Antagonism of the Prokineticin System Prevents and Reverses Allodynia and Inflammation in a Mouse Model of Diabetes.

Mara Castelli,Lucia Negri,Alberto E Panerai,Paola Sacerdote,Francesco Pistillo,Valentina Onnis,Cenzo Congu,Daniela Maftei,Giada Amodeo,Roberta Lattanzi,Cecilia Gotti,Silvia Franchi,Bradley Taylor

doi:10.1371/journal.pone.0146259

Abstract

Neuropathic pain is a severe diabetes complication and its treatment is not satisfactory. It is associated with neuroinflammation-related events that participate in pain generation and chronicization. Prokineticins are a new family of chemokines that has emerged as critical players in immune system, inflammation and pain. We investigated the role of prokineticins and their receptors as modulators of neuropathic pain and inflammatory responses in experimental diabetes. In streptozotocin-induced-diabetes in mice, the time course expression of prokineticin and its receptors was evaluated in spinal cord and sciatic nerves, and correlated with mechanical allodynia. Spinal cord and sciatic nerve pro- and anti-inflammatory cytokines were measured as protein and mRNA, and spinal cord GluR subunits expression studied. The effect of preventive and therapeutic treatment with the prokineticin receptor antagonist PC1 on behavioural and biochemical parameters was evaluated. Peripheral immune activation was assessed measuring macrophage and T-helper cytokine production. An up-regulation of the Prokineticin system was present in spinal cord and nerves of diabetic mice, and correlated with allodynia. Therapeutic PC1 reversed allodynia while preventive treatment blocked its development. PC1 normalized prokineticin levels and prevented the up-regulation of GluN2B subunits in the spinal cord. The antagonist restored the pro-/anti-inflammatory cytokine balance altered in spinal cord and nerves and also reduced peripheral immune system activation in diabetic mice, decreasing macrophage proinflammatory cytokines and the T-helper 1 phenotype. The prokineticin system contributes to altered sensitivity in diabetic neuropathy and its inhibition blocked both allodynia and inflammatory events underlying disease.

Highlights

The number of available agents to manage diabetes continues to rapidly expand, the treatment of diabetes complications remains a substantial challenge.Diabetic neuropathy is one of the most frequent complications in diabetes mellitus [1]
The prokineticin 2 (PROK2 or mammalian Bv8), displays a major role in triggering inflammatory pain acting on two G-protein coupled receptors, the prokineticin receptor 1 (PKR1) and the prokineticin receptor 2 (PKR2) [10,11] localized in regions of the nervous system related with pain, both on neurons and glia [12]
We have recently demonstrated that the block of this system with a specific receptor antagonist provides an efficacious control of development and maintenance of inflammatory pain and of neuropathic pain (NP) derived from traumatic nerve lesion [12,16,17]

Summary

Introduction

Diabetic neuropathy is one of the most frequent complications in diabetes mellitus [1]. We and others have demonstrated that pro- and anti-inflammatory cytokines produced by immune cells as well as by glia and microglia in nerve and spinal cord are common denominators in NP [5,6]. These start a cascade of neuroinflammation-related events that may maintain and worsen the original injury, participating in pain generation and chronicization [7,8,9]. We have recently demonstrated that the block of this system with a specific receptor antagonist provides an efficacious control of development and maintenance of inflammatory pain and of NP derived from traumatic nerve lesion [12,16,17]

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