CD26 modulates nociception in mice via its dipeptidyl-peptidase IV activity

Background: CD26 is a multifunctional cell surface glycoprotein expressed h T and B cells, It exhibits it 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 endornorphin 2. two DPP-IV substrates. Results: CD26 inactivation induced a three-fold decrease in circulating endopeptidase activity while that found in brain extracts wits normal. albeit very weak. CD26-/- mice had high SP concentrations in plasma (3.4 + 1 pg/ml versus 1.5 +/- 03 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 +/- 1.2s versus 8.6 +/- 1.5s. P < 10 (4): tail pinch test: 3.1 +/- 0.6s 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 K I receptors in nociception. (c) 2005 Published by Elsevier B.V.