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 °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.
aUniversity 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
bINSERM, U677, Paris F-75013, France
cDepartment of Cellular and Molecular Pharmacology, University of California, San Francisco, CA 94143, USA
dDepartment of Psychiatry, College of Physicians and Surgeons, Columbia University, New York 10032, USA
*Corresponding author. Present address: UMR 677 INSERM/UPMC, Faculté de Médecine Pierre et Marie Curie, Site Pitié-Salpétrière, 91, Boulevard de l’Hôpital, 75634 Paris Cedex 13, France. Tel.: +33 1 40 77 97 09; fax: +33 1 40 77 97 90.
Submitted December 29, 2005; received in revised form November 7, 2006; accepted November 29, 2006.