scholarly journals A tingling sanshool derivative excites primary sensory neurons and elicits nocifensive behavior in rats

2011 ◽  
Vol 105 (4) ◽  
pp. 1701-1710 ◽  
Author(s):  
Amanda H. Klein ◽  
Carolyn M. Sawyer ◽  
Karen L. Zanotto ◽  
Margaret A. Ivanov ◽  
Susan Cheung ◽  
...  
Keyword(s):  
Dorsal Root ◽  
Transient Receptor Potential ◽  
Thermal Sensitivity ◽  
Receptor Potential ◽  
Size Distributions ◽  
Mechanical Sensitivity ◽  
Drg Neurons ◽  
Intraplantar Injection ◽  
Cinnamic Aldehyde ◽  
Transient Receptor

Szechuan peppers contain hydroxy-α-sanshool that imparts desirable tingling, cooling, and numbing sensations. Hydroxy-α-sanshool activates a subset of sensory dorsal root ganglion (DRG) neurons by inhibiting two-pore potassium channels. We presently investigated if a tingle-evoking sanshool analog, isobutylalkenyl amide (IBA), excites rat DRG neurons and, if so, if these neurons are also activated by agonists of TRPM8, TRPA1, and/or TRPV1. Thirty-four percent of DRG neurons tested responded to IBA, with 29% of them also responding to menthol, 29% to cinnamic aldehyde, 66% to capsaicin, and subsets responding to two or more transient receptor potential (TRP) agonists. IBA-responsive cells had similar size distributions regardless of whether they responded to capsaicin or not; cells only responsive to IBA were larger. Responses to repeated application of IBA at a 5-min interstimulus interval exhibited self-desensitization (tachyphylaxis). Capsaicin did not cross-desensitize responses to IBA to any greater extent than the tachyphylaxis observed with repeated IBA applications. These findings are consistent with psychophysical observations that IBA elicits tingle sensation accompanied by pungency and cooling, with self-desensitization but little cross-desensitization by capsaicin. Intraplantar injection of IBA elicited nocifensive responses (paw licking, shaking-flinching, and guarding) in a dose-related manner similar to the effects of intraplantar capsaicin and serotonin. IBA had no effect on thermal sensitivity but enhanced mechanical sensitivity at the highest dose tested. These observations suggest that IBA elicits an unfamiliar aversive sensation that is expressed behaviorally by the limited response repertoire available to the animal.

scholarly journals FXYD6 promotes thermal nociception by regulating TRPV1

2021 ◽  
Vol 17 ◽  
pp. ???
Author(s):  
Hao Luo ◽  
Bing Cai ◽  
Jing Pan ◽  
Hai-Xiang Shi ◽  
Kai-Kai Wang ◽  
...  
Keyword(s):  
Transient Receptor Potential ◽  
Small Diameter ◽  
Receptor Potential ◽  
Transient Receptor Potential Channel ◽  
Hek293 Cells ◽  
Drg Neurons ◽  
Intraplantar Injection ◽  
Noxious Heat ◽  
Thermal Nociception ◽  
Transient Receptor

FXYD6, an unnecessary auxiliary subunit of Na+,K+-ATPase, is expressed in the nervous system. However, its functions remain largely unclear. In the present study, we find that FXYD6 is involved in the thermal nociception. FXYD6 was mainly expressed in small-diameter DRG neurons expressing transient receptor potential channel V1 (TRPV1). In the SNS-Cre/ Fxyd6F/F mice, loss of FXYD6 in these sensory neurons impaired the behavioral responses to noxious heat stimulus and intraplantar injection of capsaicin. The capsaicin-induced and TRPV1-mediated currents were decreased in the FXYD6–deficient DRG neurons. Heterologous expression of FXYD6 could increase the TRPV1 capsaicin-sensitive currents in HEK293 cells. Furthermore, we found that the negatively charged PGDEE motif in C-terminal of FXYD6 is required for the FXYD6/TRPV1 interaction and FXYD6-mediated enhancement of TRPV1. Disrupting the FXYD6/TRPV1 interaction with the TAT-PGDEE peptide could elevate the threshold of thermal nociception. Therefore, FXYD6 maintains the thermal nociception via interacting with TRPV1 channel in nociceptors.

scholarly journals An Evaluation of Understudied Phytocannabinoids and Their Effects in Two Neuronal Models

Molecules ◽  
2021 ◽  
Vol 26 (17) ◽  
pp. 5352
Author(s):  
Alex Straiker ◽  
Sierra Wilson ◽  
Wesley Corey ◽  
Michaela Dvorakova ◽  
Taryn Bosquez ◽  
...  
Keyword(s):  
Dorsal Root ◽  
Hippocampal Neurons ◽  
Transient Receptor Potential ◽  
Trp Channels ◽  
Receptor Potential ◽  
Neuronal Model ◽  
Cb1 Receptors ◽  
Drg Neurons ◽  
Cannabidiolic Acid ◽  
Transient Receptor

Cannabis contains more than 100 phytocannabinoids. Most of these remain poorly characterized, particularly in neurons. We tested a panel of five phytocannabinoids—cannabichromene (CBC), cannabidiolic acid (CBDA), cannabidivarin (CBDV), cannabidivarinic acid (CBDVA), and Δ9-tetrahydrocannabivarin (THCV) in two neuronal models, autaptic hippocampal neurons and dorsal root ganglion (DRG) neurons. Autaptic neurons expressed a form of CB1-dependent retrograde plasticity while DRGs expressed a variety of transient receptor potential (TRP) channels. CBC, CBDA, and CBDVA had little or no effect on neuronal cannabinoid signaling. CBDV and THCV differentially inhibited cannabinoid signaling. THCV inhibited CB1 receptors presynaptically while CBDV acted post-synaptically, perhaps by inhibiting 2-AG production. None of the compounds elicited a consistent DRG response. In summary, we find that two of five ‘minor’ phytocannabinoids tested antagonized CB1-based signaling in a neuronal model, but with very different mechanisms. Our findings highlight the diversity of potential actions of phytocannabinoids and the importance of fully evaluating these compounds in neuronal models.

scholarly journals Intracellular TRPA1 mediates Ca2+ release from lysosomes in dorsal root ganglion neurons

2016 ◽  
Vol 215 (3) ◽  
pp. 369-381 ◽  
Author(s):  
Shujiang Shang ◽  
Feipeng Zhu ◽  
Bin Liu ◽  
Zuying Chai ◽  
Qihui Wu ◽  
...  
Keyword(s):  
Dorsal Root Ganglion ◽  
Dorsal Root ◽  
Transient Receptor Potential ◽  
Receptor Potential ◽  
Allyl Isothiocyanate ◽  
Dorsal Root Ganglion Neurons ◽  
Drg Neurons ◽  
Vesicle Exocytosis ◽  
Transient Receptor ◽  
Ganglion Neurons

Transient receptor potential A1 (TRPA1) is a nonselective cation channel implicated in thermosensation and inflammatory pain. In this study, we show that TRPA1 (activated by allyl isothiocyanate, acrolein, and 4-hydroxynonenal) elevates the intracellular Ca2+ concentration ([Ca2+]i) in dorsal root ganglion (DRG) neurons in the presence and absence of extracellular Ca2+. Pharmacological and immunocytochemical analyses revealed the presence of TRPA1 channels both on the plasma membrane and in endolysosomes. Confocal line-scan imaging demonstrated Ca2+ signals elicited from individual endolysosomes (“lysosome Ca2+ sparks”) by TRPA1 activation. In physiological solutions, the TRPA1-mediated endolysosomal Ca2+ release contributed to ∼40% of the overall [Ca2+]i rise and directly triggered vesicle exocytosis and calcitonin gene-related peptide release, which greatly enhanced the excitability of DRG neurons. Thus, in addition to working via Ca2+ influx, TRPA1 channels trigger vesicle release in sensory neurons by releasing Ca2+ from lysosome-like organelles.

scholarly journals A capsaicinoid-based soft drug, AG1529, for attenuating TRPV1-mediated histaminergic and inflammatory sensory neuron excitability

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Magdalena Nikolaeva-Koleva ◽  
Laura Butron ◽  
Sara González-Rodríguez ◽  
Isabel Devesa ◽  
Pierluigi Valente ◽  
...  
Keyword(s):  
Transient Receptor Potential ◽  
Primary Cultures ◽  
Receptor Potential ◽  
Neuronal Firing ◽  
In Vivo Model ◽  
Drg Neurons ◽  
Trpv1 Channels ◽  
Soft Drug ◽  
Transient Receptor

AbstractTRPV1, a member of the transient receptor potential (TRP) family, is a nonselective calcium permeable ion channel gated by physical and chemical stimuli. In the skin, TRPV1 plays an important role in neurogenic inflammation, pain and pruritus associated to many dermatological diseases. Consequently, TRPV1 modulators could represent pharmacological tools to respond to important patient needs that still represent an unmet medical demand. Previously, we reported the design of capsaicinoid-based molecules that undergo dermal deactivation (soft drugs), thus preventing their long-term dermal accumulation. Here, we investigated the pharmacological properties of the lead antagonist, 2-((4-hydroxy-2-iodo-5-methoxybenzyl) amino)-2-oxoethyl dodecanoate (AG1529), on heterologously expressed human TRPV1 (hTRPV1), on nociceptor excitability and on an in vivo model of acute pruritus. We report that AG1529 competitively blocked capsaicin-evoked activation of hTRPV1 with micromolar potency, moderately affected pH-induced gating, and did not alter voltage- and heat-mediated responses. AG1529 displays modest receptor selectivity as it mildly blocked recombinant hTRPA1 and hTRPM8 channels. In primary cultures of rat dorsal root ganglion (DRG) neurons, AG1529 potently reduced capsaicin-evoked neuronal firing. AG1529 exhibited lower potency on pH-evoked TRPV1 firing, and TRPA1-elicited nociceptor excitability. Furthermore, AG1529 abolished histaminergic and inflammation mediated TRPV1 sensitization in primary cultures of DRG neurons. Noteworthy, dermal wiping of AG1529, either in an acetone-based formulation or in an anhydrous ointment, dose-dependently attenuated acute histaminergic itch in a rodent model. This cutaneous anti-pruritic effect was devoid of the normal nocifensive action evoked by the burning sensation of capsaicin. Taken together, these preclinical results unveil the mode of action of AG1529 on TRPV1 channels and substantiate the tenet that this capsaicinoid-based soft drug is a promising candidate for drug development as a topical anti-pruritic and anti-inflammatory medication.

scholarly journals Cutaneous Neuroimmune Interactions of TSLP and TRPV4 Play Pivotal Roles in Dry Skin-Induced Pruritus

2021 ◽  
Vol 12 ◽  
Author(s):  
Wook-Joo Lee ◽  
Won-Sik Shim
Keyword(s):  
Mast Cells ◽  
Dorsal Root ◽  
Transient Receptor Potential ◽  
Skin Barrier ◽  
Receptor Potential ◽  
Barrier Dysfunction ◽  
Dry Skin ◽  
Neuroimmune Interactions ◽  
Skin Conditions ◽  
Transient Receptor

Dry skin is a symptom of skin barrier dysfunction that evokes pruritus; however, the cutaneous neuroimmune interactions underlying dry skin-induced pruritus remain unclear. Therefore, we aimed to elucidate the mechanisms underlying dry skin-induced pruritus. To this end, an acetone/ethanol/water (AEW)-induced mouse model of dry skin was used in this study. We observed that the production of thymic stromal lymphopoietin (TSLP) significantly increased in the keratinocytes of AEW mice. Importantly, treatment with an antagonist of transient receptor potential cation channel subfamily V member 4 (TRPV4), HC067047, ameliorated dry skin conditions in AEW mice. The symptoms of dry skin were significantly reduced in Trpv4 knockout (KO) mice following treatment with AEW. The increase in the intracellular calcium levels by TSLP in the dorsal root ganglia (DRG) of Trpv4 KO mice was also significantly attenuated. The spontaneous scratching bouts were significantly decreased in both the HC067047-treated and Trpv4 KO AEW mice. Importantly, the TSLP-dependent release of tryptase from the mast cells was significantly reduced in both the HC067047-treated mice and Trpv4 KO AEW mice. Notably, inhibition of the TSLP-induced signaling pathway in DRG selectively reduced the spontaneous scratching bouts in AEW mice. Overall, the results demonstrated that the cutaneous neuroimmune interactions of TSLP and TRPV4 play pivotal roles in dry skin-induced pruritus.

scholarly journals Long-Term Diabetic Microenvironment Augments the Decay Rate of Capsaicin-Induced Currents in Mouse Dorsal Root Ganglion Neurons

Molecules ◽  
2019 ◽  
Vol 24 (4) ◽  
pp. 775
Author(s):  
Xingjuan Chen ◽  
Yaqian Duan ◽  
Ashley Riley ◽  
Megan Welch ◽  
Fletcher White ◽  
...  
Keyword(s):  
Peripheral Neuropathy ◽  
Dorsal Root Ganglion ◽  
Patch Clamp ◽  
Dorsal Root ◽  
Transient Receptor Potential ◽  
Receptor Potential ◽  
Dorsal Root Ganglion Neurons ◽  
Transient Receptor Potential Vanilloid ◽  
Drg Neurons ◽  
Ganglion Neurons

Individuals with end-stage diabetic peripheral neuropathy present with decreased pain sensation. Transient receptor potential vanilloid type 1 (TRPV1) is implicated in pain signaling and resides on sensory dorsal root ganglion (DRG) neurons. We investigated the expression and functional activity of TRPV1 in DRG neurons of the Ins2+/Akita mouse at 9 months of diabetes using immunohistochemistry, live single cell calcium imaging, and whole-cell patch-clamp electrophysiology. 2′,7′-Dichlorodihydrofluorescein diacetate (DCFH-DA) fluorescence assay was used to determine the level of Reactive Oxygen Species (ROS) in DRGs. Although TRPV1 expressing neuron percentage was increased in Ins2+/Akita DRGs at 9 months of diabetes compared to control, capsaicin-induced Ca2+ influx was smaller in isolated Ins2+/Akita DRG neurons, indicating impaired TRPV1 function. Consistently, capsaicin-induced Ca2+ influx was decreased in control DRG neurons cultured in the presence of 25 mM glucose for seven days versus those cultured with 5.5 mM glucose. The high glucose environment increased cytoplasmic ROS accumulation in cultured DRG neurons. Patch-clamp recordings revealed that capsaicin-activated currents decayed faster in isolated Ins2+/Akita DRG neurons as compared to those in control neurons. We propose that in poorly controlled diabetes, the accelerated rate of capsaicin-sensitive TRPV1 current decay in DRG neurons decreases overall TRPV1 activity and contributes to peripheral neuropathy.

Thermal sensitivity of isolated vagal pulmonary sensory neurons: role of transient receptor potential vanilloid receptors

2006 ◽  
Vol 291 (3) ◽  
pp. R541-R550 ◽  
Author(s):  
Dan Ni ◽  
Qihai Gu ◽  
Hong-Zhen Hu ◽  
Na Gao ◽  
Michael X. Zhu ◽  
...  
Keyword(s):  
Sensory Neurons ◽  
Transient Receptor Potential ◽  
Thermal Sensitivity ◽  
Receptor Potential ◽  
Ruthenium Red ◽  
Transient Receptor Potential Vanilloid ◽  
Temperature Sensitive ◽  
Inward Current ◽  
Transient Receptor ◽  
Increasing Temperature

A recent study has demonstrated that increasing the intrathoracic temperature from 36°C to 41°C induced a distinct stimulatory and sensitizing effect on vagal pulmonary C-fiber afferents in anesthetized rats ( J Physiol 565: 295–308, 2005). We postulated that these responses are mediated through a direct activation of the temperature-sensitive transient receptor potential vanilloid (TRPV) receptors by hyperthermia. To test this hypothesis, we studied the effect of increasing temperature on pulmonary sensory neurons that were isolated from adult rat nodose/jugular ganglion and identified by retrograde labeling, using the whole cell perforated patch-clamping technique. Our results showed that increasing temperature from 23°C (or 35°C) to 41°C in a ramp pattern evoked an inward current, which began to emerge after exceeding a threshold of ∼34.4°C and then increased sharply in amplitude as the temperature was further increased, reaching a peak current of 173 ± 27 pA ( n = 75) at 41°C. The temperature coefficient, Q10, was 29.5 ± 6.4 over the range of 35–41°C. The peak inward current was only partially blocked by pretreatment with capsazepine (Δ I = 48.1 ± 4.7%, n = 11) or AMG 9810 (Δ I = 59.2 ± 7.8%, n = 8), selective antagonists of the TRPV1 channel, but almost completely abolished (Δ I = 96.3 ± 2.3%) by ruthenium red, an effective blocker of TRPV1–4 channels. Furthermore, positive expressions of TRPV1–4 transcripts and proteins in these neurons were demonstrated by RT-PCR and immunohistochemistry experiments, respectively. On the basis of these results, we conclude that increasing temperature within the normal physiological range can exert a direct stimulatory effect on pulmonary sensory neurons, and this effect is mediated through the activation of TRPV1, as well as other subtypes of TRPV channels.

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