title: Prokineticin 2 upregulation in the peripheral nervous system has a major role in triggering and maintaining neuropathic pain in the chronic constriction injury model.
abstract: The new chemokine Prokineticin 2 (PROK2) and its receptors (PKR1 and PKR2) have a role in inflammatory pain and immunomodulation. Here we identified 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 PKR1-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, infiltrating macrophages and axons in the peripheral nerve and in the neuronal bodies and some satellite cells in the DRG. Therapeutic treatment of neuropathic mice with the PKR-antagonist, PC1, impaired the PROK2 upregulation and signalling. This fact, besides alleviating pain, brought down the burden of proinflammatory cytokines in the damaged nerve and prompted an anti-inflammatory 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. These findings suggest that PROK2 plays a crucial role in neuropathic pain and might represent a novel target of treatment for this disease.
authors: Department of Physiology and Pharmacology "Vittorio Erspamer", Sapienza University of Rome, 00185 Rome, Italy.
authors: Roberta
authors: R
authors: Lattanzi
authors: Department of Physiology and Pharmacology "Vittorio Erspamer", Sapienza University of Rome, 00185 Rome, Italy.
authors: Daniela
authors: D
authors: Maftei
authors: Department of Physiology and Pharmacology "Vittorio Erspamer", Sapienza University of Rome, 00185 Rome, Italy.
authors: Veronica
authors: V
authors: Marconi
authors: Confocal Microscopy Unit, European Brain Research Institute (EBRI) "Rita Levi-Montalcini", 00143 Rome, Italy.
authors: Fulvio
authors: F
authors: Florenzano
authors: Department of Pharmacological and Biomolecular Sciences, University of Milan, 20129 Milan, Italy.
authors: Silvia
authors: S
authors: Franchi
authors: Unit of Human Anatomy, Department of Biomedical Sciences and Biotechnologies, University of Brescia, 25123 Brescia, Italy.
authors: Elisa
authors: E
authors: Borsani
authors: Unit of Human Anatomy, Department of Biomedical Sciences and Biotechnologies, University of Brescia, 25123 Brescia, Italy.
authors: Luigi Fabrizio
authors: LF
authors: Rodella
authors: Department of Life and Environment Sciences, University of Cagliari, 09124 Cagliari, Italy.
authors: Gianfranco
authors: G
authors: Balboni
authors: Department of Chemical and Pharmaceutical Sciences, University of Ferrara, 44-100 Ferrara, Italy.
authors: Severo
authors: S
authors: Salvadori
authors: Department of Pharmacological and Biomolecular Sciences, University of Milan, 20129 Milan, Italy.
authors: Paola
authors: P
authors: Sacerdote
authors: Department of Physiology and Pharmacology "Vittorio Erspamer", Sapienza University of Rome, 00185 Rome, Italy.
authors: Lucia
authors: L
authors: Negri
mesh_terms: D000818:Animals; D005768:Gastrointestinal Hormones / Q000096:biosynthesis*; D008264:Macrophages / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D009437:Neuralgia / Q000378:metabolism* / Q000473:pathology; D009479:Neuropeptides / Q000096:biosynthesis*; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism; D012583:Schwann Cells / Q000378:metabolism* / Q000473:pathology; D012584:Sciatic Nerve / Q000293:injuries / Q000378:metabolism* / Q000473:pathology; D015398:Signal Transduction; D013381:Subtilisins / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D005768:Gastrointestinal Hormones; D009479:Neuropeptides; C525015:PKR1 protein, mouse; C525016:PKR2 protein, mouse; C486586:Prok2 protein, mouse; D043562:Receptors, G-Protein-Coupled; C490930:Pcsk7 protein, mouse; D013381:Subtilisins