title: PC1, a non-peptide PKR1-preferring antagonist, reduces pain behavior and spinal neuronal sensitization in neuropathic mice.
abstract: Peripheral neuropathy is characterized by abnormal pain responses triggered by the release of several mediators and neuronal hyperexcitability at the spinal cord level. Emerging evidence indicates that the enhanced activity of dorsal horn neurons requires communication with glia and microglia, cells that are physiologically involved in neuronal wellbeing. Prokineticins (PKs), which include PK1 and PK2, represent a novel family of chemokines characterized by a unique structural motif comprising five disulfide bonds. They are expressed in the peripheral and central nervous system. PKs bind two G protein coupled receptors, PKR1 and PKR2, and participate in the regulation of several biological processes, including pain sensation. This study aimed to investigate the anti-nociceptive effect of PC1, a non-peptide PKR1-preferring antagonist, in a mouse model of neuropathic pain. To do this, we assessed the activity of spinal cord nociceptive neurons as well as astrocyte and microglia phenotypes after repeated administration of PC1 in vivo. PC1 treatment strongly delayed the development of thermal hyperalgesia and tactile and mechanical allodynia. It also reduced spinal microglial and glial activation 8 days post injury in spared nerve injury (SNI) mice. Neuropathic mice showed an increased level of PK2 protein in the spinal cord, mostly in astrocytes. PC1 treatment completely reversed the increased responsiveness to mechanical stimuli, the decreased threshold of neuronal activation, and the increased spontaneous activity that were observed in nociceptive specific (NS) neurons of SNI mice.
authors.affiliation: Department of Experimental Medicine, Section of Pharmacology L. Donatelli, Second University of Naples, 80138 Naples, Italy.
authors.forename: F
authors.initials: F
authors.lastname: Guida
authors.affiliation: Department of Physiology and Pharmacology, Sapienza University of Rome, 00185 Rome, Italy.
authors.forename: R
authors.initials: R
authors.lastname: Lattanzi
authors.affiliation: Department of Experimental Medicine, Section of Pharmacology L. Donatelli, Second University of Naples, 80138 Naples, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Boccella
authors.affiliation: Department of Physiology and Pharmacology, Sapienza University of Rome, 00185 Rome, Italy.
authors.forename: D
authors.initials: D
authors.lastname: Maftei
authors.affiliation: Department of Experimental Medicine, Section of Pharmacology L. Donatelli, Second University of Naples, 80138 Naples, Italy.
authors.forename: R
authors.initials: R
authors.lastname: Romano
authors.affiliation: Department of Physiology and Pharmacology, Sapienza University of Rome, 00185 Rome, Italy.
authors.forename: V
authors.initials: V
authors.lastname: Marconi
authors.affiliation: Department of Life and Environmental Sciences, Unit of Pharmaceutical, Pharmacological and Nutraceutical Sciences, University of Cagliari, I-09124 Cagliari, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Balboni
authors.affiliation: Department of Pharmaceutical Science, University of Ferrara, Via Fossato di Mortara 17/19, 44-100 Ferrara, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Salvadori
authors.affiliation: Department of Experimental Medicine, Section of Pharmacology L. Donatelli, Second University of Naples, 80138 Naples, Italy; Department of Anaesthesia and Intensive Care, Second University of Naples, Via De Crecchio, 80138 Naples, Italy.
authors.forename: M A
authors.initials: MA
authors.lastname: Scafuro
authors.affiliation: Department of Experimental Medicine, Section of Pharmacology L. Donatelli, Second University of Naples, 80138 Naples, Italy.
authors.forename: V
authors.initials: V
authors.lastname: de Novellis
authors.affiliation: Department of Physiology and Pharmacology, Sapienza University of Rome, 00185 Rome, Italy.
authors.forename: L
authors.initials: L
authors.lastname: Negri
authors.affiliation: Department of Experimental Medicine, Section of Pharmacology L. Donatelli, Second University of Naples, 80138 Naples, Italy. Electronic address: sabatino.maione@unina2.it.
authors.forename: S
authors.initials: S
authors.lastname: Maione
authors.affiliation: Department of Experimental Medicine, Section of Pharmacology L. Donatelli, Second University of Naples, 80138 Naples, Italy. Electronic address: livio.luongo@gmail.com.
authors.forename: L
authors.initials: L
authors.lastname: Luongo
mesh_terms: D000700:Analgesics / Q000627:therapeutic use*; D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism; D001522:Behavior, Animal / Q000187:drug effects; D005768:Gastrointestinal Hormones / Q000235:genetics / Q000378:metabolism*; D006358:Hot Temperature; D006930:Hyperalgesia / Q000188:drug therapy / Q000378:metabolism; D008297:Male; D051379:Mice; D009437:Neuralgia / Q000188:drug therapy* / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D009479:Neuropeptides / Q000235:genetics / Q000378:metabolism*; D059348:Peripheral Nerve Injuries / Q000188:drug therapy / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D012584:Sciatic Nerve / Q000187:drug effects / Q000293:injuries / Q000378:metabolism; D013116:Spinal Cord / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D014227:Triazines / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D000700:Analgesics; D005768:Gastrointestinal Hormones; D009479:Neuropeptides; C525015:PKR1 protein, mouse; C525016:PKR2 protein, mouse; C486586:Prok2 protein, mouse; D012333:RNA, Messenger; D043562:Receptors, G-Protein-Coupled; D014227:Triazines
keywords: Electrophysiology; Glia; Microglia; Neuropathic pain; Prokineticin system; Spinal cord