title: Antagonism of the Prokineticin System Prevents and Reverses Allodynia and Inflammation in a Mouse Model of Diabetes.
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.
authors.affiliation: Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Milano, Italy.
authors.forename: Mara
authors.initials: M
authors.lastname: Castelli
authors.affiliation: Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Milano, Italy.
authors.forename: Giada
authors.initials: G
authors.lastname: Amodeo
authors.affiliation: Department of Physiology and Pharmacology 'Vittorio Erspamer', University of Rome, Roma, Italy.
authors.forename: Lucia
authors.initials: L
authors.lastname: Negri
authors.affiliation: Department of Physiology and Pharmacology 'Vittorio Erspamer', University of Rome, Roma, Italy.
authors.forename: Roberta
authors.initials: R
authors.lastname: Lattanzi
authors.affiliation: Department of Physiology and Pharmacology 'Vittorio Erspamer', University of Rome, Roma, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Maftei
authors.affiliation: Consiglio Nazionale delle Ricerche, Institute of Neuroscience, Milano, Italy.
authors.forename: Cecilia
authors.initials: C
authors.lastname: Gotti
authors.affiliation: Consiglio Nazionale delle Ricerche, Institute of Neuroscience, Milano, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Pistillo
authors.affiliation: Department of Life and Environmental Sciences, Unit of Pharmaceutical, Pharmacological and Nutraceutical Sciences, University of Cagliari, Cagliari, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Onnis
authors.affiliation: Department of Life and Environmental Sciences, Unit of Pharmaceutical, Pharmacological and Nutraceutical Sciences, University of Cagliari, Cagliari, Italy.
authors.forename: Cenzo
authors.initials: C
authors.lastname: Congu
authors.affiliation: Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Milano, Italy.
authors.forename: Alberto E
authors.initials: AE
authors.lastname: Panerai
authors.affiliation: Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Milano, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Sacerdote
authors.affiliation: Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Milano, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Franchi
mesh_terms: D000818:Animals; D015153:Blotting, Western; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D005768:Gastrointestinal Hormones / Q000235:genetics / Q000378:metabolism*; D015870:Gene Expression; D006930:Hyperalgesia / Q000235:genetics / Q000378:metabolism* / Q000517:prevention & control; D007249:Inflammation / Q000235:genetics / Q000378:metabolism* / Q000517:prevention & control; D008297:Male; D008810:Mice, Inbred C57BL; D009437:Neuralgia / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control; D009479:Neuropeptides / Q000235:genetics / Q000378:metabolism*; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012584:Sciatic Nerve / Q000378:metabolism; D013116:Spinal Cord / Q000378:metabolism; D014227:Triazines / Q000494:pharmacology
chemical_list: D016207:Cytokines; D005768:Gastrointestinal Hormones; C121001:NR2B NMDA receptor; D009479:Neuropeptides; C525015:PKR1 protein, mouse; C525016:PKR2 protein, mouse; C486586:Prok2 protein, mouse; D043562:Receptors, G-Protein-Coupled; D016194:Receptors, N-Methyl-D-Aspartate; D014227:Triazines