Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0009443 (cold)
 92,137 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Neurons of the peripheral nervous system detect changes in temperature through activation of specialised ion channels. Members of the transient receptor potential family TRPM8 and TRPA1 are candidates for the principal transducers of cold stimuli. Using ratiometric calcium imaging we now show that 19% of acutely dissociated mouse dorsal root (DRG) and 45% of superior cervical ganglia (SCG) neurons responded to a brief cold stimulus. Amongst cold-responsive DRG neurons 34+/-2% responded to the TRPM8 agonist menthol, 18+/-3% to the TRPA1 agonist mustard oil and 5% to both stimuli. A third of the cold-sensitive neurons did not respond to any TRP channel agonist. Cold-sensitive neurons of the SCG did not respond to menthol and only 3% responded to mustard oil. The threshold of SCG neurons was at significantly cooler temperatures than that of DRG neurons. Using real-time PCR, TRPA1 was expressed over 100-fold more in DRG than SCG, while TRPM8 was present in DRG only. The relatively small amount of TRPA1 transcript present in SCG did not correlate with the high level of cold sensitivity. We conclude that cold sensitivity in sympathetic neurons and in a significant proportion of sensory neurons is generated in the absence of TRPM8 and TRPA1.
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PMID:Many cold sensitive peripheral neurons of the mouse do not express TRPM8 or TRPA1. 1694 52

The interaction between cold sensitivity and inflammation in mammals is not entirely understood. We have used adult rat dorsal root ganglion neurones in primary culture together with calcium microfluorimetry to assess the effects of selected inflammatory mediators on cold responses of cold- and menthol-sensitive (most likely TRPM8-expressing) neurones. We observed a high degree of functional co-expression of TRPM8, the receptors for the inflammatory agents bradykinin, prostaglandin E2 and histamine, and TRPA1 in cultured sensory neurones. Treatment with either bradykinin or prostaglandin E2 led to a reduction in the amplitude of the response to cooling and shifted the threshold temperature to colder values, and we provide evidence for a role of protein kinases C and A, respectively, in mediating these effects. In both cases the effects were mainly restricted to the subgroups of cold- and menthol-sensitive cells which had responded to the application of the inflammatory agents at basal temperature. This desensitization of cold-sensitive neurones may enhance inflammatory pain by removing the analgesic effects of gentle cooling.
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PMID:Desensitization of cold- and menthol-sensitive rat dorsal root ganglion neurones by inflammatory mediators. 1700 82

The recent discoveries of cold-sensitive transient receptor potential (TRP) channels prompted us to investigate the responses of neurons in trigeminal subnucleus caudalis (Vc) to intraoral cooling and agonists of TRPM8 and TRPA1. Single units responsive to lingual cooling were recorded in superficial laminae of Vc in thiopental-anesthetized rats. All units responded to noxious heat and 88% responded to menthol. Responses increased with menthol concentration from 0.1 to 1% (6.4-64 mM) and plateaued at 10% (640 mM). Noxious cold-evoked responses were significantly enhanced after menthol in a concentration-dependent manner. Constant-flow application of 1% menthol elicited a phasic discharge that adapted over 2-8 min and significantly enhanced subsequent cold-evoked but not heat-evoked responses; vehicle (10% ethanol) was ineffective. Reapplication of menthol 15 min later elicited a significantly reduced response (self-desensitization). Vc units were similarly excited phasically by 1% menthol dissolved in 40% ethanol. The 40% ethanol briefly excited Vc units during the first minute and reduced subsequent responses to noxious heat and cold while exhibiting neither self-desensitization nor cross-desensitization to menthol. Menthol cross-desensitized Vc responses to 40% ethanol. Most menthol-responsive units also responded to the TRPA1 agonists cinnamaldehyde and mustard oil, and the TRPV1 agonist capsaicin. Units in superficial Vc receive convergent input from primary afferents that express TRPM8, TRPA1, and/or TRPV1 channels, either directly or indirectly via intersubnuclear pathways. The convergent nature of these units suggests a general role in signaling noxious stimuli.
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PMID:Neurons in superficial trigeminal subnucleus caudalis responsive to oral cooling, menthol, and other irritant stimuli. 1715 Dec 23

Animals sense temperature--either cold or hot--by the direct activation of temperature-sensitive members of the TRP family of ion channels, the thermo-TRPs. To date, six TRP channels--TRPV1-4, TRPM8 and TRPA1--have been reported to be directly activated by heat and to be involved in thermosensation. Temperature sensing can be modulated by phosphorylation of intracellular residues by protein kinases or by insertion of new channels into the cell membrane. In this review we provide a brief overview of the properties of thermo-TRPs, and we summarise signalling pathways involved in their regulation.
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PMID:Modulation of temperature-sensitive TRP channels. 1718 12

Alterations in the intracellular signal transduction pathway in primary afferents may contribute to pain hypersensitivity. Recently, we have reported that the phosphorylation of extracellular signal-regulated protein kinase 1/2 (ERK1/2) and p38 mitogen-activated protein kinase (MAPK) occurs in primary afferent neurons in response to noxious stimulation of the peripheral tissue, i.e., activity-dependent activation of ERK1/2 and p38 MAPK in dorsal root ganglion (DRG) neurons. In the present study, we investigated the phosphorylation of ERK5, also known as big MAPK1, in the DRG by noxious stimulation using immunohistochemistry. Capsaicin injection induced phosphorylated ERK5 (p-ERK5) in small-to-medium diameter sensory neurons with a peak at 2 min after capsaicin injection. Furthermore, we examined the p-ERK5 labeling in the DRG after noxious heat and cold stimuli and found a stimulus intensity-dependent increase in the number of activated neurons. Most of these p-ERK5-immunoreactive neurons were small- and medium-sized neurons, which coexpressed transient receptor potential (TRP) ion channel TRPV1 and TRPA1 after noxious heat and cold stimuli, respectively. In contrast, there was no change in ERK5 phosphorylation in the spinal dorsal horn. The i.t. administration of ERK5 antisense oligodeoxynucleotide reversed heat hyperalgesia, but not mechanical allodynia, produced by capsaicin injection. Taken together, these findings suggest that the in vivo activation of the ERK5 signaling pathway in sensory neurons by noxious stimulation may be, at least in part, correlated with functional activity and, further, involved in the development of pain hypersensitivity.
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PMID:Intensity-dependent activation of extracellular signal-regulated protein kinase 5 in sensory neurons contributes to pain hypersensitivity. 1723 56

The nervous system senses peripheral damage through nociceptive neurons that transmit a pain signal. TRPA1 is a member of the Transient Receptor Potential (TRP) family of ion channels and is expressed in nociceptive neurons. TRPA1 is activated by a variety of noxious stimuli, including cold temperatures, pungent natural compounds, and environmental irritants. How such diverse stimuli activate TRPA1 is not known. We observed that most compounds known to activate TRPA1 are able to covalently bind cysteine residues. Here we use click chemistry to show that derivatives of two such compounds, mustard oil and cinnamaldehyde, covalently bind mouse TRPA1. Structurally unrelated cysteine-modifying agents such as iodoacetamide (IA) and (2-aminoethyl)methanethiosulphonate (MTSEA) also bind and activate TRPA1. We identified by mass spectrometry fourteen cytosolic TRPA1 cysteines labelled by IA, three of which are required for normal channel function. In excised patches, reactive compounds activated TRPA1 currents that were maintained at least 10 min after washout of the compound in calcium-free solutions. Finally, activation of TRPA1 by disulphide-bond-forming MTSEA is blocked by the reducing agent dithiothreitol (DTT). Collectively, our data indicate that covalent modification of reactive cysteines within TRPA1 can cause channel activation, rapidly signalling potential tissue damage through the pain pathway.
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PMID:Noxious compounds activate TRPA1 ion channels through covalent modification of cysteines. 1723 60

TRPA1 is an ion channel expressed by nociceptors and activated by irritant compounds such as mustard oil. The endogenous function of TRPA1 has remained unclear, a fact highlighted by ongoing debate over its potential role as a sensor of noxious cold. Here we show that intracellular Ca(2+) activates human TRPA1 via an EF-hand domain and that cold sensitivity occurs indirectly (and nonphysiologically) through increased [Ca(2+)](i) during cooling in heterologous systems.
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PMID:Direct activation of the ion channel TRPA1 by Ca2+. 1725 81

TRPA1 is expressed in primary sensory neurons and hair cells, and it is proposed to be activated by cold stimuli, mechanical stimuli, or pungent ingredients. However, its role in regulating synaptic transmission has never been documented yet. In the present study, we examined whether activation of the TRPA1 channels affects synaptic transmission in substantia gelatinosa (SG) neurons of adult rat spinal cord slices by using the whole-cell patch-clamp technique. A chief ingredient of mustard oil, allyl isothiocyanate (AITC), superfused for 2 min markedly increased the frequency and amplitude of spontaneous EPSCs (sEPSCs), which was accompanied by an inward current. Similar actions were produced by cinnamaldehyde and allicin. The AITC-induced increases in sEPSC frequency and amplitude were resistant to tetrodotoxin (TTX) and La3+, whereas being significantly reduced in extent in a Ca2+-free bath solution. In the presence of glutamate receptor antagonists CNQX and AP5, AITC did not generate any synaptic activities. The AITC-induced increases in sEPSC frequency and amplitude were reduced by ruthenium red, whereas being unaffected by capsazepine. AITC also increased the frequency and amplitude of spontaneous inhibitory postsynaptic currents; this AITC action was abolished in the presence of TTX or glutamate receptor antagonists. These results indicate that TRPA1 appears to be localized not only at presynaptic terminals on SG neurons to enhance glutamate release, but also in terminals of primary afferents innervating onto spinal inhibitory interneurons, which make synapses with SG neurons. This central modulation of sensory signals may be associated with physiological and pathological pain sensations.
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PMID:Activation of TRPA1 channel facilitates excitatory synaptic transmission in substantia gelatinosa neurons of the adult rat spinal cord. 1744 29

Members of the transient receptor potential (TRP) ion channel family mediate diverse sensory transduction processes in both vertebrates and invertebrates. In particular, members of the TRPA subfamily have distinct thermosensory roles in Drosophila, and mammalian TRPA1 is postulated to have a function in noxious cold sensation and mechanosensation. Here we show that mutations in trpa-1, the C. elegans ortholog of mouse Trpa1, confer specific defects in mechanosensory behaviors related to nose-touch responses and foraging. trpa-1 is expressed and functions in sensory neurons required for these mechanosensory behaviors, and contributes to neural responses of these cells to touch, particularly after repeated mechanical stimulation. Furthermore, mechanical pressure can activate C. elegans TRPA-1 heterologously expressed in mammalian cells. Collectively, these data demonstrate that trpa-1 encodes an ion channel that can be activated in response to mechanical pressure and is required for mechanosensory neuron function, suggesting a possible role in mechanosensory transduction or modulation.
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PMID:Caenorhabditis elegans TRPA-1 functions in mechanosensation. 1745 Jan 39

ThermoTRPs, a subset of the Transient Receptor Potential (TRP) family of cation channels, have been implicated in sensing temperature. TRPM8 and TRPA1 are both activated by cooling; however, it is unclear whether either ion channel is required for thermosensation in vivo. We show that mice lacking TRPM8 have severe behavioral deficits in response to cold stimuli. In thermotaxis assays of temperature gradient and two-temperature choice assays, TRPM8-deficient mice exhibit strikingly reduced avoidance of cold temperatures. TRPM8-deficient mice also lack behavioral response to cold-inducing icilin application and display an attenuated response to acetone, an unpleasant cold stimulus. However, TRPM8-deficient mice have normal nociceptive-like responses to subzero centigrade temperatures, suggesting the presence of at least one additional noxious cold receptor. Finally, we show that TRPM8 mediates the analgesic effect of moderate cooling after administration of formalin, a painful stimulus. Therefore, depending on context, TRPM8 contributes to sensing unpleasant cold stimuli or mediating the effects of cold analgesia.
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PMID:TRPM8 is required for cold sensation in mice. 1748 85


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