CD26 modulates nociception in mice via its dipeptidyl-peptidase IV activity.
BACKGROUND
CD26 is a multifunctional cell surface glycoprotein expressed by T and B cells. It exhibits a dipeptidyl-peptidase activity (DPP-IV) that cleaves the penultimate proline from the N-terminus of polypeptides, thereby regulating their activity and concentration.


METHODS
Using CD26-/- mice resulting from targeted inactivation of the gene, we examined the consequences of a DPP-IV defect on behavioural response to nociceptive stimuli and concentration of the pain modulator peptides substance P (SP) and endomorphin 2, two DPP-IV substrates.


RESULTS
CD26 inactivation induced a three-fold decrease in circulating endopeptidase activity while that found in brain extracts was normal, albeit very weak. CD26-/- mice had high SP concentrations in plasma (3.4+/-1 pg/ml versus 1.5+/-0.3 pg/ml, P<10(-3)) but not in brain extracts (35+/-12 pg/ml versus 32+/-9 pg/ml, P>0.05). Endomorphin-2 levels in the two groups were in the same range for plasma and brain extracts. CD26-/- mice displayed short latencies to nociceptive stimuli (hot plate test: 6.6+/-1.2 s versus 8.6+/-1.5 s, P<10(-4); tail pinch test: 3.1+/-0.6 s versus 4.2+/-0.8 s, P<10(-3)). Administration of an SP (NK1) receptor antagonist or DPP-IV to CD26-/- mice normalised latencies. DPP-IV inhibitors decreased latencies only in CD26+/+ mice.


CONCLUSIONS
Our observations represent the first fundamental evidence showing that DPP-IV influences pain perception via modulation of the peripheral SP concentration. Our work also highlights the role of peripheral NK1 receptors in nociception.
Guieu
Regis
R
FRE CNRS 2738, Institut Federatif de Recherche Jean Roche (IFR 11), Faculte de Medecine Nord, Universite de la Mediterranee (Aix-Marseille II), 16 Boulevard Pierre Dramard, 13916 Marseille Cedex 20, France. guieu.r@jean-roche.univ-mrs.fr
Fenouillet
Emmanuel
E
Devaux
Christiane
C
Fajloun
Ziad
Z
Carrega
Louis
L
Sabatier
Jean-Marc
JM
Sauze
Nicole
N
Marguet
Didier
D
D000704:Analysis of Variance; D000731:Androstanes / Q000494:pharmacology; D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology; D018819:Dipeptidyl Peptidase 4 / Q000235:genetics / Q000502:physiology* / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D005260:Female; D008214:Lymphocytes / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009842:Oligopeptides / Q000097:blood; D010146:Pain / Q000178:diet therapy / Q000235:genetics / Q000378:metabolism*; D010147:Pain Measurement / Q000379:methods; D011930:Reaction Time / Q000187:drug effects / Q000502:physiology; D013373:Substance P / Q000097:blood
D000731:Androstanes; D001562:Benzimidazoles; D009842:Oligopeptides; C086111:WIN 51708; D013373:Substance P; C105294:endomorphin 2; D018819:Dipeptidyl Peptidase 4