Glial cell type-specific changes in spinal dipeptidyl peptidase 4 expression and effects of its inhibitors in inflammatory and neuropatic pain

Kornél Király,Erika Lukácsi,Zsuzsanna Helyes,Judit Szabon,Zita Puskár,Gábor Gerber,Valéria Tékus,Márk Kozsurek,Tamás Balázsa,Alán Alpár,Károly Pap,Kata Bölcskei,Zsuzsanna E Tóth,Csaba Fekete,Benjamin Barta

doi:10.1038/s41598-018-21799-8

Abstract

Altered pain sensations such as hyperalgesia and allodynia are characteristic features of various pain states, and remain difficult to treat. We have shown previously that spinal application of dipeptidyl peptidase 4 (DPP4) inhibitors induces strong antihyperalgesic effect during inflammatory pain. In this study we observed low level of DPP4 mRNA in the rat spinal dorsal horn in physiological conditions, which did not change significantly either in carrageenan-induced inflammatory or partial nerve ligation-generated neuropathic states. In naïve animals, microglia and astrocytes expressed DPP4 protein with one and two orders of magnitude higher than neurons, respectively. DPP4 significantly increased in astrocytes during inflammation and in microglia in neuropathy. Intrathecal application of two DPP4 inhibitors tripeptide isoleucin-prolin-isoleucin (IPI) and the antidiabetic drug vildagliptin resulted in robust opioid-dependent antihyperalgesic effect during inflammation, and milder but significant opioid-independent antihyperalgesic action in the neuropathic model. The opioid-mediated antihyperalgesic effect of IPI was exclusively related to mu-opioid receptors, while vildagliptin affected mainly delta-receptor activity, although mu- and kappa-receptors were also involved. None of the inhibitors influenced allodynia. Our results suggest pathology and glia-type specific changes of DPP4 activity in the spinal cord, which contribute to the development and maintenance of hyperalgesia and interact with endogenous opioid systems.

Highlights

DPP4 is a type II integral transmembrane glycoprotein expressed on many cell types, but appears in soluble form in body fluids including cerebrospinal fluid[1]
DPP4 mRNA was detected in cortical areas in adult naïve animals and its level did not change after cerebral
DPP4 immunoreactivity was not found in the same regions in physiological state but its expression appeared in microglia, neurons and astrocytes in different time points during cerebral ischaemia[19]

Summary

Introduction

DPP4 is a type II integral transmembrane glycoprotein expressed on many cell types, but appears in soluble form in body fluids including cerebrospinal fluid[1]. Incretins are the most familiar substrates of DPP4 since these hormones are major regulators of postprandial insulin secretion. We have demonstrated dramatic reduction of mechanical hyperalgesia following spinal application of DPP4 inhibitors (IPI and vildagliptin) in subacute inflammation and this action was naloxone reversible suggesting an opioid receptor-mediated effect. Inducing/regulating the endogenous opioid machinery would provide a powerful tool to control pain propagation, this possibility has remained largely unexploited. We identify DPP4 in the spinal dorsal horn, show that its expression changes during pathological conditions, and demonstrate that it shapes opioid signalling in a receptor- and treatment-specific manner. Synaptic DPP4 may have a key role in neuronal mechanisms of pain propagation, we identify glial cells as inducible DPP4-batteries, in this way playing a role in hyperalgesia and opioid signalling

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Results

Conclusion