Mechanical, thermal and formalin-induced nociception is differentially altered in 5-HT1A-/-, 5-HT1B-/-, 5-HT2A-/-, 5-HT3A-/- and 5-HTT-/- knock-out male mice.
Extensive studies in rodents suggest that serotonin (5-HT) modulates nociceptive responses through the stimulation of several receptor types. However, it remains to demonstrate that these receptors participate in the control of nociception under physiological conditions. Pain behaviors of mutants which do not express 5-HT1A, 5-HT1B, 5-HT2A or 5-HT3A receptors, or lacking the 5-HT transporter, compared to paired wild-type mice of the same genetic background, were examined using validated tests based on different sensory modalities. Mechanical (von Frey filaments, tail pressure, tail clip tests), thermal (radiant heat, 46 degrees C water bath, hot-plate test) and formalin-induced nociception were determined in 2- to 3-month-old males. 5-HT1A knock-out mice differed from wild-types by higher thermal sensitivity (hot-plate test only), and 5-HT1B knock-out mice by higher thermal and formalin sensitivity. Both 5-HT2A and 5-HT3A knock-out mice differed from wild-types by a dramatic decrease in the formalin-induced nociceptive responses for phase II (16-45 min after injection/inflammatory phase). In contrast, neither mechanical, thermal nor formalin-induced nociception differed between mutants lacking the 5-HT transporter and paired wild-type mice. Although differences in spontaneous locomotor activity in 5-HT1B-/- (increase) and 5-HT3A-/- (decrease) knock-out mice versus paired wild-types might have confounded differences in nociception, acute 5-HT receptor blockade by selective antagonists was found to replicate in wild-type mice the effects on pain behavior, but not on locomotor activity, of the respective gene knock-out in mutants. These results support the conclusion that the complex control of pain mechanisms by 5-HT, acting at multiple receptors, is physiologically relevant in mice.
Kayser
Valérie
V
University Pierre et Marie Curie-Paris 6, Faculté de Médecine Pierre et Marie Curie, Site Pitié-Salpétrière, IFR 70 des Neurosciences, UMR S677, Paris, F-75013, France INSERM, U677, Paris F-75013, France Department of Cellular and Molecular Pharmacology, University of California, San Francisco, CA 94143, USA Department of Psychiatry, College of Physicians and Surgeons, Columbia University, New York 10032, USA.
Elfassi
Iskander Elfihri
IE
Aubel
Bertrand
B
Melfort
Maxette
M
Julius
David
D
Gingrich
Jay A
JA
Hamon
Michel
M
Bourgoin
Sylvie
S
D000818:Animals; D005464:Fluorobenzenes / Q000494:pharmacology; D017829:Granisetron / Q000494:pharmacology; D006614:Hindlimb; D006358:Hot Temperature; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009043:Motor Activity; D009619:Nociceptors / Q000502:physiology*; D010147:Pain Measurement; D010812:Physical Stimulation; D010879:Piperazines / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D044282:Receptor, Serotonin, 5-HT1A / Q000235:genetics / Q000378:metabolism; D044402:Receptor, Serotonin, 5-HT2A / Q000235:genetics / Q000378:metabolism; D011985:Receptors, Serotonin / Q000235:genetics* / Q000378:metabolism*; D044406:Receptors, Serotonin, 5-HT3 / Q000235:genetics / Q000378:metabolism; D058829:Serotonin 5-HT1 Receptor Antagonists; D058830:Serotonin 5-HT2 Receptor Antagonists; D058831:Serotonin 5-HT3 Receptor Antagonists; D012702:Serotonin Antagonists / Q000494:pharmacology; D050486:Serotonin Plasma Membrane Transport Proteins / Q000235:genetics* / Q000378:metabolism*; D012881:Skin Temperature
D005464:Fluorobenzenes; D017829:Granisetron; D010879:Piperazines; D010880:Piperidines; D011725:Pyridines; D044282:Receptor, Serotonin, 5-HT1A; D044402:Receptor, Serotonin, 5-HT2A; D011985:Receptors, Serotonin; D044406:Receptors, Serotonin, 5-HT3; D058829:Serotonin 5-HT1 Receptor Antagonists; D058830:Serotonin 5-HT2 Receptor Antagonists; D058831:Serotonin 5-HT3 Receptor Antagonists; D012702:Serotonin Antagonists; D050486:Serotonin Plasma Membrane Transport Proteins; C493231:Slc6a4 protein, mouse; C090413:N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide; C079049:volinanserin