title: Palmitoylethanolamide reduces pain-related behaviors and restores glutamatergic synapses homeostasis in the medial prefrontal cortex of neuropathic mice.
abstract: BACKGROUND
  Enhanced supraspinal glutamate levels following nerve injury are associated with pathophysiological mechanisms responsible for neuropathic pain. Chronic pain can interfere with specific brain areas involved in glutamate-dependent neuropsychological processes, such as cognition, memory, and decision-making. The medial prefrontal cortex (mPFC) is thought to play a critical role in pain-related depression and anxiety, which are frequent co-morbidities of chronic pain. Using an animal model of spared nerve injury (SNI) of the sciatic nerve, we assess bio-molecular modifications in glutamatergic synapses in the mPFC that underlie neuropathic pain-induced plastic changes at 30 days post-surgery. Moreover, we examine the effects of palmitoylethanolamide (PEA) administration on pain-related behaviours, as well as the cortical biochemical and morphological changes that occur in SNI animals.
  
  
  RESULTS
  At 1 month, SNI was associated with mechanical and thermal hypersensitivity, as well as depression-like behaviour, cognitive impairments, and obsessive-compulsive activities. Moreover, we observed an overall glutamate synapse modification in the mPFC, characterized by changes in synaptic density proteins and amino acid levels. Finally, with regard to the resolution of pain and depressive-like syndrome in SNI mice, PEA restored the glutamatergic synapse proteins and changes in amino acid release.
  
  
  CONCLUSIONS
  Given the potential role of the mPFC in pain mechanisms, our findings may provide novel insights into neuropathic pain forebrain processes and indicate PEA as a new pharmacological tool to treat neuropathic pain and the related negative affective states. Graphical Abstract Palmitoylethanolamide: a new pharmacological tool to treat neuropathic pain and the related negative affective states.
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 Experimental Medicine, Section of Pharmacology L. Donatelli, Second University of Naples, 80138, Naples, Italy.
authors.forename: L
authors.initials: L
authors.lastname: Luongo
authors.affiliation: Department of Neuroscience, Laboratory of Molecular and Translational Psychiatry, University School of Medicine "Federico II", Naples, Italy.
authors.forename: F
authors.initials: F
authors.lastname: Marmo
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 Experimental Medicine, Section of Pharmacology L. Donatelli, Second University of Naples, 80138, Naples, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Iannotta
authors.affiliation: Behavioural Neuroscience Laboratory, CEINGE - Biotecnologie Avanzate, Via Comunale Margherita 482, 80145, Naples, Italy.
authors.forename: F
authors.initials: F
authors.lastname: Napolitano
authors.affiliation: Department of Experimental Medicine, Section of Pharmacology L. Donatelli, Second University of Naples, 80138, Naples, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Belardo
authors.affiliation: Department of Experimental Medicine, Section of Pharmacology L. Donatelli, Second University of Naples, 80138, Naples, Italy.
authors.forename: I
authors.initials: I
authors.lastname: Marabese
authors.affiliation: Stazione Zoologica "Anton Dohrn", Naples, Italy.
authors.forename: A
authors.initials: A
authors.lastname: D'Aniello
authors.affiliation: Department of Experimental Medicine, Section of Pharmacology L. Donatelli, Second University of Naples, 80138, Naples, Italy.
authors.forename: D
authors.initials: D
authors.lastname: De Gregorio
authors.affiliation: Department of Women, Child and General and Specialistic Surgery, Second University of Naples, Naples, Italy.
authors.forename: F
authors.initials: F
authors.lastname: Rossi
authors.affiliation: Institute of Biomolecular Chemistry, Consiglio Nazionale delle Ricerche, Via Campi Flegrei 34, 80078, Pozzuoli, NA, Italy.
authors.forename: F
authors.initials: F
authors.lastname: Piscitelli
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 Neuroscience, Laboratory of Molecular and Translational Psychiatry, University School of Medicine "Federico II", Naples, Italy.
authors.forename: A
authors.initials: A
authors.lastname: de Bartolomeis
authors.affiliation: Behavioural Neuroscience Laboratory, CEINGE - Biotecnologie Avanzate, Via Comunale Margherita 482, 80145, Naples, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Usiello
authors.affiliation: Institute of Biomolecular Chemistry, Consiglio Nazionale delle Ricerche, Via Campi Flegrei 34, 80078, Pozzuoli, NA, Italy.
authors.forename: V
authors.initials: V
authors.lastname: Di Marzo
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 Experimental Medicine, Section of Pharmacology L. Donatelli, Second University of Naples, 80138, Naples, Italy. sabatino.maione@unina2.it.
authors.forename: S
authors.initials: S
authors.lastname: Maione
mesh_terms: D000577:Amides; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism; D002478:Cells, Cultured; D055724:Electrophysiological Phenomena / Q000187:drug effects; D004983:Ethanolamines / Q000494:pharmacology / Q000627:therapeutic use*; D018698:Glutamic Acid / Q000378:metabolism*; D006706:Homeostasis / Q000187:drug effects*; D007103:Immobilization; D008297:Male; D051379:Mice; D017628:Microglia / Q000187:drug effects / Q000378:metabolism; D008845:Microinjections; D009437:Neuralgia / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D010169:Palmitic Acids / Q000494:pharmacology / Q000627:therapeutic use*; D017397:Prefrontal Cortex / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D020813:Receptor, trkB / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013569:Synapses / Q000187:drug effects / Q000378:metabolism*; D013623:Tail
chemical_list: D000577:Amides; D019208:Brain-Derived Neurotrophic Factor; D004983:Ethanolamines; D010169:Palmitic Acids; D018698:Glutamic Acid; C005958:palmidrol; D020813:Receptor, trkB; D051057:Proto-Oncogene Proteins c-akt