptill, Michael J. Iadarola, Xizhong Cui, Alfia Khaibullina, Jason M Keller, Nicholas Spornick, Andrew J Mannes, Zenaide M N QuezadoAbstract:Background: Previous studies suggest that the transient receptor potential vanilloid 1 (TRPV1) channel has a role in sepsis, but it is unclear whether its effect on survival and immune response is beneficial or harmful. Methods: We studied the effects of genetic (Trpv1-knockout vs. wild-type [WT] mice) and pharmacologic disruption of TRPV1 with Resiniferatoxin (an agonist) or capsazepine (an antagonist) on mortality, bacterial clearance, and cytokine expression during lipopolysaccharide or cecal ligation and puncture—induced sepsis. Results: After cecal ligation and puncture, genetic disruption of TRPV1 in Trpv1-knockout versus WT mice was associated with increased mortality risk (hazard ratio, 2.17; 95% CI, 1.23―3.81; P = 0.01). Furthermore, pharmacologic disruption of TRPV1 with intrathecal Resiniferatoxin, compared with vehicle, increased mortality risk (hazard ratio, 1.80; 95% CI, 1.05―3.2; P = 0.03) in WT, but not in Trpv1-knockout, mice. After lipopolysaccharide, neither genetic (Trpv1 knockout) nor pharmacologic disruption of TRPV1 with Resiniferatoxin had significant effect on survival compared with respective controls. In contrast, after lipopolysaccharide, pharmacologic disruption of TRPV1 with capsazepine, compared with vehicle, increased mortality risk (hazard ratio, 1.92; 95% CI, 1.02―3.61; P = 0.04) in WT animals. Furthermore, after cecal ligation and puncture, increased mortality in Resiniferatoxin-treated WT animals was associated with higher blood bacterial count (P = 0.0004) and higher nitrate/nitrite concentrations and down-regulation of tumor necrosis factor α expression (P = 0.004) compared with controls. Conclusions: Genetic or pharmacologic disruption of TRPV1 can affect mortality, blood bacteria clearance, and cytokine response in sepsis in patterns that may vary according to the sepsis-inducing event and the method of TRPV1 disruption.
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Perineural Resiniferatoxin selectively inhibits inflammatory hyperalgesia
Molecular Pain, 2008Co-Authors: John K Neubert, Laszlo Karai, Andrew J Mannes, Alan C Jenkins, Lanel Zawatski, Mones Abu-asab, Michael J. IadarolaAbstract:Resiniferatoxin (RTX) is an ultrapotent capsaicin analog that binds to the transient receptor potential channel, vanilloid subfamily member 1 (TRPV1). There is a large body of evidence supporting a role for TRPV1 in noxious-mediated and inflammatory hyperalgesic responses. In this study, we evaluated low, graded, doses of perineural RTX as a method for regional pain control. We hypothesized that this approach can provide long-term, but reversible, blockade of a portion of nociceptive afferent fibers within peripheral nerves when given at a site remote from the neuronal perikarya in the dorsal root ganglia. Following perineural RTX application to the sciatic nerve, we demonstrated a significant inhibition of inflammatory nociception that was dose- and time-dependent. At the same time, treated animals maintained normal proprioceptive sensations and motor control, and other nociceptive responses were largely unaffected. Using a range of mechanical and thermal algesic tests, we found that the most sensitive measure following perineural RTX administration was inhibition of inflammatory hyperalgesia. Recovery studies showed that physiologic sensory function could return as early as two weeks post-RTX treatment, however, immunohistochemical examination of the DRG revealed a partial, but significant reduction in the number of the TRPV1-positive neurons. We propose that this method could represent a beneficial treatment for a range of chronic pain problems, including neuropathic and inflammatory pain not responding to other therapies.
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physiologic and antinociceptive effects of intrathecal Resiniferatoxin in a canine bone cancer model
Anesthesiology, 2005Co-Authors: Dorothy Cimino Brown, Zoltán Oláh, Michael J. Iadarola, Sandra Z Perkowski, Hardam Erin, Frances S Shofer, Karai J Laszlo, Andrew J MannesAbstract:BACKGROUND Resiniferatoxin is a potent capsaicin analog. Intrathecal administration leads to selective, prolonged opening of the transient receptor potential V1 ion channel, which is localized mainly to C-fiber primary afferent nociceptive sensory neurons. Following work in laboratory animals, the authors explored the use of intrathecal Resiniferatoxin to control spontaneous bone cancer pain in companion (pet) dogs. METHODS Normal canine population: Behavioral testing was performed to establish baseline paw withdrawal latency; subsequently, general anesthesia was induced and Resiniferatoxin was administered intrathecally while hemodynamic parameters were recorded. Behavior testing was repeated for 12 days after administration of Resiniferatoxin. Clinical canine population: Twenty companion dogs with bone cancer pain were recruited. The animal's baseline level of discomfort and analgesic use were recorded. Resiniferatoxin was administered intrathecally and hemodynamic parameters were monitored while the dogs were under general anesthesia. Dogs were reevaluated up to 14 weeks after Resiniferatoxin administration. RESULTS Normal canine population: In the first minutes after Resiniferatoxin injection, there were significant (P < 0.05) increases in mean arterial blood pressure and heart rate from baseline. Two days after injection, limb withdrawal latencies increased to the point of cutoff in the dogs that received at least 1.2 microg/kg Resiniferatoxin. Clinical canine population: From baseline, there were significant (P < 0.05) increases in mean arterial blood pressure and heart rate after Resiniferatoxin injection. Comfort scores were significantly improved at 2, 6, 10, and 14 weeks after Resiniferatoxin administration (P < 0.0001). There was decreased or discontinued use of supplemental analgesics in 67% of the dogs 2 weeks after Resiniferatoxin administration. CONCLUSIONS Intrathecal Resiniferatoxin elicits transient hemodynamic effects. In controls, a profound and sustained blockade of thermal stimuli is produced in a dose-dependent fashion. Similar administration in dogs with bone cancer produces a prolonged antinociceptive response.
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Vanilloid receptor 1 regulates multiple calcium compartments and contributes to Ca2+-induced Ca2+ release in sensory neurons.
The Journal of biological chemistry, 2004Co-Authors: Laszlo Karai, Michael J. Iadarola, James T. Russell, Zoltán OláhAbstract:Vanilloid receptor 1 belongs to the transient receptor potential ion channel family and transduces sensations of noxious heat and inflammatory hyperalgesia in nociceptive neurons. These neurons contain two vanilloid receptor pools, one in the plasma membrane and the other in the endoplasmic reticulum. The present experiments characterize these two pools and their functional significance using calcium imaging and 45Ca uptake in stably transfected cells or dorsal root ganglion neurons. The plasma membrane localized receptor is directly activated by vanilloids. The endoplasmic reticulum pool was demonstrated to be independently activated with 20 microm capsaicin or 1.6 microm Resiniferatoxin using a bathing solution containing 10 microm Ruthenium Red (to selectively block plasma membrane-localized receptors) and 100 microm EGTA. We also demonstrate an overlap between the endoplasmic reticulum-localized vanilloid receptor regulated stores and thapsigargin-sensitive stores. Direct depletion of calcium via activation of endoplasmic reticulum-localized vanilloid receptor 1 triggered store operated calcium entry. Furthermore, we found that, in the presence of low extracellular calcium (10(-5) m), either 2 microm capsaicin or 0.1 nm-1.6 microm Resiniferatoxin caused a pronounced calcium-induced calcium release in either vanilloid receptor-expressing neurons or heterologous expression systems. This phenomenon may allow new insight into how nociceptive neuron function in response to a variety of nociceptive stimuli both acutely and during prolonged nociceptive signaling.
Peter M. Blumberg - One of the best experts on this subject based on the ideXlab platform.
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Novel Radiolabeled Vanilloid with Enhanced Specificity for Human Transient Receptor Potential Vanilloid 1 (TRPV1)
2017Co-Authors: Larry V. Pearce, Peter M. Blumberg, Jihyae Ann, Aeran Jung, Shivaji A. Thorat, Brienna K. A. Herold, Amelework D. Habtemichael, Jeewoo LeeAbstract:Transient receptor potential vanilloid 1 (TRPV1) has emerged as a promising therapeutic target. While radiolabeled Resiniferatoxin (RTX) has provided a powerful tool for characterization of vanilloid binding to TRPV1, TRPV1 shows 20-fold weaker binding to the human TRPV1 than to the rodent TRPV1. We now describe a tritium radiolabeled synthetic vanilloid antagonist, 1-((2-(4-(methyl-[3H])piperidin-1-yl-4-[3H])-6-(trifluoromethyl)pyridin-3-yl)methyl)-3-(3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-8-yl)urea ([3H]MPOU), that embodies improved absolute affinity for human TRPV1 and improved synthetic accessibility
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design of a high affinity competitive antagonist of the vanilloid receptor selective for the calcium entry linked receptor population
Molecular Pharmacology, 2004Co-Authors: Attila Toth, Peter M. Blumberg, Zili Chen, Alan P KozikowskiAbstract:We describe the synthesis and characterization of N-(4-chlorobenzyl) -N′-(4-hydroxy-3-iodo-5-methoxybenzyl)thiourea (IBTU), a novel antagonist of the vanilloid receptor 1 (TRPV1 or VR1). IBTU competitively inhibited 45Ca2+ uptake into CHO cells heterologously expressing rat TRPV1, whether induced by capsaicin or Resiniferatoxin (Ki = 99 ± 23 and 93 ± 34 nM, respectively). IBTU was thus somewhat more potent (5-fold) than capsazepine. In contrast to its antagonism of vanilloid-induced calcium uptake, IBTU (30 μM) inhibited [3H]Resiniferatoxin binding to TRPV1 by less than 10%. We hypothesize that these dramatically distinct potencies reflect different fractions of TRPV1 in this system: namely, a minor plasma membrane fraction controlling 45Ca2+ uptake, and the predominant intracellular fraction that dominates the [3H]Resiniferatoxin binding measurements. Intracellular Ca2+ imaging supports this explanation. IBTU antagonized the elevation in intracellular Ca2+ in response to 50 nM capsaicin with an IC50 of 106 ± 35 nM. Likewise, 600 nM IBTU was able to antagonize the elevation in intracellular Ca2+ in response to 100 pM Resiniferatoxin in the presence of normal (1.8 mM) extracellular Ca2+, where the increase in intracellular calcium reflects calcium influx. In contrast, in the absence of extracellular Ca2+, where in this system Resiniferatoxin induces a modest increase in calcium from intracellular stores, IBTU was unable to block the response to Resiniferatoxin, although the TRPV1 antagonist 5-iodoResiniferatoxin was able to do so. In summary, IBTU is a novel, potent TRPV1 antagonist with marked selectivity between subpopulations of TRPV1 and may permit the function of these distinct pools to be explored and potentially exploited.
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functional analysis of capsaicin receptor vanilloid receptor subtype 1 multimerization and agonist responsiveness using a dominant negative mutation
The Journal of Neuroscience, 2001Co-Authors: Eldo V Kuzhikandathil, Peter M. Blumberg, Tamás Szabó, Haibin Wang, Natasha Morozova, Gerry S OxfordAbstract:The recently cloned vanilloid receptor subtype 1 (VR1) is a ligand-gated channel that is activated by capsaicin, protons, and heat. We have attempted to develop a dominant negative isoform by targeting several mutations of VR1 at highly conserved amino acids or at residues of potential functional importance and expressing the mutants in Chinese hamster ovary cells. Mutation of three highly conserved amino acid residues in the putative sixth transmembrane domain disrupts activation of the VR1 receptor by both capsaicin and Resiniferatoxin. The vanilloid binding site in this mutant is intact, although the affinity for [(3)H]Resiniferatoxin (RTX) is diminished by nearly 40-fold. Interestingly, this mutant retains a significant but diminished response to protons, supporting the existence of multiple gating mechanisms for different stimuli. The mutant appears to function by interfering with the gating induced by vanilloids rather than the expression level or permeability of the receptor. In addition, this mutant was found to function as a strong dominant negative mutation when coexpressed with wild-type VR1, providing functional evidence that the VR1 receptor forms a multimeric complex. Analysis of both current density and [(3)H]RTX affinity in cells cotransfected with different ratios of wild-type and mutant VR1 is consistent with tetrameric stoichiometry for the native capsaicin receptor.
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n 3 acyloxy 2 benzylpropyl n dihydroxytetrahydrobenzazepine and tetrahydroisoquinoline thiourea analogues as vanilloid receptor ligands
Bioorganic & Medicinal Chemistry, 2001Co-Authors: Tamás Szabó, Adamar F Gonzalez, Jacqueline D Welter, Peter M. BlumbergAbstract:Abstract The vanilloid receptor represents a promising target for drug development. Building on our previous strategies which have generated potent agonists for VR1, we now describe a series of novel N -(3-acyloxy-2-benzylpropyl)- N′ -dihydroxytetrahydrobenzazepine and tetrahydroisoquinoline thiourea analogues, several of which are potent VR1 antagonists. We report here the rationale for the design, the synthesis, and the in vitro characterization of activity in assays for [ 3 H]Resiniferatoxin binding and 45 Ca influx using heterologously expressed rat VR1.
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ligand induced dynamic membrane changes and cell deletion conferred by vanilloid receptor 1
Journal of Biological Chemistry, 2001Co-Authors: Zoltán Oláh, Laszlo Karai, Peter M. Blumberg, Tamás Szabó, Chris Hough, Douglas R Fields, Robert M Caudle, Michael J. IadarolaAbstract:The real time dynamics of vanilloid-induced cytotoxicity and the specific deletion of nociceptive neurons expressing the wild-type vanilloid receptor (VR1) were investigated. VR1 was C-terminally tagged with either the 27-kDa enhanced green fluorescent protein (eGFP) or a 12-amino acid epsilon-epitope. Upon exposure to Resiniferatoxin, VR1eGFP- or VR1epsilon-expressing cells exhibited pharmacological responses similar to those of cells expressing the untagged VR1. Within seconds of vanilloid exposure, the intracellular free calcium ([Ca(2+)](i)) was elevated in cells expressing VR1. A functional pool of VR1 also was localized to the endoplasmic reticulum that, in the absence of extracellular calcium, also was capable of releasing calcium upon agonist treatment. Confocal imaging disclosed that Resiniferatoxin treatment induced vesiculation of the mitochondria and the endoplasmic reticulum ( approximately 1 min), nuclear membrane disruption (5-10 min), and cell lysis (1-2 h). Nociceptive primary sensory neurons endogenously express VR1, and Resiniferatoxin treatment induced a sudden increase in [Ca(2+)](i) and mitochondrial disruption which was cell-selective, as glia and non-VR1-expressing neurons were unaffected. Early hallmarks of cytotoxicity were followed by specific deletion of VR1-expressing cells. These data demonstrate that vanilloids disrupt vital organelles within the cell body and, if administered to sensory ganglia, may be employed to rapidly and selectively delete nociceptive neurons.
Zoltán Oláh - One of the best experts on this subject based on the ideXlab platform.
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Competitive inhibition of TRPV1-calmodulin interaction by vanilloids.
FEBS Letters, 2016Co-Authors: Anasztázia Hetényi, Lukács J. Németh, Edit Wéber, Gerda Szakonyi, Zoltán Winter, Katalin Jósvay, Éva Bartus, Zoltán Oláh, Tamás A. MartinekAbstract:There is enormous interest toward vanilloid agonists of the pain receptor TRPV1 in analgesic therapy, but the mechanisms of their sensory neuron-blocking effects at high or repeated doses are still a matter of debate. Our results have demonstrated that capsaicin and Resiniferatoxin form nanomolar complexes with calmodulin, and competitively inhibit TRPV1–calmodulin interaction. These interactions involve the protein recognition interface of calmodulin, which is responsible for all of the cell-regulatory calmodulin–protein interactions. These results draw attention to a previously unknown vanilloid target, which may contribute to the explanation of the paradoxical pain-modulating behavior of these important pharmacons.
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Resiniferatoxin mediated ablation of trpv1 neurons removes trpa1 as well
Canadian Journal of Neurological Sciences, 2009Co-Authors: László Pecze, Zoltán Winter, Krisztián Kaszás, Tamás Letoha, Peter Pelsoczi, Miklos Kecskes, Andras Papp, Csaba Vizler, Zoltán OláhAbstract:Objectifs : La Resiniferatoxine, l'agoniste le plus puissant de la douleur inflammatoire/du recepteur vanilloide/du canal cationique (TRPV1), peut etre utilisee pour l'ablation specifique par excytotoxicite Ca2+, d'un sous-type de neurones faisant partie des cellules generatrices de douleur au niveau du systeme nerveux peripherique. La neurochirurgie moleculaire est une technologie emergente, pour soulager la douleur cancereuse severe ou pour traiter ou prevenir differentes neuropathies locales. Notre but etait de determiner les pertes sensitives suite au traitement par la Resiniferatoxine. Methodes : Des souris ont ete traitees par la Resiniferatoxine a la periode neonatale ou adulte et les changements de la sensibilite chimique et calorique ont ete correles aux alterations de la composition cellulaire des ganglions sensitifs. Resultats : Seules les souris traitees a l'âge adulte sont devenues moins sensibles aux stimuli caloriques alors que les deux groupes traites ont perdu la sensibilite aux agonistes vanilloides specifiques de TRPV1 et, ce qui est fort interessant, a l'allyl-isothiocyanate, un agoniste selectif de TRPA1. Nos resultats d'analyses in vivo et post mortem ont confirme que TRPV1 et TRPA1 fonctionnent conjointement et que la neurochirurgie au moyen de la Resiniferatoxine elimine les deux molecules detectrices. Discussion: Chez les souris adultes la Resiniferatoxine cause: 1) une desensibilisation a la chaleur et 2) une sensibilisation au froid. Une hyperalgesie au froid, qui est un desequilibre dans la thermosensibilite, pourrait etre mediee par un recepteur important au froid qui est exprime dans les neurones sensitifs resistants a la Resiniferatoxine survivants et qui compense pour les signaux douloureux perdus des cellules doublement positives pour TRPA1 et TRPV1 dans le systeme nerveux peripherique.
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physiologic and antinociceptive effects of intrathecal Resiniferatoxin in a canine bone cancer model
Anesthesiology, 2005Co-Authors: Dorothy Cimino Brown, Zoltán Oláh, Michael J. Iadarola, Sandra Z Perkowski, Hardam Erin, Frances S Shofer, Karai J Laszlo, Andrew J MannesAbstract:BACKGROUND Resiniferatoxin is a potent capsaicin analog. Intrathecal administration leads to selective, prolonged opening of the transient receptor potential V1 ion channel, which is localized mainly to C-fiber primary afferent nociceptive sensory neurons. Following work in laboratory animals, the authors explored the use of intrathecal Resiniferatoxin to control spontaneous bone cancer pain in companion (pet) dogs. METHODS Normal canine population: Behavioral testing was performed to establish baseline paw withdrawal latency; subsequently, general anesthesia was induced and Resiniferatoxin was administered intrathecally while hemodynamic parameters were recorded. Behavior testing was repeated for 12 days after administration of Resiniferatoxin. Clinical canine population: Twenty companion dogs with bone cancer pain were recruited. The animal's baseline level of discomfort and analgesic use were recorded. Resiniferatoxin was administered intrathecally and hemodynamic parameters were monitored while the dogs were under general anesthesia. Dogs were reevaluated up to 14 weeks after Resiniferatoxin administration. RESULTS Normal canine population: In the first minutes after Resiniferatoxin injection, there were significant (P < 0.05) increases in mean arterial blood pressure and heart rate from baseline. Two days after injection, limb withdrawal latencies increased to the point of cutoff in the dogs that received at least 1.2 microg/kg Resiniferatoxin. Clinical canine population: From baseline, there were significant (P < 0.05) increases in mean arterial blood pressure and heart rate after Resiniferatoxin injection. Comfort scores were significantly improved at 2, 6, 10, and 14 weeks after Resiniferatoxin administration (P < 0.0001). There was decreased or discontinued use of supplemental analgesics in 67% of the dogs 2 weeks after Resiniferatoxin administration. CONCLUSIONS Intrathecal Resiniferatoxin elicits transient hemodynamic effects. In controls, a profound and sustained blockade of thermal stimuli is produced in a dose-dependent fashion. Similar administration in dogs with bone cancer produces a prolonged antinociceptive response.
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Vanilloid receptor 1 regulates multiple calcium compartments and contributes to Ca2+-induced Ca2+ release in sensory neurons.
The Journal of biological chemistry, 2004Co-Authors: Laszlo Karai, Michael J. Iadarola, James T. Russell, Zoltán OláhAbstract:Vanilloid receptor 1 belongs to the transient receptor potential ion channel family and transduces sensations of noxious heat and inflammatory hyperalgesia in nociceptive neurons. These neurons contain two vanilloid receptor pools, one in the plasma membrane and the other in the endoplasmic reticulum. The present experiments characterize these two pools and their functional significance using calcium imaging and 45Ca uptake in stably transfected cells or dorsal root ganglion neurons. The plasma membrane localized receptor is directly activated by vanilloids. The endoplasmic reticulum pool was demonstrated to be independently activated with 20 microm capsaicin or 1.6 microm Resiniferatoxin using a bathing solution containing 10 microm Ruthenium Red (to selectively block plasma membrane-localized receptors) and 100 microm EGTA. We also demonstrate an overlap between the endoplasmic reticulum-localized vanilloid receptor regulated stores and thapsigargin-sensitive stores. Direct depletion of calcium via activation of endoplasmic reticulum-localized vanilloid receptor 1 triggered store operated calcium entry. Furthermore, we found that, in the presence of low extracellular calcium (10(-5) m), either 2 microm capsaicin or 0.1 nm-1.6 microm Resiniferatoxin caused a pronounced calcium-induced calcium release in either vanilloid receptor-expressing neurons or heterologous expression systems. This phenomenon may allow new insight into how nociceptive neuron function in response to a variety of nociceptive stimuli both acutely and during prolonged nociceptive signaling.
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peripherally induced Resiniferatoxin analgesia
Pain, 2003Co-Authors: John K Neubert, Zoltán Oláh, Laszlo Karai, Jae H Jun, Hyungsuk Kim, Michael J. IadarolaAbstract:Selective blockade of nociceptive pathways represents a mechanism-based approach that has attracted a large variety of pharmacological and molecular investigations. A potential site for selective intervention is the primary afferent nociceptive nerve terminal. Binding of Resiniferatoxin (RTX) to the vanilloid-1 receptor (VR1) stimulates and then inactivates heat and vanilloid-responsive nerve endings involved in heat and inflammatory pain signaling which can progress to localized degeneration of the peripheral ending followed by regeneration. Application of RTX directly to peripheral nerve endings produces a long term, reversible attenuation of nociceptive transmission. Heat hyperalgesia and mechanical allodynia were assessed prior to injection of RTX into the hindpaw (baseline) and at acute (minutes-hours) and more chronic (days-weeks) times after injection. Acutely, an inverse dose-to-pain response (guarding, licking) for RTX (0.0625-2.0 microg) occurs, followed by selective attenuation of peripheral pain transmission. Thermal nociception was decreased in a concentration-dependent fashion and lasted up to 21 days, without impairing motor function. Administration of RTX blocked both inflammation-induced hyperalgesia and spinal c-Fos induction. The results demonstrate the efficacy and therapeutic potential of reversible, peripheral C-fiber 'inactivation' for intermediate duration pain control.
Michael H Hsieh - One of the best experts on this subject based on the ideXlab platform.
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ipse a parasite derived host immunomodulatory infiltrin protein alleviates Resiniferatoxin induced bladder pain
Molecular Pain, 2020Co-Authors: Kenji Ishida, Evaristus Chibunna Mbanefo, Olivia K Lamanna, Luke F Pennington, Julia Finkel, Theodore S Jardetzky, Franco H Falcone, Michael H HsiehAbstract:The transient receptor potential cation channel subfamily V member 1 (TRPV1) receptor is an important mediator of nociception and its expression is enriched in nociceptive neurons. TRPV1 signaling has been implicated in bladder pain and is a potential analgesic target. Resiniferatoxin is the most potent known agonist of TRPV1. Acute exposure of the rat bladder to Resiniferatoxin has been demonstrated to result in pain-related freezing and licking behaviors that are alleviated by virally encoded IL-4. The interleukin-4-inducing principle of Schistosoma mansoni eggs (IPSE) is a powerful inducer of IL-4 secretion, and is also known to alter host cell transcription through a nuclear localization sequence-based mechanism. We previously reported that IPSE ameliorates ifosfamide-induced bladder pain in an IL-4- and nuclear localization sequence-dependent manner. We hypothesized that pre-administration of IPSE to Resiniferatoxin-challenged mice would dampen pain-related behaviors. IPSE indeed lessened Resiniferatoxin-triggered freezing behaviors in mice. This was a nuclear localization sequence-dependent phenomenon, since administration of a nuclear localization sequence mutant version of IPSE abrogated IPSE's analgesic effect. In contrast, IPSE's analgesic effect did not seem IL-4-dependent, since use of anti-IL-4 antibody in mice given both IPSE and Resiniferatoxin did not significantly affect freezing behaviors. RNA-Seq analysis of Resiniferatoxin- and IPSE-exposed bladders revealed differential expression of TNF/NF-κb-related signaling pathway genes. In vitro testing of IPSE uptake by urothelial cells and TRPV1-expressing neuronal cells showed uptake by both cell types. Thus, IPSE's nuclear localization sequence-dependent therapeutic effects on TRPV1-mediated bladder pain may act on TRPV1-expressing neurons and/or may rely upon urothelial mechanisms.
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ipse a parasite derived host immunomodulatory infiltrin protein alleviates Resiniferatoxin induced bladder pain
bioRxiv, 2020Co-Authors: Kenji Ishida, Evaristus Chibunna Mbanefo, Olivia K Lamanna, Luke F Pennington, Julia Finkel, Theodore S Jardetzky, Franco H Falcone, Michael H HsiehAbstract:The transient receptor potential cation channel subfamily V member 1 (TRPV1) receptor is an important mediator of nociception and its expression is enriched in nociceptive neurons. TRPV1 signaling has been implicated in bladder pain and is a potential analgesic target. Resiniferatoxin is the most potent known agonist of TRPV1. Acute exposure of the rat bladder to Resiniferatoxin has been demonstrated to result in pain-related freezing and licking behaviors that are alleviated by virally encoded IL-4. The interleukin-4-inducing principle of Schistosoma mansoni eggs (IPSE) is a powerful inducer of IL-4 secretion, and is also known to alter host cell transcription through a nuclear localization sequence-dependent mechanism. We previously reported that IPSE ameliorates ifosfamide-induced bladder pain in an IL-4- and nuclear localization sequence-dependent manner. We hypothesized that pre-administration of IPSE to Resiniferatoxin-challenged mice would dampen pain-related behaviors. IPSE indeed lessened Resiniferatoxin-triggered freezing behaviors in mice. This was a nuclear localization sequence-dependent phenomenon, since administration of a nuclear localization sequence mutant version of IPSE abrogated IPSEs analgesic effect. In contrast, IPSEs analgesic effect did not seem IL-4-dependent, since use of anti-IL-4 antibody in mice given both IPSE and Resiniferatoxin did not dramatically affect freezing behaviors. RNA-Seq analysis of Resiniferatoxin- and IPSE-exposed bladders revealed differential expression of TNF/NF-Kb-related signaling pathway genes. In vitro testing of IPSE uptake by urothelial cells and TRPV1-expressing neuronal cells showed uptake by both cell types. Thus, IPSEs nuclear localization sequence-dependent therapeutic effects on TRPV1-mediated bladder pain may act on TRPV1-expressing neurons and/or may rely upon urothelial mechanisms.
Laszlo Karai - One of the best experts on this subject based on the ideXlab platform.
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Perineural Resiniferatoxin selectively inhibits inflammatory hyperalgesia
Molecular Pain, 2008Co-Authors: John K Neubert, Laszlo Karai, Andrew J Mannes, Alan C Jenkins, Lanel Zawatski, Mones Abu-asab, Michael J. IadarolaAbstract:Resiniferatoxin (RTX) is an ultrapotent capsaicin analog that binds to the transient receptor potential channel, vanilloid subfamily member 1 (TRPV1). There is a large body of evidence supporting a role for TRPV1 in noxious-mediated and inflammatory hyperalgesic responses. In this study, we evaluated low, graded, doses of perineural RTX as a method for regional pain control. We hypothesized that this approach can provide long-term, but reversible, blockade of a portion of nociceptive afferent fibers within peripheral nerves when given at a site remote from the neuronal perikarya in the dorsal root ganglia. Following perineural RTX application to the sciatic nerve, we demonstrated a significant inhibition of inflammatory nociception that was dose- and time-dependent. At the same time, treated animals maintained normal proprioceptive sensations and motor control, and other nociceptive responses were largely unaffected. Using a range of mechanical and thermal algesic tests, we found that the most sensitive measure following perineural RTX administration was inhibition of inflammatory hyperalgesia. Recovery studies showed that physiologic sensory function could return as early as two weeks post-RTX treatment, however, immunohistochemical examination of the DRG revealed a partial, but significant reduction in the number of the TRPV1-positive neurons. We propose that this method could represent a beneficial treatment for a range of chronic pain problems, including neuropathic and inflammatory pain not responding to other therapies.
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Vanilloid receptor 1 regulates multiple calcium compartments and contributes to Ca2+-induced Ca2+ release in sensory neurons.
The Journal of biological chemistry, 2004Co-Authors: Laszlo Karai, Michael J. Iadarola, James T. Russell, Zoltán OláhAbstract:Vanilloid receptor 1 belongs to the transient receptor potential ion channel family and transduces sensations of noxious heat and inflammatory hyperalgesia in nociceptive neurons. These neurons contain two vanilloid receptor pools, one in the plasma membrane and the other in the endoplasmic reticulum. The present experiments characterize these two pools and their functional significance using calcium imaging and 45Ca uptake in stably transfected cells or dorsal root ganglion neurons. The plasma membrane localized receptor is directly activated by vanilloids. The endoplasmic reticulum pool was demonstrated to be independently activated with 20 microm capsaicin or 1.6 microm Resiniferatoxin using a bathing solution containing 10 microm Ruthenium Red (to selectively block plasma membrane-localized receptors) and 100 microm EGTA. We also demonstrate an overlap between the endoplasmic reticulum-localized vanilloid receptor regulated stores and thapsigargin-sensitive stores. Direct depletion of calcium via activation of endoplasmic reticulum-localized vanilloid receptor 1 triggered store operated calcium entry. Furthermore, we found that, in the presence of low extracellular calcium (10(-5) m), either 2 microm capsaicin or 0.1 nm-1.6 microm Resiniferatoxin caused a pronounced calcium-induced calcium release in either vanilloid receptor-expressing neurons or heterologous expression systems. This phenomenon may allow new insight into how nociceptive neuron function in response to a variety of nociceptive stimuli both acutely and during prolonged nociceptive signaling.
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peripherally induced Resiniferatoxin analgesia
Pain, 2003Co-Authors: John K Neubert, Zoltán Oláh, Laszlo Karai, Jae H Jun, Hyungsuk Kim, Michael J. IadarolaAbstract:Selective blockade of nociceptive pathways represents a mechanism-based approach that has attracted a large variety of pharmacological and molecular investigations. A potential site for selective intervention is the primary afferent nociceptive nerve terminal. Binding of Resiniferatoxin (RTX) to the vanilloid-1 receptor (VR1) stimulates and then inactivates heat and vanilloid-responsive nerve endings involved in heat and inflammatory pain signaling which can progress to localized degeneration of the peripheral ending followed by regeneration. Application of RTX directly to peripheral nerve endings produces a long term, reversible attenuation of nociceptive transmission. Heat hyperalgesia and mechanical allodynia were assessed prior to injection of RTX into the hindpaw (baseline) and at acute (minutes-hours) and more chronic (days-weeks) times after injection. Acutely, an inverse dose-to-pain response (guarding, licking) for RTX (0.0625-2.0 microg) occurs, followed by selective attenuation of peripheral pain transmission. Thermal nociception was decreased in a concentration-dependent fashion and lasted up to 21 days, without impairing motor function. Administration of RTX blocked both inflammation-induced hyperalgesia and spinal c-Fos induction. The results demonstrate the efficacy and therapeutic potential of reversible, peripheral C-fiber 'inactivation' for intermediate duration pain control.
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ligand induced dynamic membrane changes and cell deletion conferred by vanilloid receptor 1
Journal of Biological Chemistry, 2001Co-Authors: Zoltán Oláh, Laszlo Karai, Peter M. Blumberg, Tamás Szabó, Chris Hough, Douglas R Fields, Robert M Caudle, Michael J. IadarolaAbstract:The real time dynamics of vanilloid-induced cytotoxicity and the specific deletion of nociceptive neurons expressing the wild-type vanilloid receptor (VR1) were investigated. VR1 was C-terminally tagged with either the 27-kDa enhanced green fluorescent protein (eGFP) or a 12-amino acid epsilon-epitope. Upon exposure to Resiniferatoxin, VR1eGFP- or VR1epsilon-expressing cells exhibited pharmacological responses similar to those of cells expressing the untagged VR1. Within seconds of vanilloid exposure, the intracellular free calcium ([Ca(2+)](i)) was elevated in cells expressing VR1. A functional pool of VR1 also was localized to the endoplasmic reticulum that, in the absence of extracellular calcium, also was capable of releasing calcium upon agonist treatment. Confocal imaging disclosed that Resiniferatoxin treatment induced vesiculation of the mitochondria and the endoplasmic reticulum ( approximately 1 min), nuclear membrane disruption (5-10 min), and cell lysis (1-2 h). Nociceptive primary sensory neurons endogenously express VR1, and Resiniferatoxin treatment induced a sudden increase in [Ca(2+)](i) and mitochondrial disruption which was cell-selective, as glia and non-VR1-expressing neurons were unaffected. Early hallmarks of cytotoxicity were followed by specific deletion of VR1-expressing cells. These data demonstrate that vanilloids disrupt vital organelles within the cell body and, if administered to sensory ganglia, may be employed to rapidly and selectively delete nociceptive neurons.
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ligand induced dynamic membrane changes and cell deletion conferred by vanilloid receptor 1
Journal of Biological Chemistry, 2001Co-Authors: Zoltán Oláh, Laszlo Karai, Peter M. Blumberg, Tamás Szabó, Chris Hough, Douglas R Fields, Robert M Caudle, Michael J. IadarolaAbstract:The real time dynamics of vanilloid-induced cytotoxicity and the specific deletion of nociceptive neurons expressing the wild-type vanilloid receptor (VR1) were investigated. VR1 was C-terminally tagged with either the 27-kDa enhanced green fluorescent protein (eGFP) or a 12-amino acid e-epitope. Upon exposure to Resiniferatoxin, VR1eGFP- or VR1e-expressing cells exhibited pharmacological responses similar to those of cells expressing the untagged VR1. Within seconds of vanilloid exposure, the intracellular free calcium ([Ca2+]i) was elevated in cells expressing VR1. A functional pool of VR1 also was localized to the endoplasmic reticulum that, in the absence of extracellular calcium, also was capable of releasing calcium upon agonist treatment. Confocal imaging disclosed that Resiniferatoxin treatment induced vesiculation of the mitochondria and the endoplasmic reticulum (∼1 min), nuclear membrane disruption (5–10 min), and cell lysis (1–2 h). Nociceptive primary sensory neurons endogenously express VR1, and Resiniferatoxin treatment induced a sudden increase in [Ca2+]i and mitochondrial disruption which was cell-selective, as glia and non-VR1-expressing neurons were unaffected. Early hallmarks of cytotoxicity were followed by specific deletion of VR1-expressing cells. These data demonstrate that vanilloids disrupt vital organelles within the cell body and, if administered to sensory ganglia, may be employed to rapidly and selectively delete nociceptive neurons.