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THERMAL GRADIENT TEST
(Model: BIO-GRADIENT - Lanes - Mice: 2 / Rats: 1)
The operator-independant Thermal Gradient Test is a new analgesia/nociceptive research instrument to demonstrate place preference / temperature comfort threshold on rodents (mouse and rat) freely moving on a plate offering a temperature gradient - an innovative tool for analgesic drug screening and research on thermal nociception.

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  • CNRS Marseille, France
  • UNIL Lausanne, Suisse
  • UNIVERSIDAD MIGUEL HERNANDEZ CSIC San Juan de Alicante, Espagne
  • SWISS FEDERAL INTITUTE OF TECHNOLOGY Lausanne, Suisse
  • PFIZER Sandwich, USA
  • CNRS Montpellier, France
  • HARVARD MEDICAL SCHOOL Boston, USA
  • PFISER Sandwich, UK
  • KU LEUVEN Leuven, Belgium
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! NEW RESEARCH WORK ! A recent publication by M Bohic, I Marics, C Santos, P Malapert, N Ben-Arie et al in "Cell Reports" highlights the merits of using Bioseb's Thermal Gradient Test: Loss of bhlha9 Impairs Thermotaxis and Formalin-Evoked Pain in a Sexually Dimorphic Manner

Loss of bhlha9 Impairs Thermotaxis and Formalin-Evoked Pain in a Sexually Dimorphic Manner
M Bohic, I Marics, C Santos, P Malapert, N Ben-Arie et al
Aix-Marseille Université, CNRS, Institut de Biologie du Développement de Marseille, Marseille, France
Published in "Cell Reports" (2020-01-21)


C-LTMRs are known to convey affective aspects of touch and to modulate injury-induced pain in humans and mice. However, a role for these neurons in temperature sensation has been suggested, but not fully demonstrated. Here, we report that deletion of C-low-threshold mechanoreceptor (C-LTMR)-expressed bhlha9 causes impaired thermotaxis behavior and exacerbated formalin-evoked pain in male, but not female, mice. Positive modulators of GABAA receptors failed to relieve inflammatory formalin pain and failed to decrease the frequency of spontaneous excitatory post-synaptic currents (sEPSCs) selectively in bhlha9 knockout (KO) males. This could be explained by a drastic change in the GABA content of lamina II inner inhibitory interneurons contacting C-LTMR central terminals. Finally, C-LTMR-specific deep RNA sequencing revealed more genes differentially expressed in male than in female bhlha9 KO C-LTMRs. Our data consolidate the role of C-LTMRs in modulation of formalin pain and provide in vivo evidence of their role in the discriminative aspects of temperature sensation.
Presentation

Bioseb's Thermal Gradient Test: Software screenshot
Thermal Gradient Test: Software screenshot
Bioseb’s operator-independant Thermal Gradient Test is a new analgesia/nociceptive research instrument to demonstrate place preference and temperature comfort threshold on rodents (mouse and rat) freely moving on a long plate offering a stable temperature gradient between two compartments.

As advised by A. MOQRICH, and published in Moqrich et al (Science 2005, 307: 1468-72), the Thermal Gradient Test, like the Thermal Place Preference test, allows researchers to work on unrestrained animals (mice and rats) let free to choose their preferred position (comfort zone) between 2 compartments set at different temperatures. This behavioural assay will allow monitoring temperature preferences, nociceptive thresholds and state in the role of a given gene or a compound on these pain thresholds associated to cold and hot stimulation.

The Thermal Gradient Test, unlike the cold/hot plate test, is one of the very few thermal nociception tests to be operator-independant on freely moving rodents (mice and rat). The "Thermal Gradient Test" will return a nociceptive response without any action from the operator, and the obtained value is a temperature range corresponding to the comfort zone of the animal (rat or mouse), and indicating its sensitivity resulting to the exposure to different stimulations (cold or heat).

Bioseb’s Thermal Gradient Test is ideal for your research on analgesia and nociception, and especially suitable for studies on alodynia.

Operating principle

Using the included controls on the the electronic console, a continuous and stable temperature gradient (5 to 55°C) is established over a 120 cm long base plate, on which the animal is free to walk in an unrestrained manner.

Following the exploration period, the rodent (mouse or rat) shows a distinct zone preference, or comfort zone, which is an indication of his level of thermal sensitivity, and which can be determined by mesuring the time spent by the rodent in each of the 20 different temperature zones which can be set using the software.

Bioseb's Thermal Gradient Test: Software screenshot
Thermal Gradient Test: Software screenshot
The Gradient test allow to work independently and simultaneously with 2 mice (or small rats) or 1 adult rat.

Software

The Thermal Gradient Test software, coupled to a video camera, measures and displays for each animal (rat or mouse), and for up to 20 temperature zones, the time spent per time period in each temperature zone, together with the overall traveled distance.

The encrypted data and the video images are recorded synchronously in real time during the nociception experiments. This allows the operator to replay and check the animal behavior at any time and remotely. Results can also be exported in .xls format for further analysis.

Key features

• Simple to use, fast and accurate
• Fully automated
• Operator-independent
• Thermal nociception tests on freely moving rodents
Domains of application

• Analgesic drug screening
• Basal pain sensitivity phenotyping
• Ion channel related pain
• Cold/Hot hypersensivity
• Dysesthesia

Publications (Click on an article to show details and read the abstract)

PAIN
- General pain -
Decreased alertness due to sleep loss increases pain sensitivity in mice (2017)
Decreased alertness due to sleep loss increases pain sensitivity in mice
C Alexandre, A Latremoliere, A Ferreira, G Miracca, M Yamamoto, TE Scammell, CJ Woolf
Department of Neurology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA
Published in "Nature Medicine" (2017-06-01)

Extended daytime and nighttime activities are major contributors to the growing sleep deficiency epidemic, as is the high prevalence of sleep disorders like insomnia. The consequences of chronic insufficient sleep for health remain uncertain3. Sleep quality and duration predict presence of pain the next day in healthy subjects, suggesting that sleep disturbances alone may worsen pain, and experimental sleep deprivation in humans supports this claim. We demonstrate that sleep loss, but not sleep fragmentation, in healthy mice increases sensitivity to noxious stimuli (referred to as ‘pain’) without general sensory hyper-responsiveness. Moderate daily repeated sleep loss leads to a progressive accumulation of sleep debt and also to exaggerated pain responses, both of which are rescued after restoration of normal sleep. Caffeine and modafinil, two wake-promoting agents that have no analgesic activity in rested mice, immediately normalize pain sensitivity in sleep-deprived animals, without affecting sleep debt. The reversibility of mild sleeploss-induced pain by wake-promoting agents reveals an unsuspected role for alertness in setting pain sensitivity. Clinically, insufficient or poor-quality sleep may worsen pain and this enhanced pain may be reduced not by analgesics, whose effectiveness is reduced, but by increasing alertness or providing better sleep.

Genetic ablation of GINIP-expressing primary sensory neurons strongly impairs Formalin-evoked pain. (2017)
Genetic ablation of GINIP-expressing primary sensory neurons strongly impairs Formalin-evoked pain.
Urien L, Gaillard S, Lo Re L, Malapert P, Bohic M, Reynders A, Moqrich A
"Aix-Marseille-Université, Institut de Biologie du Développement de Marseille, Marseille, France "
Published in "Scientific Reports" (2017-02-17)

Primary sensory neurons are heterogeneous by myriad of molecular criteria. However, the functional significance of this remarkable heterogeneity is just emerging. We precedently described the GINIP(+) neurons as a new subpopulation of non peptidergic C-fibers encompassing the free nerve ending cutaneous MRGPRD(+) neurons and C-LTMRs. Using our recently generated ginip mouse model, we have been able to selectively ablate the GINIP(+) neurons and assess their functional role in the somatosensation. We found that ablation of GINIP(+) neurons affected neither the molecular contents nor the central projections of the spared neurons. GINIP-DTR mice exhibited impaired sensation to gentle mechanical stimuli applied to their hairy skin and had normal responses to noxious mechanical stimuli applied to their glabrous skin, under acute and injury-induced conditions. Importantly, loss of GINIP(+) neurons significantly altered formalin-evoked first pain and drastically suppressed the second pain response. Given that MRGPRD(+) neurons have been shown to be dispensable for formalin-evoked pain, our study suggest that C-LTMRs play a critical role in the modulation of formalin-evoked pain.

- Mechanical allodynia & hyperlagesia -
Genetic ablation of GINIP-expressing primary sensory neurons strongly impairs Formalin-evoked pain. (2017)
Genetic ablation of GINIP-expressing primary sensory neurons strongly impairs Formalin-evoked pain.
Urien L, Gaillard S, Lo Re L, Malapert P, Bohic M, Reynders A, Moqrich A
"Aix-Marseille-Université, Institut de Biologie du Développement de Marseille, Marseille, France "
Published in "Scientific Reports" (2017-02-17)

Primary sensory neurons are heterogeneous by myriad of molecular criteria. However, the functional significance of this remarkable heterogeneity is just emerging. We precedently described the GINIP(+) neurons as a new subpopulation of non peptidergic C-fibers encompassing the free nerve ending cutaneous MRGPRD(+) neurons and C-LTMRs. Using our recently generated ginip mouse model, we have been able to selectively ablate the GINIP(+) neurons and assess their functional role in the somatosensation. We found that ablation of GINIP(+) neurons affected neither the molecular contents nor the central projections of the spared neurons. GINIP-DTR mice exhibited impaired sensation to gentle mechanical stimuli applied to their hairy skin and had normal responses to noxious mechanical stimuli applied to their glabrous skin, under acute and injury-induced conditions. Importantly, loss of GINIP(+) neurons significantly altered formalin-evoked first pain and drastically suppressed the second pain response. Given that MRGPRD(+) neurons have been shown to be dispensable for formalin-evoked pain, our study suggest that C-LTMRs play a critical role in the modulation of formalin-evoked pain.

- Neuropathic pain -
Impaired Thermosensation in Mice Lacking TRPV3, a Heat and Camphor Sensor in the Skin (2015)
Impaired Thermosensation in Mice Lacking TRPV3, a Heat and Camphor Sensor in the Skin
Aziz Moqrich, Sun Wook Hwang, Taryn J. Earley et al.
Department of Cell Biology, Scripps Research Insti- tute, La Jolla, CA 92037, USA
Published in "Science" (2015-03-04)

Environmental temperature is thought to be directly sensed by neurons through their projections in the skin. A subset of the mammalian transient receptor potential (TRP) family of ion channels has been implicated in this process. These ‘‘thermoTRPs’’ are activated at distinct temperature thresholds and are typically expressed in sensory neurons. TRPV3 is activated by heat (933-C) and, unlike most thermoTRPs, is expressed in mouse keratinocytes. We found that TRPV3 null mice have strong deficits in responses to innocuous and noxious heat but not in other sensory modalities; hence, TRPV3 has a specific role in thermosensation. The natural compound camphor, which modulates sensations of warmth in humans, proved to be a specific activator of TRPV3. Camphor activated cultured primary keratinocytes but not sensory neurons, and this activity was abolished in TRPV3 null mice. Therefore, heat-activated receptors in keratinocytes are important for mammalian thermosensation.

The Low Threshold Calcium Channel Cav3.2 Determines Low Threshold Mechanoreceptor Function (2015)
The Low Threshold Calcium Channel Cav3.2 Determines Low Threshold Mechanoreceptor Function
François A, Schüetter N, Laffray S, Sanguesa J et al
Institut de Génomique Fonctionnelle, 141 rue de la Cardonille, 34094 Montpellier, France
Published in "Cell Reports" (2015-01-20)

The T-type calcium channel Cav3.2 emerges as a key regulator of sensory functions, but its expression pattern within primary afferent neurons and its contribution to modality-specific signaling remain obscure. Here, we elucidate this issue using a unique knockin/flox mouse strain wherein Cav3.2 is replaced by a functional Cav3.2-surface-ecliptic GFP fusion. We demonstrate that Cav3.2 is a selective marker of two major low-threshold mechanoreceptors (LTMRs), A_- and C-LTMRs, innervating the most abundant skin hair follicles. The presence of Cav3.2 along LTMR-fiber trajectories is consistent with critical roles at multiple sites, setting their strong excitability. Strikingly, the C-LTMR-specific knockout uncovers that Cav3.2 regulates light-touch perception and noxious mechanical cold and chemical sensations and is essential to build up that debilitates allodynic symptoms of neuropathic pain, a mechanism thought to be entirely A-LTMR specific. Collectively, our findings support a fundamental role for Cav3.2 in touch/pain pathophysiology, validating their critic pharmacological relevance to relieve mechanical and cold allodynia.

Oxaliplatin-induced cold hypersensitivity is due to remodelling of ion channel expression in nociceptors. (2011)
Oxaliplatin-induced cold hypersensitivity is due to remodelling of ion channel expression in nociceptors.
J. Descoeur, V. Pereira, A. Pizzoccaro, A. Francois, B. Ling et al. (Team of Dr Bourinet)
Institut de Génomique Fonctionnelle, CNRS, UMR-5203, Département de Physiologie, Montpellier, France.
Published in "EMBO Molecular Medicine" (2011-05-24)

Cold hypersensitivity is the hallmark of oxaliplatin-induced neuropathy, which develops in nearly all patients under this chemotherapy. To date, pain management strategies have failed to alleviate these symptoms, hence development of adapted analgesics is needed. Here, we report that oxaliplatin exaggerates cold perception in mice as well as in patients. These symptoms are mediated by primary afferent sensory neurons expressing the thermoreceptor TRPM8. Mechanistically, oxaliplatin promotes over-excitability by drastically lowering the expression of distinct potassium channels (TREK1, TRAAK) and by increasing the expression of pro-excitatory channels such as the hyperpolarization-activated channels (HCNs). These findings are corroborated by the analysis of TREK1-TRAAK mice and use of the specific HCN inhibitor ivabradine, which abolishes the oxaliplatin-induced cold hypersensibility. These results suggest that oxaliplatin exacerbates cold perception by modulating the transcription of distinct ionic conductances that together shape sensory neuron responses to cold. The translational and clinical implication of these findings would be that ivabradine may represent a tailored treatment for oxaliplatin-induced neuropathy.



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Gradient Models TGT2 (2/1 lanes)
Power supply 220 / 110 Volts
Number of Lanes TGT2 Model - Mouse: 2 / Rat: 1
Temperature range °C (at plate surface)
@ environnement 20 to 25°C & %RH 45 to 55%RH
5 to 55
Temp. stability °C
(surface, over time)
1°C
Supplied with 2 thermal units and controlers, Cage and Base plate.
Materials Base Plate: Aluminum alloy
Walls: Grey ppc
Cover: Transparent ppc
Software TGS Allows to measure per animal: up to 20 temperature zones, time spent/temp.Zone/ time period, overall distance travelled.
Results: .xls type, presented per time periods. Raw datas encrypted with video recording (synchronous).
Replay: at any time
Sotware requirement Core i5, 4g ram, Windows 7 32/64 bits
Supplied with: webcam , mini usb cables
Option Infra Red Thermometer / temp control IRB153

Model:
BIO-GRADIENT
Thermal Gradient Test
Lanes - Mice: 2 / Rats: 1 Contact us

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Thermal Place Preference, 2 Temperatures Choice Nociception Test
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