title: BDNF-dependent plasticity induced by peripheral inflammation in the primary sensory and the cingulate cortex triggers cold allodynia and reveals a major role for endogenous BDNF as a tuner of the affective aspect of pain.
abstract: Painful experiences are multilayered, composed of sensory, affective, cognitive and behavioral facets. Whereas it is well accepted that the development of chronic pain is due to maladaptive neuronal changes, the underlying molecular mechanisms, their relationship to the different pain modalities, and indeed the localization of these changes are still unknown. Brain-derived neurotrophic factor (BDNF) is an activity-dependent neuromodulator in the adult brain, which enhances neuronal excitability. In the spinal cord, BDNF underlies the development and maintenance of inflammatory and neuropathic pain. Here, we hypothesized that BDNF could be a trigger of some of these plastic changes. Our results demonstrate that BDNF is upregulated in the anterior cingulate cortex (ACC) and the primary sensory cortex (S1) in rats with inflammatory pain. Injections of recombinant BDNF (into the ACC) or a viral vector synthesizing BDNF (into the ACC or S1) triggered both neuronal hyperexcitability, as shown by elevated long-term potentiation, and sustained pain hypersensitivity. Finally, pharmacological blockade of BDNF-tropomyosin receptor kinase B (TrkB) signaling in the ACC, through local injection of cyclotraxin-B (a novel, highly potent, and selective TrkB antagonist) prevented neuronal hyperexcitability, the emergence of cold hypersensitivity, and passive avoidance behavior. These findings show that BDNF-dependent neuronal plasticity in the ACC, a structure known to be involved in the affective-emotional aspect of pain, is a key mechanism in the development and maintenance of the emotional aspect of chronic pain.
authors.affiliation: Brain Plasticity Unit, ESPCI-ParisTech, 75005 Paris, France, Centre National de la Recherche Scientifique, UMR 8249, 75794 Paris cedex 16, France.
authors.forename: Karine
authors.initials: K
authors.lastname: Thibault
authors.affiliation: Department of Pharmacology, University of Oxford, Oxford OX1 3QT, United Kingdom.
authors.forename: Wee Khang
authors.initials: WK
authors.lastname: Lin
authors.affiliation: Brain Plasticity Unit, ESPCI-ParisTech, 75005 Paris, France, Centre National de la Recherche Scientifique, UMR 8249, 75794 Paris cedex 16, France.
authors.forename: Armelle
authors.initials: A
authors.lastname: Rancillac
authors.affiliation: Brain Plasticity Unit, ESPCI-ParisTech, 75005 Paris, France, Centre National de la Recherche Scientifique, UMR 8249, 75794 Paris cedex 16, France.
authors.forename: Marie
authors.initials: M
authors.lastname: Fan
authors.affiliation: Organisation Nucléaire et Oncogenèse, INSERM U993, Département de Biologie Cellulaire et Infection, Institut Pasteur, 75015 Paris, France.
authors.forename: Thibaut
authors.initials: T
authors.lastname: Snollaerts
authors.affiliation: Brain Plasticity Unit, ESPCI-ParisTech, 75005 Paris, France, Centre National de la Recherche Scientifique, UMR 8249, 75794 Paris cedex 16, France.
authors.forename: Vallier
authors.initials: V
authors.lastname: Sordoillet
authors.affiliation: UMR894 INSERM-CPN-UPMC, Faculté de Médecine Pierre et Marie Curie, Site Pitié-Salpêtrière, 75634 Paris cedex 13, France, and.
authors.forename: Michel
authors.initials: M
authors.lastname: Hamon
authors.affiliation: Shriners Hospitals Pediatric Research Center, Temple University, School of Medicine, Philadelphia, Pennsylvania 19140-5104.
authors.forename: George M
authors.initials: GM
authors.lastname: Smith
authors.affiliation: Brain Plasticity Unit, ESPCI-ParisTech, 75005 Paris, France, Centre National de la Recherche Scientifique, UMR 8249, 75794 Paris cedex 16, France.
authors.forename: Zsolt
authors.initials: Z
authors.lastname: Lenkei
authors.affiliation: Brain Plasticity Unit, ESPCI-ParisTech, 75005 Paris, France, Centre National de la Recherche Scientifique, UMR 8249, 75794 Paris cedex 16, France, sophie.pezet@espci.fr.
authors.forename: Sophie
authors.initials: S
authors.lastname: Pezet
mesh_terms: D000339:Affect / Q000187:drug effects / Q000502:physiology*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects / Q000502:physiology; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D006179:Gyrus Cinguli / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D006930:Hyperalgesia / Q000139:chemically induced / Q000378:metabolism* / Q000503:physiopathology; D007249:Inflammation / Q000139:chemically induced / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D009473:Neuronal Plasticity / Q000187:drug effects / Q000502:physiology*; D010456:Peptides, Cyclic / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D020813:Receptor, trkB / Q000037:antagonists & inhibitors; D013003:Somatosensory Cortex / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D015854:Up-Regulation / Q000502:physiology
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D010456:Peptides, Cyclic; C554840:cyclotraxin-B; D020813:Receptor, trkB
keywords: hyperexcitability; neurotrophic factor; pain; viral vector