Hot plate test

The hot plate test is a test of the pain response in animals, similar to the tail flick test. Both hot plate and tail-flick methods are used generally for centrally acting analgesic,[1] while peripherally acting drugs are ineffective in these tests but sensitive to acetic acid-induced writhing test.[2]

The hot plate test is used in basic pain research and in testing the effectiveness of analgesics by observing the reaction to pain caused by heat. It was proposed by Eddy and Leimbach in 1953.[3] They used a behavioral model of nociception where behaviors such as jumping and hind paw-licking are elicited following a noxious thermal stimulus. Licking is a rapid response to painful thermal stimuli that is a direct indicator of nociceptive threshold. Jumping represents a more elaborated response, with a latency, and encompasses an emotional component of escaping.[4]

Procedure
  • A transparent glass cylinder is used to keep the animal on the heated surface of the plate.[5]
  • The temperature of the hot plate is set using a thermoregulated water-circulated pump.
  • The time of latency is defined as the time period between the zero point, when the animal is placed on the hot plate surface, and the time when the animal licks its paw or jumps off to avoid thermal pain.[6][7]

Research findings

Sex studies using antidepressants

Significant differences in pain sensitivity in male and female mice have been observed in laboratory studies. The SSRI antidepressant paroxetine did not display a gender difference in antinociceptive effects in mice.[8]

Ion channels

Voltage-gated ion channels are implicated in pain sensation and transmission signaling mechanisms within both peripheral nociceptors and the spinal cord. Specific ion channel isoforms such as Nav1.7 and Nav1.8 sodium channels and Cav3.2 T-type calcium channels have distinct pro-nociceptive roles.[9]

Opioid receptors

Activation of the μ-opioid receptor (MOR) and norepinephrine reuptake inhibition (NRI) are mechanisms of acute and chronic pain. OPRM1 knockout mice were used to determine the relative contribution of MOR activation to tapentadol and morphine induced analgesia. Wild-type mice exhibited an antinociceptive effect ten times that of OPM1 knockouts. However, the OPRM1 knockouts still exhibited a slight analgesic effect to tapentadol but not to morphine. This indicated that the antinociceptive effect of tapentadol is based on a combined mechanism of action involving both MOR and NRI.[10]

Benzodiazepines and GABA receptors

Diazepam is a GABAA receptor benzodiazepine ligand that is an anxiety modulator. Studies using diazepam with the hot plate test showed that diazepam modified the behavioral structure of the pain response not from pain modulation but rather by reducing anxiety levels.[11]

Ethics
Further information: Animal testing

The Ethical Committee of the International Association for the Study of Pain has developed guidelines for the ethical use of this procedure.[12] In the United States, such experiments must be approved by an Institutional Animal Care and Use Committee.[13]

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References
  1. Carlsson, Karl-Heinz; Jurna, Ilmar (1987). "Depression by flupirtine, a novel analgesic agent, of motor and sensory responses of the nociceptive system in the rat spinal cord". European Journal of Pharmacology. 143 (1): 89–99. doi:10.1016/0014-2999(87)90738-2. ISSN 0014-2999. PMID 3691652.
  2. Matera, Carlo; Flammini, Lisa; Quadri, Marta; Vivo, Valentina; Ballabeni, Vigilio; Holzgrabe, Ulrike; Mohr, Klaus; De Amici, Marco; Barocelli, Elisabetta; Bertoni, Simona; Dallanoce, Clelia (2014). "Bis(ammonio)alkane-type agonists of muscarinic acetylcholine receptors: Synthesis, in vitro functional characterization, and in vivo evaluation of their analgesic activity". European Journal of Medicinal Chemistry. 75: 222–232. doi:10.1016/j.ejmech.2014.01.032. ISSN 0223-5234.
  3. Eddy, NB; Leimbach, D (1953). "Synthetic analgesics. II. Dithienylbutenyl- and dithienylbutylamines". J Pharmacol Exp Ther. 107 (3): 385–393. PMID 13035677.
  4. ESPEJO, E; Mir, D (30 September 1993). "Structure of the rat's behaviour in the hot plate test". Behavioural Brain Research. 56 (2): 171–176. doi:10.1016/0166-4328(93)90035-O. PMID 8240711.
  5. Hunskaar, Steinar; Berge, Odd-Geir; Hole, Kjell (1 August 1986). "A modified hot-plate test sensitivie to mild analgesics". Behavioural Brain Research. 21 (2): 101–108. doi:10.1016/0166-4328(86)90088-4. PMID 3755945.
  6. Ripoll N, Hascoet M, Bourin M. The four-plates test: Anxiolytic or analgesic paradigm? Progress in Neuro-Psychopharmacology and Biological Psychiatry, July 2006 vol. 30 issue 5, 873-880.
  7. Tzschentke, T. M.; Christoph, T.; Kogel, B.; Schiene, K.; Hennies, H.-H.; Englberger, W.; Haurand, M.; Jahnel, U.; Cremers, T. I. F. H.; Friderichs, E.; De Vry, J. (23 July 2007). "( )-(1R,2R)-3-(3-Dimethylamino-1-ethyl-2-methyl-propyl)-phenol Hydrochloride (Tapentadol HCl): a Novel -Opioid Receptor Agonist/Norepinephrine Reuptake Inhibitor with Broad-Spectrum Analgesic Properties". Journal of Pharmacology and Experimental Therapeutics. 323 (1): 265–276. doi:10.1124/jpet.107.126052. PMID 17656655.
  8. Duman, E., Kesim, M., Kadioglu, M., Ulku, C., Kalyoncu, N., Yaris, E. 2006. Effect of gender on antinociceptive effect of paroxetine in hot plate test in mice. Progress in Neuro-Pharmacology and Biological Psychiatry. 30. 292–296.
  9. Hildebrand, M.; Smith, P.; Bladen, C.; Eduljee, C.; Xie, J.; Chen, L.; Fee-Maki, M.; Doering, C.; Mezeyova, J.; et al. (2011). "A novel slow-inactivation-specific ion channel modulator attenuates neuropathic pain". Pain. 152 (4): 833–843. doi:10.1016/j.pain.2010.12.035. hdl:1880/106710. PMID 21349638.
  10. Kögel, B.; De Vry, J.; Tzschentke, T.; Christoph, T. (2011). "The antinociceptive and antihyperalgesic effect of tapentadol is partially retained in OPRM1 (μ-opioid receptor) knockout mice". Neuroscience Letters. 491 (2): 104–107. doi:10.1016/j.neulet.2011.01.014. PMID 21232580.
  11. Casarrubea, M.; Sorbera, F.; Santangelo, A.; Crescimanno, G. (2012). "The effects of diazepam on the behavioral structure of the rat's response to pain in the hot-plate test: Anxiolysis vs. Pain modulation". Neuropharmacology. 63 (2): 310–321. doi:10.1016/j.neuropharm.2012.03.026. PMID 22521500.
  12. Zimmermann, M. (1983). "Ethical guidelines for investigations of experimental pain in conscious animals". Pain. 16 (2): 109–10. CiteSeerX 10.1.1.651.9572. doi:10.1016/0304-3959(83)90201-4. PMID 6877845.
  13. Institutional Animal Care and Use Committee
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