Research Article Prokineticin 2 Upregulation in the Peripheral Nervous System Has a Major Role in Triggering and Maintaining Neuropathic Pain in the Chronic Constriction Injury Model Roberta Lattanzi, 1 Daniela Maftei, 1 Veronica Marconi, 1 Fulvio Florenzano, 2 Silvia Franchi, 3 Elisa Borsani, 4 Luigi Fabrizio Rodella, 4 Gianfranco Balboni, 5 Severo Salvadori, 6 Paola Sacerdote, 3 and Lucia Negri 1 1 Department of Physiology and Pharmacology “Vittorio Erspamer”, Sapienza University of Rome, 00185 Rome, Italy 2 Confocal Microscopy Unit, European Brain Research Institute (EBRI) “Rita Levi-Montalcini”, 00143 Rome, Italy 3 Department of Pharmacological and Biomolecular Sciences, University of Milan, 20129 Milan, Italy 4 Unit of Human Anatomy, Department of Biomedical Sciences and Biotechnologies, University of Brescia, 25123 Brescia, Italy 5 Department of Life and Environment Sciences, University of Cagliari, 09124 Cagliari, Italy 6 Department of Chemical and Pharmaceutical Sciences, University of Ferrara, 44-100 Ferrara, Italy Correspondence should be addressed to Lucia Negri; lucia.negri@uniroma1.it Received 11 June 2014; Accepted 3 October 2014 Academic Editor: Livio Luongo Copyright © 2015 Roberta Lattanzi et al. Tis is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Te new chemokine Prokineticin 2 (PROK2) and its receptors (PKR 1 and PKR 2 ) have a role in infammatory pain and immunomodulation. Here we identifed PROK2 as a critical mediator of neuropathic pain in the chronic constriction injury (CCI) of the sciatic nerve in mice and demonstrated that blocking the prokineticin receptors with two PKR 1 -preferring antagonists (PC1 and PC7) reduces pain and nerve damage. PROK2 mRNA expression was upregulated in the injured nerve since day 3 post injury (dpi) and in the ipsilateral DRG since 6 dpi. PROK2 protein overexpression was evident in Schwann Cells, infltrating macrophages and axons in the peripheral nerve and in the neuronal bodies and some satellite cells in the DRG. Terapeutic treatment of neuropathic mice with the PKR-antagonist, PC1, impaired the PROK2 upregulation and signalling. Tis fact, besides alleviating pain, brought down the burden of proinfammatory cytokines in the damaged nerve and prompted an anti-infammatory repair program. Such a treatment also reduced intraneural oedema and axon degeneration as demonstrated by the physiological skin innervation and thickness conserved in CCI-PC1 mice. Tese fndings suggest that PROK2 plays a crucial role in neuropathic pain and might represent a novel target of treatment for this disease. 1. Introduction Identifcation of the neurobiological processes engaged in the pathological state that occurs during neuropathic pain may provide future therapeutic targets. Chemokines and their receptors are receiving growing interest as modulators of neuronal plasticity and for their ability to enhance nocicep- tive transmission under conditions of neuropathic pain [1]. In particular a new family of chemokines, Prokineticin 2 (PROK2) also known as Bv8 and its receptors, two G-protein coupled receptors, PKR 1 and PKR 2 , emerged as key signals in immune system and infammatory diseases [2]. In an animal model of CFA-induced paw infammation, we brought evidence that Bv8/PROK2, upregulated in gran- ulocyte invading the infamed tissue is a major determinant in triggering and maintaining infammatory pain [3]. Neu- trophils and macrophages are the major sources of PROK2 which is strongly upregulated in infammatory diseases and tumours, associated with infltrating cells [4, 5]. In vivo and in vitro experiments from our and other groups demonstrated Hindawi Publishing Corporation BioMed Research International Volume 2015, Article ID 301292, 15 pages http://dx.doi.org/10.1155/2015/301292