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Journal ArticleDOI

Impaired Nociception and Pain Sensation in Mice Lacking the Capsaicin Receptor

14 Apr 2000-Science (American Association for the Advancement of Science)-Vol. 288, Iss: 5464, pp 306-313
TL;DR: Sensory neurons from mice lacking VR1 are severely deficient in their responses to each of these noxious stimuli and are impaired in the detection of painful heat, and showed little thermal hypersensitivity in the setting of inflammation.
Abstract: The capsaicin (vanilloid) receptor VR1 is a cation channel expressed by primary sensory neurons of the "pain" pathway. Heterologously expressed VR1 can be activated by vanilloid compounds, protons, or heat (>43 degrees C), but whether this channel contributes to chemical or thermal sensitivity in vivo is not known. Here, we demonstrate that sensory neurons from mice lacking VR1 are severely deficient in their responses to each of these noxious stimuli. VR1-/- mice showed normal responses to noxious mechanical stimuli but exhibited no vanilloid-evoked pain behavior, were impaired in the detection of painful heat, and showed little thermal hypersensitivity in the setting of inflammation. Thus, VR1 is essential for selective modalities of pain sensation and for tissue injury-induced thermal hyperalgesia.
Citations
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Journal ArticleDOI
16 Oct 2009-Cell
TL;DR: Genetic, electrophysiological, and pharmacological studies are elucidating the molecular mechanisms that underlie detection, coding, and modulation of noxious stimuli that generate pain.

3,394 citations


Cites background from "Impaired Nociception and Pain Sensa..."

  • ...Lack of such sensitization in TRPV1-deficient mice provides genetic support for the idea that TRPV1 is a key component of the mechanism through which inflammation produces thermal hyperalgesia (Caterina et al., 2000; Davis et al., 2000)....

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  • ...These studies also demonstrated an essential role for this channel in the process whereby tissue injury and inflammation leads to heat hypersensitivity, reflecting the ability of TRPV1 to serve as a molecular integrator of thermal and chemical stimuli (Caterina et al., 2000; Davis et al., 2000)....

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  • ...Fourth, analysis of mice lacking this ion channel not only revealed a complete loss of capsaicin sensitivity, but these animals also exhibited significant impairment in their ability to detect and respond to noxious heat (Caterina et al., 2000; Davis et al., 2000)....

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Journal ArticleDOI
TL;DR: The present review focuses on the organisation of descending pathways and their pathophysiological significance, the role of individual transmitters and specific receptor types in the modulation and expression of mechanisms of descending inhibition and facilitation and the advantages and limitations of established and innovative analgesic strategies which act by manipulation of descending controls.

2,565 citations


Cites background from "Impaired Nociception and Pain Sensa..."

  • ...Accordingly, stimulation of VR1 receptors on the central and peripheral terminals of C fibres may contribute to its influence upon nociception (Caterina et al., 2000; Di Marzo et al., 2000; De Petrocellis et al., 2001; Gauldie et al., 2001; Morisset et al., 2001; Tognetto et al., 2001)....

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Journal ArticleDOI
04 Dec 2003-Nature
TL;DR: TRP channels are the vanguard of the authors' sensory systems, responding to temperature, touch, pain, osmolarity, pheromones, taste and other stimuli, but their role is much broader than classical sensory transduction.
Abstract: TRP channels are the vanguard of our sensory systems, responding to temperature, touch, pain, osmolarity, pheromones, taste and other stimuli. But their role is much broader than classical sensory transduction. They are an ancient sensory apparatus for the cell, not just the multicellular organism, and they have been adapted to respond to all manner of stimuli, from both within and outside the cell.

2,502 citations

Journal ArticleDOI
13 Sep 2001-Nature
TL;DR: Efforts to determine how primary sensory neurons detect pain-producing stimuli of a thermal, mechanical or chemical nature have revealed new signalling mechanisms and brought us closer to understanding the molecular events that facilitate transitions from acute to persistent pain.
Abstract: The sensation of pain alerts us to real or impending injury and triggers appropriate protective responses. Unfortunately, pain often outlives its usefulness as a warning system and instead becomes chronic and debilitating. This transition to a chronic phase involves changes within the spinal cord and brain, but there is also remarkable modulation where pain messages are initiated - at the level of the primary sensory neuron. Efforts to determine how these neurons detect pain-producing stimuli of a thermal, mechanical or chemical nature have revealed new signalling mechanisms and brought us closer to understanding the molecular events that facilitate transitions from acute to persistent pain.

2,416 citations

Journal ArticleDOI
07 Mar 2002-Nature
TL;DR: These findings, together with the previous identification of the heat-sensitive channels VR1 and VRL-1, demonstrate that TRP channels detect temperatures over a wide range and are the principal sensors of thermal stimuli in the mammalian peripheral nervous system.
Abstract: The cellular and molecular mechanisms that enable us to sense cold are not well understood. Insights into this process have come from the use of pharmacological agents, such as menthol, that elicit a cooling sensation. Here we have characterized and cloned a menthol receptor from trigeminal sensory neurons that is also activated by thermal stimuli in the cool to cold range. This cold- and menthol-sensitive receptor, CMR1, is a member of the TRP family of excitatory ion channels, and we propose that it functions as a transducer of cold stimuli in the somatosensory system. These findings, together with our previous identification of the heat-sensitive channels VR1 and VRL-1, demonstrate that TRP channels detect temperatures over a wide range and are the principal sensors of thermal stimuli in the mammalian peripheral nervous system.

2,377 citations

References
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Journal ArticleDOI
22 Oct 1997-Nature
TL;DR: The cloned capsaicin receptor is also activated by increases in temperature in the noxious range, suggesting that it functions as a transducer of painful thermal stimuli in vivo.
Abstract: Capsaicin, the main pungent ingredient in 'hot' chilli peppers, elicits a sensation of burning pain by selectively activating sensory neurons that convey information about noxious stimuli to the central nervous system We have used an expression cloning strategy based on calcium influx to isolate a functional cDNA encoding a capsaicin receptor from sensory neurons This receptor is a non-selective cation channel that is structurally related to members of the TRP family of ion channels The cloned capsaicin receptor is also activated by increases in temperature in the noxious range, suggesting that it functions as a transducer of painful thermal stimuli in vivo

8,186 citations

Journal ArticleDOI
01 Jan 1988-Pain
TL;DR: Both the thermal method and the Randall‐Selitto mechanical method detected dose‐related hyperalgesia and its blockade by either morphine or indomethacin, but the Thermal method showed greater bioassay sensitivity and allowed for the measurement of other behavioral parameters in addition to the nociceptive threshold.
Abstract: A method to measure cutaneous hyperalgesia to thermal stimulation in unrestrained animals is described. The testing paradigm uses an automated detection of the behavioral end-point; repeated testing does not contribute to the development of the observed hyperalgesia. Carrageenan-induced inflammation resulted in significantly shorter paw withdrawal latencies as compared to saline-treated paws and these latency changes corresponded to a decreased thermal nociceptive threshold. Both the thermal method and the Randall-Selitto mechanical method detected dose-related hyperalgesia and its blockade by either morphine or indomethacin. However, the thermal method showed greater bioassay sensitivity and allowed for the measurement of other behavioral parameters in addition to the nociceptive threshold.

4,829 citations

Journal ArticleDOI
29 Jul 1999-Nature
TL;DR: It is shown that the vasodilator response to anandamide in isolated arteries is capsaicin-sensitive and accompanied by release of calcitonin-gene-related peptide (CGRP), which indicates that the vanilloid receptor may be another molecular target for endogenousAnandamide, besides cannabinoid receptors, in the nervous and cardiovascular systems.
Abstract: The endogenous cannabinoid receptor agonist anandamide is a powerful vasodilator of isolated vascular preparations, but its mechanism of action is unclear. Here we show that the vasodilator response to anandamide in isolated arteries is capsaicin-sensitive and accompanied by release of calcitonin-gene-related peptide (CGRP). The selective CGRP-receptor antagonist 8-37 CGRP, but not the cannabinoid CB1 receptor blocker SR141716A, inhibited the vasodilator effect of anandamide. Other endogenous (2-arachidonylglycerol, palmitylethanolamide) and synthetic (HU 210, WIN 55,212-2, CP 55,940) CB1 and CB2 receptor agonists could not mimic the action of anandamide. The selective 'vanilloid receptor' antagonist capsazepine inhibited anandamide-induced vasodilation and release of CGRP. In patch-clamp experiments on cells expressing the cloned vanilloid receptor (VR1), anandamide induced a capsazepine-sensitive current in whole cells and isolated membrane patches. Our results indicate that anandamide induces vasodilation by activating vanilloid receptors on perivascular sensory nerves and causing release of CGRP. The vanilloid receptor may thus be another molecular target for endogenous anandamide, besides cannabinoid receptors, in the nervous and cardiovascular systems.

2,113 citations

Journal Article
TL;DR: This paper focuses on hot pepper, which is eaten on a daily basis by an estimated one-quarter of the world’s population and has potential to be a biological target for regenerative medicine.
Abstract: Natural products afford a window of opportunity to study important biology. If the natural product is used or abused by human beings, finding its biological target(s) is all the more significant. Hot pepper is eaten on a daily basis by an estimated one-quarter of the world’s population and

1,848 citations