Absence of thermal hyperalgesia in serotonin transporter-deficient mice.
Antidepressants in the treatment of neuropathic pain are thought to partially exert their effect by inhibition of serotonin (5-HT) reuptake and thus activation of central antinociceptive pathways. Mice deficient for the 5-HT transporter (5-HTT-/- mice) are regarded as a model of lifelong treatment with a serotonin reuptake inhibitor. Here we investigated 5-HTT-/- mice and compared their pain-related behavior after a unilateral chronic constrictive sciatic nerve injury (CCI) with that of wild-type littermates. Wild-type mice reproducibly developed ipsilateral thermal hyperalgesia and mechanical allodynia after CCI. 5-HTT-/- mice did not develop thermal hyperalgesia, but showed bilateral mechanical allodynia after the nerve injury. 5-HT levels as measured with HPLC increased after CCI in the injured nerve in both genotypes and decreased in the lumbar spinal cord in wild-type mice. 5-HTT-/- mice had significantly lower 5-HT concentrations than wild-type mice in all tissues investigated. Thus, in 5-HTT-/- mice, reduced 5-HT levels in the injured peripheral nerves correlate with diminished behavioral signs of thermal hyperalgesia, a pain-related symptom caused by peripheral sensitization. In contrast, bilateral mechanical allodynia, a centrally mediated phenomenon, was associated with decreased spinal 5-HT concentrations in 5-HTT-/- mice and may possibly be caused by a lack of spinal inhibition.
Vogel
Carola
C
Department of Neurology, University of Würzburg, 97080 Würzburg, Germany.
Mössner
Rainald
R
Gerlach
Manfred
M
Heinemann
Thoralf
T
Murphy
Dennis L
DL
Riederer
Peter
P
Lesch
Klaus-Peter
KP
Sommer
Claudia
C
D000311:Adrenal Glands / Q000378:metabolism; D000818:Animals; D001522:Behavior, Animal; D002352:Carrier Proteins / Q000235:genetics; D004195:Disease Models, Animal; D006614:Hindlimb / Q000503:physiopathology; D006358:Hot Temperature; D006897:Hydroxyindoleacetic Acid / Q000378:metabolism; D006930:Hyperalgesia / Q000503:physiopathology*; D008161:Lumbosacral Region; D008562:Membrane Glycoproteins / Q000172:deficiency* / Q000235:genetics; D026901:Membrane Transport Proteins; D051379:Mice; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins; D010147:Pain Measurement; D017288:Pain Threshold; D011930:Reaction Time; D012584:Sciatic Nerve / Q000503:physiopathology; D020426:Sciatic Neuropathy / Q000503:physiopathology*; D012701:Serotonin / Q000378:metabolism; D050486:Serotonin Plasma Membrane Transport Proteins; D012881:Skin Temperature; D013116:Spinal Cord / Q000503:physiopathology
D002352:Carrier Proteins; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D050486:Serotonin Plasma Membrane Transport Proteins; C493231:Slc6a4 protein, mouse; D012701:Serotonin; D006897:Hydroxyindoleacetic Acid