scholarly journals Inflammatory and neuropathic cold allodynia are selectively mediated by the neurotrophic factor receptor GFRα3

2016 ◽  
Vol 113 (16) ◽  
pp. 4506-4511 ◽  
Author(s):  
Erika K. Lippoldt ◽  
Serra Ongun ◽  
Geoffrey K. Kusaka ◽  
David D. McKemy
Keyword(s):  
Chronic Pain ◽  
Neurotrophic Factor ◽  
Neutralizing Antibodies ◽  
Tissue Injury ◽  
Cold Sensitivity ◽  
Mechanical Stimuli ◽  
Cold Pain ◽  
Cold Allodynia ◽  
Cold Sensitive ◽  
Striking Contrast

Tissue injury prompts the release of a number of proalgesic molecules that induce acute and chronic pain by sensitizing pain-sensing neurons (nociceptors) to heat and mechanical stimuli. In contrast, many proalgesics have no effect on cold sensitivity or can inhibit cold-sensitive neurons and diminish cooling-mediated pain relief (analgesia). Nonetheless, cold pain (allodynia) is prevalent in many inflammatory and neuropathic pain settings, with little known of the mechanisms promoting pain vs. those dampening analgesia. Here, we show that cold allodynia induced by inflammation, nerve injury, and chemotherapeutics is abolished in mice lacking the neurotrophic factor receptor glial cell line-derived neurotrophic factor family of receptors-α3 (GFRα3). Furthermore, established cold allodynia is blocked in animals treated with neutralizing antibodies against the GFRα3 ligand, artemin. In contrast, heat and mechanical pain are unchanged, and results show that, in striking contrast to the redundant mechanisms sensitizing other modalities after an insult, cold allodynia is mediated exclusively by a single molecular pathway, suggesting that artemin–GFRα3 signaling can be targeted to selectively treat cold pain.

scholarly journals Detection of Cold Pain, Cold Allodynia and Cold Hyperalgesia in Freely Behaving Rats

2005 ◽  
Vol 1 ◽  
pp. 1744-8069-1-36 ◽  
Author(s):  
Andrew J Allchorne ◽  
Daniel C Broom ◽  
Clifford J Woolf
Keyword(s):  
Neuropathic Pain ◽  
Nerve Injury ◽  
Effective Means ◽  
Response Threshold ◽  
Cold Sensitivity ◽  
Spared Nerve Injury ◽  
Cold Pain ◽  
Cold Allodynia ◽  
Cold Hyperalgesia ◽  
Withdrawal Response

Background: Pain is elicited by cold, and a major feature of many neuropathic pain states is that normally innocuous cool stimuli begin to produce pain (cold allodynia). To expand our understanding of cold induced pain states we have studied cold pain behaviors over a range of temperatures in several animal models of chronic pain. Results: We demonstrate that a Peltier-cooled cold plate with ± 1°C sensitivity enables quantitative measurement of a detection withdrawal response to cold stimuli in unrestrained rats. In naïve rats the threshold for eliciting cold pain behavior is 5°C. The withdrawal threshold for cold allodynia is 15°C in both the spared nerve injury and spinal nerve ligation models of neuropathic pain. Cold hyperalgesia is present in the spared nerve injury model animals, manifesting as a reduced latency of withdrawal response threshold at temperatures that elicit cold pain in naïve rats. We also show that following the peripheral inflammation produced by intraplantar injection of complete Freund's adjuvant, a hypersensitivity to cold occurs. Conclusion: The peltier-cooled provides an effective means of assaying cold sensitivity in unrestrained rats. Behavioral testing of cold allodynia, hyperalgesia and pain will greatly facilitate the study of the neurobiological mechanisms involved in cold/cool sensations and enable measurement of the efficacy of pharmacological treatments to reduce these symptoms.

Suppressors of a Cold-Sensitive Mutation in Yeast U4 RNA Define Five Domains in the Splicing Factor Prp8 That Influence Spliceosome Activation

Genetics ◽  
2000 ◽  
Vol 155 (4) ◽  
pp. 1667-1682 ◽  
Author(s):  
Andreas N Kuhn ◽  
David A Brow
Keyword(s):  
Large Scale ◽  
Splicing Factor ◽  
Cold Sensitivity ◽  
Splicing Factors ◽  
Loss Of Function ◽  
U1 Snrnp ◽  
Snrnp Protein ◽  
Cold Sensitive ◽  
Spliceosome Activation ◽  
U4 Rna

AbstractThe highly conserved splicing factor Prp8 has been implicated in multiple stages of the splicing reaction. However, assignment of a specific function to any part of the 280-kD U5 snRNP protein has been difficult, in part because Prp8 lacks recognizable functional or structural motifs. We have used a large-scale screen for Saccharomyces cerevisiae PRP8 alleles that suppress the cold sensitivity caused by U4-cs1, a mutant U4 RNA that blocks U4/U6 unwinding, to identify with high resolution five distinct regions of PRP8 involved in the control of spliceosome activation. Genetic interactions between two of these regions reveal a potential long-range intramolecular fold. Identification of a yeast two-hybrid interaction, together with previously reported results, implicates two other regions in direct and indirect contacts to the U1 snRNP. In contrast to the suppressor mutations in PRP8, loss-of-function mutations in the genes for two other splicing factors implicated in U4/U6 unwinding, Prp44 (Brr2/Rss1/Slt22/Snu246) and Prp24, show synthetic enhancement with U4-cs1. On the basis of these results we propose a model in which allosteric changes in Prp8 initiate spliceosome activation by (1) disrupting contacts between the U1 snRNP and the U4/U6-U5 tri-snRNP and (2) orchestrating the activities of Prp44 and Prp24.

scholarly journals Odontoblast TRPC5 channels signal cold pain in teeth

2021 ◽  
Vol 7 (13) ◽  
pp. eabf5567
Author(s):  
Laura Bernal ◽  
Pamela Sotelo-Hitschfeld ◽  
Christine König ◽  
Viktor Sinica ◽  
Amanda Wyatt ◽  
...  
Keyword(s):  
Relative Sensitivity ◽  
Cellular Component ◽  
Sensory Transduction ◽  
Cold Sensation ◽  
Cold Pain ◽  
Sensing System ◽  
Cold Sensitive ◽  
Cellular Components ◽  
Cold Sensor ◽  
Cold Sensing

Teeth are composed of many tissues, covered by an inflexible and obdurate enamel. Unlike most other tissues, teeth become extremely cold sensitive when inflamed. The mechanisms of this cold sensation are not understood. Here, we clarify the molecular and cellular components of the dental cold sensing system and show that sensory transduction of cold stimuli in teeth requires odontoblasts. TRPC5 is a cold sensor in healthy teeth and, with TRPA1, is sufficient for cold sensing. The odontoblast appears as the direct site of TRPC5 cold transduction and provides a mechanism for prolonged cold sensing via TRPC5’s relative sensitivity to intracellular calcium and lack of desensitization. Our data provide concrete functional evidence that equipping odontoblasts with the cold-sensor TRPC5 expands traditional odontoblast functions and renders it a previously unknown integral cellular component of the dental cold sensing system.

scholarly journals C-terminal domain small phosphatase 1 (CTDSP1) regulates growth factor expression and axonal regeneration in peripheral nerve tissue

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Noreen M. Gervasi ◽  
Alexander Dimtchev ◽  
Desraj M. Clark ◽  
Marvin Dingle ◽  
Alexander V. Pisarchik ◽  
...  
Keyword(s):  
Chronic Pain ◽  
Peripheral Nerve ◽  
Neurotrophic Factor ◽  
Axon Growth ◽  
Nerve Tissue ◽  
Mesenchymal Progenitor Cells ◽  
Drg Neurons ◽  
Peripheral Neurons ◽  
Terminal Domain ◽  
Factor Expression

AbstractPeripheral Nerve Injury (PNI) represents a major clinical and economic burden. Despite the ability of peripheral neurons to regenerate their axons after an injury, patients are often left with motor and/or sensory disability and may develop chronic pain. Successful regeneration and target organ reinnervation require comprehensive transcriptional changes in both injured neurons and support cells located at the site of injury. The expression of most of the genes required for axon growth and guidance and for synapsis formation is repressed by a single master transcriptional regulator, the Repressor Element 1 Silencing Transcription factor (REST). Sustained increase of REST levels after injury inhibits axon regeneration and leads to chronic pain. As targeting of transcription factors is challenging, we tested whether modulation of REST activity could be achieved through knockdown of carboxy-terminal domain small phosphatase 1 (CTDSP1), the enzyme that stabilizes REST by preventing its targeting to the proteasome. To test whether knockdown of CTDSP1 promotes neurotrophic factor expression in both support cells located at the site of injury and in peripheral neurons, we transfected mesenchymal progenitor cells (MPCs), a type of support cells that are present at high concentrations at the site of injury, and dorsal root ganglion (DRG) neurons with REST or CTDSP1 specific siRNA. We quantified neurotrophic factor expression by RT-qPCR and Western blot, and brain-derived neurotrophic factor (BDNF) release in the cell culture medium by ELISA, and we measured neurite outgrowth of DRG neurons in culture. Our results show that CTDSP1 knockdown promotes neurotrophic factor expression in both DRG neurons and the support cells MPCs, and promotes DRG neuron regeneration. Therapeutics targeting CTDSP1 activity may, therefore, represent a novel epigenetic strategy to promote peripheral nerve regeneration after PNI by promoting the regenerative program repressed by injury-induced increased levels of REST in both neurons and support cells.

Sequential cold-sensitive mutations in Aspergillus fumigatus

1978 ◽  
Vol 24 (2) ◽  
pp. 84-88 ◽  
Author(s):  
Ole Nielsen ◽  
Kenneth F. Gregory
Keyword(s):  
Aspergillus Fumigatus ◽  
Type A ◽  
Maximum Growth ◽  
Cold Sensitivity ◽  
Nonpermissive Temperature ◽  
Wild Type ◽  
Cold Sensitive ◽  
Wild Type Parent ◽  
Thermotolerant Fungus

Mutants of the thermotolerant fungus Aspergillus fumigatus I-21 (ATCC 32722) unable to grow at 37 °C were sought. Cold-sensitive mutants were enriched from progeny spores of γ-irradiated conidia by two or more incubations at various nonpermissive temperatures alternating with filtrations through cheesecloth. The approximate minimum, optimum, and maximum growth temperatures of the parent were 12, 40, and 50 °C, respectively. Mutants unable to grow at 37 °C were not successfully isolated directly from the wild type. A mutant unable to grow at 25 °C was isolated and mutations further increasing the cold sensitivity by increments of 3–5 °C were found to occur. Mutants completely unable to grow at 37 °C were obtained by five sequential mutations. All mutants grew as fast as the wild-type parent at 45 °C and higher. Each mutant produced revenants able to grow not only at the nonpermissive temperature used for its isolation but also at lower temperatures.

scholarly journals Suppression of ΔbipA Phenotypes in Escherichia coli by Abolishment of Pseudouridylation at Specific Sites on the 23S rRNA

2008 ◽  
Vol 190 (23) ◽  
pp. 7675-7683 ◽  
Author(s):  
Karthik Krishnan ◽  
Ann M. Flower
Keyword(s):  
Escherichia Coli ◽  
Target Genes ◽  
Regulatory Protein ◽  
Elongation Factor ◽  
Direct Interaction ◽  
Cold Sensitivity ◽  
23S Rrna ◽  
Pseudouridine Synthase ◽  
Suppressor Effect ◽  
Cold Sensitive

ABSTRACT The BipA protein of Escherichia coli has intriguing similarities to the elongation factor subfamily of GTPases, including EF-Tu, EF-G, and LepA. In addition, phenotypes of a bipA deletion mutant suggest that BipA is involved in regulation of a variety of pathways. These two points have led to speculation that BipA may be a novel regulatory protein that affects efficient translation of target genes through direct interaction with the ribosome. We isolated and characterized suppressors of the cold-sensitive growth phenotype exhibited by ΔbipA strains and identified insertion mutations in rluC. The rluC gene encodes a pseudouridine synthase responsible for pseudouridine modification of 23S rRNA at three sites, all located near the peptidyl transferase center. Deletion of rluC not only suppressed cold sensitivity but also alleviated the decrease in capsule synthesis exhibited by bipA mutants, suggesting that the phenotypic effects of BipA are manifested through an effect on the ribosome. The suppressor effect is specific to rluC, as deletion of other rlu genes did not relieve cold sensitivity, and further, more than a single pseudouridine residue is involved, as alteration of single residues did not produce suppressors. These results are consistent with a role for BipA in either the structure or the function of the ribosome and imply that wild-type ribosomes are dependent on BipA for efficient expression of target mRNAs and that the lack of pseudouridylation at these three sites renders the ribosomes BipA independent.

Evidence for the involvement of peripheral cold-sensitive TRPM8 channels in human cutaneous hygrosensation

2020 ◽  
Vol 318 (3) ◽  
pp. R579-R589 ◽  
Author(s):  
Oliver Typolt ◽  
Davide Filingeri
Keyword(s):  
Human Skin ◽  
Chemical Activation ◽  
The Body ◽  
Cold Sensitivity ◽  
Trpm8 Channel ◽  
Body Regions ◽  
Skin Cooling ◽  
Cold Sensitive ◽  
Skin Wetness

In contrast to other species, humans are believed to lack hygroreceptors for sensing skin wetness. Yet, the molecular basis of human hygrosensation is currently unknown, and it remains unclear whether we possess a receptor-mediated sensing mechanism for skin wetness. The aim of this study was to assess the role of the cutaneous cold-sensitive transient receptor potential melastatin-8 (TRPM8) channel as a molecular mediator of human hygrosensation. To this end, we exploited both the thermal and chemical activation of TRPM8-expressing cutaneous Aδ cold thermoreceptors, and we assessed wetness sensing in healthy young men in response to 1) dry skin cooling in the TRPM8 range of thermosensitivity and 2) application of the TRPM8 agonist menthol. Our results indicate that 1) independently of contact with moisture, a cold-dry stimulus in the TRPM8 range of activation induced wetness perceptions across 12 different body regions and those wetness perceptions varied across the body following regional differences in cold sensitivity; and 2) independently of skin cooling, menthol-induced stimulation of TRPM8 triggered wetness perceptions that were greater than those induced by physical dry cooling and by contact with an aqueous cream containing actual moisture. For the first time, we show that the cutaneous cold-sensing TRPM8 channel plays the dual role of cold and wetness sensor in human skin and that this ion channel is a peripheral mediator of human skin wetness perception.

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