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COLD HOT PLATE TEST
(Model: BIO-CHP)
For testing animal's thermal sensitivity to pain resulting from exposure to heat or cold: the Cold Hot Plate is an innovative instrument opening new investigation fields for your analgesia and nociception research, and a useful tool for analgesic drug screening using rats or mice models.

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  • HARVARD MEDICAL SCHOOL Charlestown, Etats-Unis
  • INMED Marseille, France
  • BIOCODEX Compiegne, France
  • UNIL Lausanne, Suisse
  • COLLEGE DE FRANCE Paris, France
  • ESPCI Paris, France
  • INSTITUT DE RECHERCHE PIERRE FABRE Castres, France
  • NEUROFIT Illkirch, France
  • ESPCI Paris, France
  • BIOCODEX Compiègne,France
  • INSERM Clermont-Ferrand, Paris, Bordeaux, Marseille,France
  • MEDICAL UNIVERSITY OF SILESIA Katowice, Pologne
  • CNRS Orleans, Caen, Strasbourg, Valbonne, France
  • SANOFI AVENTIS Vitry sur Seine, Montpellier, France
  • UNIVERSITY OF HEIDELBERG Heidelberg, Allemagne
  • PORSOLT AND PARTNERS PHARMACOLOGY Le Genest St Isle,France
  • IGBMC Strasbourg, France
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! NEW RESEARCH WORK ! A recent publication by Poras H, Bonnard E, Fournié-Zaluski MC, Roques BP in "Eur J Med Chem." highlights the merits of using Bioseb's Cold Hot Plate Test: Modulation of Disulfide Dual ENKephalinase Inhibitors (DENKIs) Activity by a Transient N-protection for Pain Alleviation by Oral Route

Modulation of Disulfide Dual ENKephalinase Inhibitors (DENKIs) Activity by a Transient N-protection for Pain Alleviation by Oral Route
Poras H, Bonnard E, Fournié-Zaluski MC, Roques BP
Pharmaleads, Paris BioPark, Paris, France
Published in "Eur J Med Chem." (2015-09-18)


The endogenous opioid system, essentially constituted by two opioid receptors which are stimulated by the natural internal effectors enkephalins (Met-enkephalin and Leu-enkephalin), is present at the different sites (peripheral, spinal, central) of the control of pain. We have demonstrated that the protection of the enkephalin inactivation by the two metallopeptidases (neprilysin and neutral aminopeptidase) increases their local concentration selectively induced by pain stimuli triggering analgesic responses. With the aim of increasing the orally antinociceptive responses of the previously described disulfide DENKIs ( [Formula: see text] CH(R1)CH2-S-S-CH2-C(R2R3)CONHCH(R4)COOR5), we designed new pro-drugs, in the same chemical series, with a transient protection of the free amino group by an acyloxyalkyl carbamate, giving rise to ((CH3)2CHCO2CH(CH3)OCONHCH(R1)CH2-S-S-CH2-C(R2R3)CONHCH(R4)COOR5) pro-drugs 2a-2g. These compounds were easily prepared from their parent analogs, with a good yield. They were tested per os and shown to be highly efficient in peripherally-controlled inflammatory and neuropathic pain with long lasting effects but completely inactive in the acute centrally-controlled hot plate test, a model of pain by excess of nociception. This demonstrates that DENKIs are able to relieve pain at its source thanks to the increase of enkephalin levels.
Presentation

Bioseb’s Cold and Hot Plate Test is an innovative instrument opening new investigation fields for your analgesia research by allowing you to test animal's sensitivity to pain resulting from exposure to heat or cold.

This innovative Analgesia Meter is based on a metal plate which can be heated to 55°C and cooled to -2°C (with an ambient temperature between 20°C and 25°C). An electronic thermostat maintains the plate's temperature and a front panel digital thermometer displays the current plate temperature.

The Bioseb Cold and Hot Plate is designed to be very simple to use and very fast to reach the set temperature (as example From ambient to 4°C, the most used threshold value, it takes less than 10 minutes, and from 4°C to 55°C it takes only 5 minutes). Metrology wise, is accurate to less than 0,5°C (EEC metrology standard) and perfectly constant in the animal holder system. The preset temperature will not change for more than 0,1°C when a 400g rat is placed on the plate, and return to the set temperature is almost immediate.

Bioseb's Cold Hot Plate Test - Software screenshot
Optional software - Screenshot
Operation Principle

The animal's pain sensitivity resulting from exposure to heat or cold is tested by placing the animal (mouse or rat) on the surface of the plate and starting a built-in timer. The operator stops the timer at the instant the animal lifts its paw from the plate, reacting to the discomfort. The front panel timer then displays the number of seconds it took the animal to react. Animal reaction time is a measurement of animal resistance to pain and is used to measure efficacy of analgesics.

The operator can start and stop the timer with the front panel start/stop switch or with the included footswitch, which allows "hands-free" operation.

Dedidcated software

Though it is functional as a stand-alone instrument, the Cold Hot Plate Test Analgesia Meter can also be used with our dedicated optional software, allowing the user to define temperature "ramps" and “loops”. This feature is mainly used for studies with telemetry implants. In addition to displaying the reaction time, the Cold/Hot Plate Analgesia Meter is able to send the same information via USB interface to a computer.

Key features

• Simple to use, fast and accurate
• Can be used as a stand-alone instrument
• Allows testing of sensitivity to both hot and cold stimulus
• Unmatched temperature stability and control for both heat and cold
• Fast reach to set temperatures
• Homogeneous temperature surface
• Practical foot switch timing operation
• Optional Ramp software will allow the user to define temperature ramps and loops (slope in °C/min, start and end points) and store results
Domains of application

• Analgesic drug screening
• Basal pain sensitivity phenotyping
• Integrated supraspinal responses
• Pain sensitivity alterations induced by a specific experimental context change
• Pain sensitivity alterations induced by genetic manipulations
• Animal Models of Nociception (rats and mice)

! METHOD VALIDATION ! Publication

Bioseb team presents its respectful thanks to research team of Prof. Poisbeau (Institut des Neurosciences Cellulaires et Intégratives de Strasbourg), who validated the temperature ramps method used by the Cold and Hot Plate Test during in following study:

Differentiating Thermal Allodynia and Hyperalgesia Using Dynamic Hot and Cold Plate in Rodents, by I. Yalcin, A. Charlet, MJ. Freund-Mercier, M. Barrot and P. Poisbeau, in The Journal of Pain, 2009
(Click here to download this article as a PDF file)


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

PAIN
- General pain -
Modulation of Disulfide Dual ENKephalinase Inhibitors (DENKIs) Activity by a Transient N-protection for Pain Alleviation by Oral Route (2015)
Modulation of Disulfide Dual ENKephalinase Inhibitors (DENKIs) Activity by a Transient N-protection for Pain Alleviation by Oral Route
Poras H, Bonnard E, Fournié-Zaluski MC, Roques BP
Pharmaleads, Paris BioPark, Paris, France
Published in "Eur J Med Chem." (2015-09-18)

The endogenous opioid system, essentially constituted by two opioid receptors which are stimulated by the natural internal effectors enkephalins (Met-enkephalin and Leu-enkephalin), is present at the different sites (peripheral, spinal, central) of the control of pain. We have demonstrated that the protection of the enkephalin inactivation by the two metallopeptidases (neprilysin and neutral aminopeptidase) increases their local concentration selectively induced by pain stimuli triggering analgesic responses. With the aim of increasing the orally antinociceptive responses of the previously described disulfide DENKIs ( [Formula: see text] CH(R1)CH2-S-S-CH2-C(R2R3)CONHCH(R4)COOR5), we designed new pro-drugs, in the same chemical series, with a transient protection of the free amino group by an acyloxyalkyl carbamate, giving rise to ((CH3)2CHCO2CH(CH3)OCONHCH(R1)CH2-S-S-CH2-C(R2R3)CONHCH(R4)COOR5) pro-drugs 2a-2g. These compounds were easily prepared from their parent analogs, with a good yield. They were tested per os and shown to be highly efficient in peripherally-controlled inflammatory and neuropathic pain with long lasting effects but completely inactive in the acute centrally-controlled hot plate test, a model of pain by excess of nociception. This demonstrates that DENKIs are able to relieve pain at its source thanks to the increase of enkephalin levels.

The Nav1. 9 Channel Is a Key Determinant of Cold Pain Sensation and Cold Allodynia (2015)
The Nav1. 9 Channel Is a Key Determinant of Cold Pain Sensation and Cold Allodynia
Lolignier S, Bonnet C, Gaudioso C, Noël J, Ruel J et al.
Pharmacologie Fondamentale et Clinique de la Douleur, Clermont Université, Université d'Auvergne, Clermont-Ferrand, France;
Published in "Cell Rep. " (2015-05-19)

Cold-triggered pain is essential to avoid prolonged exposure to harmfully low temperatures. However, the molecular basis of noxious cold sensing in mammals is still not completely understood. Here, we show that the voltage-gated Nav1.9 sodium channel is important for the perception of pain in response to noxious cold. Nav1.9 activity is upregulated in a subpopulation of damage-sensing sensory neurons responding to cooling, which allows the channel to amplify subthreshold depolarizations generated by the activation of cold transducers. Consequently, cold-triggered firing is impaired in Nav1.9(-/-) neurons, and Nav1.9 mice and knockdown rats show increased cold pain thresholds. Disrupting Nav1.9 expression in rodents also alleviates cold pain hypersensitivity induced by the antineoplastic agent oxaliplatin. We conclude that Nav1.9 acts as a subthreshold amplifier in cold-sensitive nociceptive neurons and is required for the perception of cold pain under normal and pathological conditions.

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
Amaury François, Niklas Schüetter, Sophie Laffray, Juan Sanguesa, Anne Pizzoccaro, Stefan Dubel, Annabelle Mantilleri, Joel Nargeot, Jacques Noël, John N. Wood, Aziz Moqrich, Olaf Pongs, Emmanuel Bourinet
Institut de Génomique Fonctionnelle, Université de 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.

Morphine glucuronidation increases its analgesic effect in guinea pigs (2014)
Morphine glucuronidation increases its analgesic effect in guinea pigs
A. Oliveira, D. Pinhod, A. Albino-Teixeirad, R. Medeirosb, R. J. Dinis-Oliveira et al.
Faculty of Pharmacy, University of Porto, Porto, Portugal
Published in "Life Sciences" (2014-06-23)

Aims
Morphine is extensively metabolized to neurotoxic morphine-3-glucuronide (M3G) and opioid agonist morphine-6-glucuronide (M6G). Due to these different roles, interindividual variability and co-administration of drugs that interfere with metabolism may lead to differences in analgesia. The aim of the study was to investigate the repercussions of administration of an inducer (2,3,7,8-tetrachlorodibenzo-p-dioxin, TCDD) and an inhibitor (ranitidine) of glucuronidation in morphine metabolism and consequent analgesia, using guinea pigs as a suitable model.
Main methods
Thirty male Dunkin–Hartley guinea pigs were divided in six groups: control, morphine, ranitidine, ranitidine + morphine, TCDD and TCDD + morphine. After previous exposure to TCDD and ranitidine, morphine effect was assessed by an increasing temperature hotplate (35–52.5 °C), during 60 min after morphine administration. Then, blood was collected and plasma morphine and metabolites were quantified.
Key findings
Animals treated with TCDD presented faster analgesic effect and 75% reached the cut-off temperature, comparing with only 25% in morphine group. Animals treated with ranitidine presented a significantly lower analgesic effect, compared with morphine group (p ˂ 0.05). Moreover, significant differences between groups were found in M3G levels and M3G/morphine ratio (p ˂ 0.001 and p ˂ 0.0001), with TCDD animals presenting the highest values for M3G, M6G, M3G/morphine and M6G/morphine, and the lowest value for morphine. The opposite was observed in the animals treated with ranitidine.
Significance
Our results indicate that modulation of morphine metabolism may result in variations in metabolite concentrations, leading to different analgesic responses to morphine, in an animal model that may be used to improve morphine effect in clinical practice.

Opiates Modulate Thermosensation by Internalizing Cold Receptor TRPM8 (2013)
Opiates Modulate Thermosensation by Internalizing Cold Receptor TRPM8
G. Shapovalov, D. Gkika, M. Devilliers, A. Kondratskyi, D. Gordienko et al.
Bogomoletz Institute of Physiology, Kiev , Ukraine
Published in "Cell Reports" (2013-08-01)

Stimulation of μ-opioid receptors (OPRMs) brings powerful pain relief, but it also leads to the development of tolerance and addiction. Ensuing withdrawal in abstinent patients manifests itself with severe symptoms, including cold hyperalgesia, often preventing addicted patients from successfully completing the rehabilitation. Unsurprisingly, OPRMs have been a central point of many studies. Nonetheless, a satisfactory understanding of the pathways leading to distorted sensory responses during opiate administration and abstinence is far from complete. Here, we present a mechanism that leads to modulation by OPRMs of one of the sensory responses, thermosensation. Activation of OPRM1 leads to internalization of a cold-sensor TRPM8, which can be reversed by a follow-up treatment with the inverse OPRM agonist naloxone. Knockout of TRPM8 protein leads to a decrease in morphine-induced cold analgesia. The proposed pathway represents a universal mechanism that is probably shared by regulatory pathways modulating general pain sensation in response to opioid treatment.

G_q/11 signaling tonically modulates nociceptor function and contributes to activity-dependent sensitization. (2012)
G_q/11 signaling tonically modulates nociceptor function and contributes to activity-dependent sensitization.
A. Tappe-Theodor, C. Constantin, I. Tegeder, S. Lechner, M. Langeslag et al.
University of Heidelberg, Pharmacology Institut, Heidelberg, Germany.
Published in "Pain" (2012-01-08)

Peripheral injury or inflammation leads to a release of mediators capable of binding to a variety of ion channels and receptors. Among these are the 7-transmembrane receptors (G protein-coupled receptors) coupling to G(s), G(i/o), G__/__, or G(q/11) G proteins. Each of the G protein-coupled receptor pathways is involved in nociceptive modulation and pain processing, but the relative contribution of individual signaling pathways in vivo has not yet been worked out. The G(q)/G__ signaling branch is of particular interest because it leads to the activation of phospholipase C-_, protein kinase C, the release of calcium from intracellular stores, and it modulates extracellular regulated kinases. To investigate the contribution of the entire G(q/11)-signaling pathway in nociceptors towards regulation of pain, we generated double-deficient mice lacking G(q/11) selectively in nociceptors using a conditional gene-targeting approach. We observed that nociceptor-specific loss of G(q) and G__ results in reduced pain hypersensitivity following paw inflammation or spared nerve injury. Surprisingly, our behavioral and electrophysiological experiments also indicated defects in basal mechanical sensitivity in G(q/11) mutant mice, suggesting a novel function for G(q/11) in tonic modulation of acute nociception. Patch-clamp recordings revealed changes in voltage-dependent tetrodotoxin-resistant and tetrodotoxin-sensitive sodium channels in nociceptors upon a loss of G(q/11), whereas potassium currents remained unchanged. Our results indicate that the functional role of the G(q)/G__ branch of G-protein signaling in nociceptors in vivo not only spans sensitization mechanisms in pathological pain states, but is also operational in tonic modulation of basal nociception and acute pain.



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Temp range -2 degrees C. to 55 degrees C (in 20 to 25 degree C. ambient environment, 50% RH)
Temp accuracy +/- 0.5 degrees C.
Temperature uniformity on plate +/- 0.5 degrees C.
Power requirements 110V/220V automatic, 100W
Plate Dimensions 165 x 165 mm
Control unit dimensions 305 x 280 x 158 mm
Weight 6,650 kg

Model:
BIO-CHP
Cold Hot Plate Test (Modif.)
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