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)

Odontoblasts function as mechanosensory receptors because of the expression of mechanosensitive channels in these cells. However, it is unclear if odontoblasts direct the signal transmission evoked by heat/cold or osmotic changes. This study investigated the effects of heat/cold or osmotic changes on calcium signaling and the functional expression of the thermo/mechanosensitive transient receptor potential (TRP) channels in primary cultured mouse odontoblastic cells, with the use of RT-PCR, fluorometric calcium imaging, and electrophysiology. TRPV1, TRPV2, TRPV3, TRPV4, and TRPM3 mRNA was expressed, but TRPM8 and TRPA1 mRNA was not. The receptor-specific stimulation of TRPV1-3 (heat-sensing receptors) and TRPV4/ TRPM3 (mechanic receptors) caused increases in the intracellular calcium concentration. Moreover, the channel activities of TRPV1-4 and TRPM3 were confirmed by a whole-cell patch-clamp technique. These results suggest that primary cultured mouse odontoblasts express heat/mechanosensitive TRP channels and play a role in the underlying mechanisms of thermo/mechanosensitive sensory transmission.
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PMID:Odontoblast TRP channels and thermo/mechanical transmission. 1982 89

The functional activity of a number of ion channels is highly sensitive to large changes in temperature. Foremost among these are the thermosensing TRP channels which include cold- (TRPM8, TRPA1), warmth- (TRPV3, TRPV4), and heat-sensing (TRPV1, TRPV2) members. TRPV1, also known as the vanilloid receptor (VR1), is activated by ligands such as capsaicin, acidic pH, and heat (an increase in temperature to approximately 42 degrees C will lead to channel opening). Screening against the thermal gating of TRPV1 is generally performed using perfusion systems or water baths for temperature control, in conjunction with electrophysiology or Ca2 + influx readouts for direct functional assessment. These approaches are very useful, but have limited throughput or minimal thermo-temporal control. A standard real-time PCR machine with standard microplates allowed us to combine fluorescent Ca2 + detection with precise temperature manipulation to develop a homogeneous (Z' = 0.53), cell-based assay that uses temperature as the agonist. A temperature response curve of TRPV1 was obtained, which provided a T50 of 46.1 degrees C, and IC50 values against heat agonism were determined for known TRPV1 antagonists. Furthermore, we expanded this approach to a cold-activated ion channel, TRPM8. We developed and validated an analytical technique with broad applications for the study and screening of temperature-gated ion channels.
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PMID:Functional assessment of temperature-gated ion-channel activity using a real-time PCR machine. 1985 57

Vital bleaching procedures are a popular means of improving the appearance of discolored teeth. There is a wide array of whitening products for home and dental office use; all involves placing peroxide containing gels or solutions in contact with the teeth. In order to whiten teeth peroxide has to be able to penetrate tooth structure and oxidize colored compounds in the dentin. Unfortunately beauty comes with a price; many patients undergoing peroxide based whitening procedures complain of bleaching sensitivity (BS) arising in the treated teeth. In BS, pain can occur in healthy intact teeth without any provoking stimulus. Currently the mechanism of nociceptors activation in BS is unknown. A more common form of dental pain-dentin sensitivity (DS) occurs when stimuli such as cold or tactile stimulation contact areas of exposed dentin in otherwise healthy teeth. In DS, stimulation of the dentin results in fluid shifts in the dentinal tubules, these fluid shifts activate mechanosensitive nerve endings in the deep dentin and pulp. Since many aspects of BS and DS symptoms differ, it is hypothesized that that the mechanism of pain generation differs for these two conditions. Recently the functional properties of a chemosensitive ion channel-TRPA1 have been described. This channel is activated by a variety of oxidizer compounds including hydrogen peroxide. Pulpal sensory afferents express TRPA1. It is hypothesized that direct activation of intradental nerve activity via TRPA1 is the mechanism of BS pain. If this theory were correct, tooth sensitivity treatments that reduce the excitability of the intradental nerves such as potassium salts, would be the treatment of choice for BS.
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PMID:Pretty painful: why does tooth bleaching hurt? 2004 65

This study investigated the role of TRPA1 in the development and maintenance of mechanical and cold hyperalgesia in persistent inflammation induced by Complete Freund's Adjuvant (CFA) in mice. The intraplantar (i.pl.) injection of CFA induced a long lasting (28 days) hyperalgesia for both mechanical and thermal (cold) stimuli. The intraperitoneal (i.p., 30-300 mg/kg), intraplantar (i.pl., 100 microg/site) or intrathecal (i.t., 10 microg/site) injection of the TRPA1 selective antagonist HC-030031 significantly reduced the mechanical hyperalgesia evaluated by the von Frey hair test. The effect of HC-030031 was evidenced on the day after CFA injection and was kept throughout the test. However, the intracerebroventricular (i.c.v., 10 microg/site) injection of HC-030031 did not interfere with CFA-induced hyperalgesia. Treatment with HC-030031 (300 mg/kg, i.p.) completely inhibited the noxious cold hyperalgesia induced by tetrafluoroethane in mice that received CFA. The pre-treatment with the TRPA1 oligonucleotide antisense (AS-ODN, i.t.) consistently prevented both mechanical and cold hyperalgesia. Interestingly, both TRPA1 protein expression and mRNA were over-expressed in spinal cord and dorsal root ganglia (DRG) of mice treated with CFA, an effect that was fully prevented by the pre-treatment with the TRPA1 antagonist HC-030031. Collectively, the present results showed that TRPA1 present at either peripheral or spinal sites play a relevant role in the development and maintenance of both mechanical and cold hyperalgesia during CFA-induced inflammation. Thus, TRPA1 selective antagonists represent promising candidates to treat hyperalgesia in persistent inflammatory states.
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PMID:The involvement of the transient receptor potential A1 (TRPA1) in the maintenance of mechanical and cold hyperalgesia in persistent inflammation. 2005 30

TRPM8 and TRPA1 are cold-activated transient receptor potential (TRP) cation channels. TRPM8 is activated by moderate cooling, while TRPA1 is activated by extreme, noxious cold temperatures. These cold receptors are expressed in different subpopulations of primary afferent neurons. TRPA1 is co-expressed in a subpopulation of somatosensory neurons expressing TRPV1, which is activated by heat. However, the distribution and co-expression of these channels in the nodose-petrosal ganglion complex, which contains the jugular (JG), petrosal (PG), and nodose ganglia (NG) (mainly involved in putative somatic, chemo- and somato-sensation, and somato and visceral sensation, respectively), remain unknown. Here, we conducted in situ hybridization analysis of the rat nodose-petrosal ganglion complex using specific riboprobes for TRPM8, TRPA1, and TRPV1 to compare the features of the cranial sensory ganglia. Hybridization signals for TRPA1 were diffusely observed throughout these ganglia, whereas TRPM8 transcripts were seen in the JG and PG but not in the NG. We retrogradely labeled cranial nerve X with Fast Blue (fluorescent dye) and found TRPM8 transcripts in the jugular-vagal ganglion but not the NG neurons. TRPA1 transcripts were not detected in TRPM8-expressing neurons but were present in the subpopulation of TRPV1-expressing visceral sensory neurons. Taken together, these findings support that in the vagal system the expression of cold-activated TRP channels differs between nodose- and jugular-ganglion neurons suggesting different mechanisms of cold-transduction and that the TRPA1 distribution is consistent with its proposed function as a cold-sensing receptor in the visceral system.
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PMID:Distinct expression of cold receptors (TRPM8 and TRPA1) in the rat nodose-petrosal ganglion complex. 2007 39

The Ca(2+)-permeable cation channel TRPA1 acts as an ionotropic receptor for various pungent compounds and as a noxious cold sensor in sensory neurons. It is unclear what proportion of the TRPA1-mediated current is carried by Ca(2+) ions and how the permeation pathway changes during stimulation. Here, based on the relative permeability of the nonstimulated channel to cations of different size, we estimated a pore diameter of approximately 11 A. Combined patch-clamp and Fura-2 fluorescence recordings revealed that with 2 mM extracellular Ca(2+), and at a membrane potential of -80 mV, approximately 17% of the inward TRPA1 current is carried by Ca(2+). Stimulation with mustard oil evoked an apparent dilatation of the pore of 3 A and an increase in divalent cation selectivity and fractional Ca(2+) current. Mutations in the putative pore that reduced the divalent permeability and fractional Ca(2+) current also prevented mustard-oil-induced increases in Ca(2+) permeation. It is interesting that fractional Ca(2+) currents for wild-type and mutant TRPA1 were consistently higher than values predicted based on biionic reversal potentials using the Goldman-Hodgkin-Katz equation, suggesting that binding of Ca(2+) in the pore hinders monovalent cation permeation. We conclude that the pore of TRPA1 is dynamic and supports a surprisingly large Ca(2+) influx.
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PMID:Agonist-induced changes in Ca(2+) permeation through the nociceptor cation channel TRPA1. 2019 30

Previous studies investigated the neural and molecular underpinnings of the tingle sensation evoked by sanshool and other natural or synthetic alkylamides. Currently, we sought to characterize the psychophysical properties associated with administration of these compounds. Like other chemesthetic stimuli, the synthetic tingle analog isobutylalkylamide (IBA) evoked a sensation that was temporally dynamic. Repeated IBA application at short (30 sec) interstimulus intervals (ISI) resulted in a tingle sensation that increased across trials. Application at longer ISIs (approximately 30 min) resulted in a sensation of decreased intensity consistent with self-desensitization. Prior treatment with the TRPV1 or TRPA1 agonists, capsaicin and mustard oil did not cross-desensitize the tingle sensation evoked by IBA suggesting that neither TRPV1 nor TRPA1 participate in the transduction mechanism sub-serving tingle. When evaluated over 30-min time period, lingual IBA evoked a sensation that was described initially as tingling and pungent but after approximately 15 min, as a cooling sensation. Further, we found that the sensation evoked by lingual IBA was potentiated by simultaneous application of cold (0 degrees C) and cool (21 degrees C) thermal stimuli but was unaffected by warm (33 degrees C) and hot (41 degrees C) temperatures. Finally, to test the hypothesis that the tingling sensation is subserved by the activation of mechanosensitve fibers, we evaluated lingual tactile thresholds in the presence and absence of lingual IBA. The presence of IBA significantly raised lingual tactile thresholds, whereas capsaicin did not, identifying a role for mechanosensitive fibers in conveying the tingle sensation evoked by sanshool-like compounds. Collectively, these results show that lingual alkylamide evokes a complex sensation that is temporally dynamic and consistent with in vitro and in vivo experiments suggesting these compounds activate mechanosensitve neurons via blockade of KCNK two-pore potassium channels to induce the novel tingling sensation.
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PMID:Psychophysical evaluation of a sanshool derivative (alkylamide) and the elucidation of mechanisms subserving tingle. 2020 90

TRPA1 agonists cinnamaldehyde (CA) and mustard oil (allyl isothiocyanate=AITC) induce heat hyperalgesia and mechanical allodynia in human skin, and sensitize responses of spinal and trigeminal dorsal horn neurons to noxious skin heating in rats. TRPA1 is also implicated in cold nociception. We presently used behavioral methods to investigate if CA affects sensitivity to thermal and mechanical stimuli in rats. Unilateral intraplantar injection of CA (5-20%) induced a significant, concentration-dependent reduction in latency for ipsilateral paw withdrawal from a noxious heat stimulus, peaking (61.7% of pre-injection baseline) by 30 min with partial recovery at 120 min. The highest dose of CA also significantly reduced the contralateral paw withdrawal latency. CA significantly reduced mechanical withdrawal thresholds of the injected paw that peaked sooner (3 min) and was more profound (44.4% of baseline), with no effect contralaterally. Bilateral intraplantar injections of CA resulted in a significant cold hyperalgesia (cold plate test) and a weak enhancement of innocuous cold avoidance (thermal preference test). The data are consistent with roles for TRPA1 in thermal (hot and cold) hyperalgesia and mechanical allodynia.
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PMID:Behavioral evidence of thermal hyperalgesia and mechanical allodynia induced by intradermal cinnamaldehyde in rats. 2021 30

Cinnamaldehyde (1) is a pharmacologically active ingredient isolated from cassia twig (Ramulus Cinnamomi), which is commonly used in herbal remedies to treat fever-related diseases. Both TRPV1 and TRPM8 ion channel proteins are abundantly expressed in sensory neurons, and are assumed to act as a thermosensor, with the former mediating the feeling of warmth and the latter the feeling of cold in the body. Both of them have recently been reported to be involved in thermoregulation. The purpose of this paper is to further uncover the antipyretic mechanisms of 1 by investigating its effects on the mRNA expression levels and functions of both TRPV1 and TRPM8. The results showed that 1 could up-regulate the mRNA expression levels of TRPV1 at both 37 and 39 degrees C, and its calcium-mediating function was significantly increased at 39 degrees C, all of which could not be blocked by pretreatment of the neuronal cells with ruthenium red, a general transient receptor potential (TRP) blocker, indicating that the action of 1 was achieved through a non-TRPA1 channel pathway. In conclusion, the findings in our in vitro studies might account for part of the peripheral molecular mechanisms for the antipyretic action of 1.
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PMID:Cinnamaldehyde up-regulates the mRNA expression level of TRPV1 receptor potential ion channel protein and its function in primary rat DRG neurons in vitro. 2039 Jul 47

The TRPA1 channel has been proposed to be a molecular transducer of cold and inflammatory nociceptive signals. It is expressed on a subset of small primary afferent neurons both in the peripheral terminals, where it serves as a sensor, and on the central nerve endings in the dorsal horn. The substantia gelatinosa (SG) of the spinal cord is a key site for integration of noxious inputs. The SG neurons are morphologically and functionally heterogeneous and the precise synaptic circuits of the SG are poorly understood. We examined how activation of TRPA1 channels affects synaptic transmission onto SG neurons using whole-cell patch-clamp recordings and morphological analyses in adult rat spinal cord slices. Cinnamaldehyde (TRPA1 agonist) elicited a barrage of excitatory postsynaptic currents (EPSCs) in a subset of the SG neurons that responded to allyl isothiocyanate (less specific TRPA1 agonist) and capsaicin (TRPV1 agonist). Cinnamaldehyde evoked EPSCs in vertical and radial but not islet or central SG cells. Notably, cinnamaldehyde produced no change in inhibitory postsynaptic currents and nor did it produce direct postsynaptic effects. In the presence of tetrodotoxin, cinnamaldehyde increased the frequency but not amplitude of miniature EPSCs. Intriguingly, cinnamaldehyde had a selective inhibitory action on monosynaptic C- (but not Adelta-) fiber-evoked EPSCs. These results indicate that activation of spinal TRPA1 presynaptically facilitates miniature excitatory synaptic transmission from primary afferents onto vertical and radial cells to initiate action potentials. The presence of TRPA1 channels on the central terminals raises the possibility of bidirectional modulatory action in morphologically identified subclasses of SG neurons.
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PMID:TRPA1-expressing primary afferents synapse with a morphologically identified subclass of substantia gelatinosa neurons in the adult rat spinal cord. 2049 66


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