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

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. 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. 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. 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.