Attenuation of thermal nociception and hyperalgesia by VR1 blockers

García-Martínez, Carolina; Humet, Marc; Planells-Cases, Rosa; Gomis, Ana; Caprini, Marco; Viana, Félix; Peña, Elvira de la; Sánchez‐Baeza, Francisco; Carbonell, Teresa; Felipe, Carmen De; Pérez‐Payá, Enrique; Belmonte, Carlos; Messeguer, Àngel; Ferrer‐Montiel, Antonio

doi:10.1073/pnas.022285899

Cited by 185 publications

(158 citation statements)

References 28 publications

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“…Oocyte Electrophysiology-Amphibian oocytes were harvested and microinjected with cRNA encoding the rat TRPV1 channel, Snapin, and Syt IX as described previously (18). Whole-cell currents in oocytes were recorded with a two-microelectrode voltage clamp amplifier.…”

Section: Methodsmentioning

confidence: 99%

“…b Ratio of the inward current elicited by 10 M capsaicin (Cap) with respect to that evoked by an acidic solution (pH 6). c EC 50 is the concentration of capsaicin required to activate the half-maximal response obtained from a dose-response curve (18). d IC 50 is the concentration of ruthenium red (RR) needed to block the half-maximal response elicited by 10 M capsaicin obtained from a dose-response curve (18).…”

Section: Fig 4 Trpv1 Localizes In Vesicles In Neuronsmentioning

confidence: 99%

“…Recent evidence shows that an increase in TRPV1 expression in peripheral nociceptors is critical for the maintenance of inflammatory hyperalgesia (14,15). The involvement of TRPV1 in heat hypersensitivity is further underscored by the reduced sensitivity of mice lacking TRPV1 (16,17) and by mice treated with receptor-specific antagonists (18).…”

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confidence: 99%

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Regulated Exocytosis Contributes to Protein Kinase C Potentiation of Vanilloid Receptor Activity

Morenilla‐Palao

Planells-Cases

García-Sanz

et al. 2004

Journal of Biological Chemistry

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386

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The vanilloid receptor-1 (TRPV1) plays a key role in the perception of peripheral thermal and inflammatory pain. TRPV1 expression and channel activity are notably up-regulated by proalgesic agents. The transduction pathways involved in TRPV1 sensitization are still elusive. We have used a yeast two-hybrid screen to identify proteins that associate with the N terminus of TRPV1. We report that two vesicular proteins, Snapin and synaptotagmin IX (Syt IX), strongly interact in vitro and in vivo with the TRPV1 N-terminal domain. In primary dorsal root ganglion neurons, TRPV1 co-distributes in vesicles with Syt IX and the vesicular protein synaptobrevin. Neither Snapin nor Syt IX affected channel function, but they notably inhibited protein kinase C (PKC)-induced potentiation of TRPV1 channel activity with a potency that rivaled the blockade evoked by botulinum neurotoxin A, a potent blocker of neuronal exocytosis. Noteworthily, we found that PKC activation induced a rapid delivery of functional TRPV1 channels to the plasma membrane. Botulinum neurotoxin A blocked the TRPV1 membrane translocation induced by PKC that was activated with a phorbol ester or the metabotropic glutamate receptor mGluR5. Therefore, our results indicate that PKC signaling promotes at least in part the SNARE-dependent exocytosis of TRPV1 to the cell surface. Taken together, these findings imply that activitydependent delivery of channels to the neuronal surface may contribute to the buildup and maintenance of thermal inflammatory hyperalgesia in peripheral nociceptor terminals.TRPV1 1 is a capsaicin-, proton-and heat-sensitive, cationselective ion channel expressed in nociceptors that participates in the transduction of noxious chemical and thermal stimuli by sensory nerve endings in peripheral tissues (1-3). Heterologous expression of TRPV1 cDNA results in ionic currents that recapitulate most of the functional properties displayed by native capsaicin-and heat-activated currents in sensory neurons (1, 2). For instance, TRPV1 exhibits a time-and Ca 2ϩ -dependent desensitization, a long lasting refractory state during which the receptor does not respond to vanilloids or other stimuli (2). In addition, the channel activity of TRPV1 is remarkably upregulated by inflammatory mediators through the activation of phospholipase C and protein kinases A and C (PKA and PKC) signaling pathways (4 -13). Recent evidence shows that an increase in TRPV1 expression in peripheral nociceptors is critical for the maintenance of inflammatory hyperalgesia (14, 15). The involvement of TRPV1 in heat hypersensitivity is further underscored by the reduced sensitivity of mice lacking TRPV1 (16, 17) and by mice treated with receptor-specific antagonists (18).TRPV1 belongs to the family of transient receptor potential channels, which structurally resembles the family of voltagegated potassium or cyclic nucleotide-gated channels (19). Accordingly, these channels are presumed to be tetrameric assemblies of identical subunits (Fig. 1A), although heteromeric assemblies have be...

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Section: Methodsmentioning

confidence: 99%

Section: Fig 4 Trpv1 Localizes In Vesicles In Neuronsmentioning

confidence: 99%

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Regulated Exocytosis Contributes to Protein Kinase C Potentiation of Vanilloid Receptor Activity

Morenilla‐Palao

Planells-Cases

García-Sanz

et al. 2004

Journal of Biological Chemistry

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386

302

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“…Capsaicin stimulates the vanilloid receptor subtype 1 (VR1) located mainly on polymodal C-fibers and initiates a complex cascade of events, including neuronal excitation and release of proinflammatory mediators, desensitization of the receptor, and neuronal toxicity 9 . It can be considered a molecular integrator of noxious chemical and heat stimuli in the peripheral terminals of polymodal nociceptors [10][11][12] . According to a previous study 13 , the application of capsaicin cream dose-dependently reversed the thermal, mechanical, and chemical hyperalgesia observed in STZinduced diabetic mice.…”

Section: Introductionmentioning

confidence: 99%

Histopathological Changes of Streptozotocin-induced Painful Diabetes and Antihyperalgesic Effect of Capsaicin Cream in Rats

et al. 2008

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Abstract:To investigate the association between streptozotocin (STZ)-induced painful diabetic neuropathy and the antihyperalgesic effect of capsaicin cream in rats, we first examined the antihyperalgesic effect of capsaicin cream and subsequently performed peripheral neurohistochemical examinations of neuropathic rats. Mechanical hyperalgesia occurred 2 weeks after STZ injection and persisted for 8 weeks of testing. The neuropathy was alleviated by a single application of 0.1% capsaicin cream, but not by cream base. The hyperalgesia did not decrease when the capsaicin cream was applied to normal animals. On the other hand, for dorsal root ganglion (DRG) neurons and hind paw cutaneous nerves, the neurohistochemical examination showed no difference between STZ rats and control rats with capsaicin (vanilloid) receptor subtype 1 (VR1) and NF200 double immunohistochemical staining of DRG neurons, but an increase in A-fibers was seen in the hind paw cutaneous nerves of the STZ rats compared to the control rats. Neither STZ rats nor control rats were toxically affected by the single application of 0.1% capsaicin cream. These results suggest that a single application of capsaicin cream exerts an antihyperalgesic effect in rats with painful neuropathy and increases peripheral A-fibers. However, we could not clarify how VR1 was involved in the effect in rats with STZ painful diabetic neuropathy. (J Toxicol Pathol 2008; 21: 97-104)

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“…Moreover, TRPV1 antagonists were reported to elevate the withdrawal reflex threshold in response to noxious heat in preclinical species [129][130][131].…”

Section: Trpv1 Antagonists and Loss Of Warm Thermal Perception In Humansmentioning

confidence: 99%

TRPV1 Antagonists as Analgesic Agents

Trevisani

Gatti²

2013

TOPAINJ

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Abstract:The last decade (2001 -2010), declared as the Decade of Pain Control and Research by the United States Congress, brought significantly advances in our understanding of pain biology. Unfortunately, this has not translated into additional effective treatments of chronic pain conditions. Chronic pain is a debilitating and complex clinical state usually associated with diabetic neuropathy, postherpetic neuralgia, low back pathology, fibromyalgia, and neurological disorders. Standard pain drugs, even narcotic opioid analgesic agents, often provide unsatisfactory pain relief while causing important side-effect such as sedation, tolerance, dependence, respiratory depression and constipation. Furthermore, the effective management of chronic pain needs a multidisciplinary management approach and still represents one of the most urgent unmet medical need. Recently, preclinical research has uncovered new molecular mechanisms underlying the generation and transduction of pain, many of which represent new targets for innovative pharmacological interventions. This review focuses on Transient Receptor Potential (TRP) Vanilloid Type 1 (TRPV1) channel as a target for treating chronic pain. TRPV1 is a multifunctional ion channel involved in thermosensation (heat) and taste perception. Importantly, TRPV1 also functions as a molecular integrator for a broad variety of seemingly unrelated noxious stimuli. Indeed, TRPV1 is thought to be a major transducer of the thermal hyperalgesia that follows inflammation and/or tissue injury. Desensitization to topical TRPV1 agonists (e.g. capsaicin creams and patches) has been in clinical use for decades to treat chronic painful conditions like diabetic neuropathy. Most recently, a number of potent, small molecule TRPV1 antagonists have been advanced into clinical trials for pain relief. Perhaps not unexpectedly given the prominent role of TRPV1 in thermosensation, some of these antagonists showed worrisome adverse effects (hyperthermia and impaired noxious heat sensation) in humans, leading to their withdrawal from clinical trials. However, recent reports of TRPV1 antagonists that do not affect core body temperature in preclinical species suggest a potential opportunity to reduce at least this important side effect.

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Attenuation of thermal nociception and hyperalgesia by VR1 blockers

Cited by 185 publications

References 28 publications

Regulated Exocytosis Contributes to Protein Kinase C Potentiation of Vanilloid Receptor Activity

Regulated Exocytosis Contributes to Protein Kinase C Potentiation of Vanilloid Receptor Activity

Histopathological Changes of Streptozotocin-induced Painful Diabetes and Antihyperalgesic Effect of Capsaicin Cream in Rats

TRPV1 Antagonists as Analgesic Agents

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