title: Increasing TNF levels solely in the rat hippocampus produces persistent pain-like symptoms.
abstract: The manifestation of chronic, neuropathic pain includes elevated levels of the cytokine tumor necrosis factor-alpha (TNF). Previously, we have shown that the hippocampus, an area of the brain most notable for its role in learning and memory formation, plays a fundamental role in pain sensation. Using an animal model of peripheral neuropathic pain, we have demonstrated that intracerebroventricular infusion of a TNF antibody adjacent to the hippocampus completely alleviated pain. Furthermore, intracerebroventricular infusion of rTNF adjacent to the hippocampus induced pain behavior in naïve animals similar to that expressed during a model of neuropathic pain. These data support our premise that enhanced production of hippocampal-TNF is integral in pain sensation. In the present study, TNF gene expression was induced exclusively in the hippocampus, eliciting increased local bioactive TNF levels, and animals were assessed for pain behaviors. Male Sprague-Dawley rats received stereotaxic injection of gold nanorod (GNR)-complexed cDNA (control or TNF) plasmids (nanoplasmidexes), and pain responses (i.e., thermal hyperalgesia and mechanical allodynia) were measured. Animals receiving hippocampal microinjection of TNF nanoplasmidexes developed thermal hyperalgesia bilaterally. Sensitivity to mechanical stimulation also developed bilaterally in the rat hind paws. In support of these behavioral findings, immunoreactive staining for TNF, bioactive levels of TNF, and levels of TNF mRNA per polymerase chain reaction analysis were assessed in several brain regions and found to be increased only in the hippocampus. These findings indicate that the specific elevation of TNF in the hippocampus is not a consequence of pain, but in fact induces these behaviors/symptoms.
authors: Department of Pathology and Anatomical Sciences, School of Medicine and Biomedical Sciences, State University of New York at Buffalo, Buffalo, NY, USA NanoAxis, LLC, Amherst, New York, USA Institute for Lasers, Photonics and Biophotonics, Buffalo, NY, USA Department of Anesthesiology, School of Medicine and Biomedical Sciences, State University of New York at Buffalo, Buffalo, NY, USA Veterans Administration Western New York Healthcare System, Buffalo, NY, USA Department of Medicine, Division of Allergy, Immunology and Rheumatology, School of Medicine and Biomedical Sciences, State University of New York at Buffalo, Buffalo, NY, USA Department of Chemistry, School of Arts and Sciences, State University of New York at Buffalo, Buffalo, NY, USA Department of Microbiology and Immunology, School of Medicine and Biomedical Sciences, State University of New York at Buffalo, Buffalo, NY, USA Program for Neuroscience, School of Medicine and Biomedical Sciences, State University of New York at Buffalo, Buffalo, NY, USA.
authors: Regina T
authors: RT
authors: Martuscello
authors: Robert N
authors: RN
authors: Spengler
authors: Adela C
authors: AC
authors: Bonoiu
authors: Bruce A
authors: BA
authors: Davidson
authors: Jadwiga
authors: J
authors: Helinski
authors: Hong
authors: H
authors: Ding
authors: Supriya
authors: S
authors: Mahajan
authors: Rajiv
authors: R
authors: Kumar
authors: Earl J
authors: EJ
authors: Bergey
authors: Paul R
authors: PR
authors: Knight
authors: Paras N
authors: PN
authors: Prasad
authors: Tracey A
authors: TA
authors: Ignatowski
mesh_terms: D000818:Animals; D018076:DNA, Complementary; D015870:Gene Expression; D006624:Hippocampus / Q000378:metabolism*; D006358:Hot Temperature; D006930:Hyperalgesia / Q000378:metabolism*; D008297:Male; D043942:Nanotubes; D010146:Pain / Q000378:metabolism*; D010957:Plasmids; D012333:RNA, Messenger / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D060888:Real-Time Polymerase Chain Reaction; D014110:Touch; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism*
chemical_list: D018076:DNA, Complementary; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha