title: Brain-derived TNFalpha: involvement in neuroplastic changes implicated in the conscious perception of persistent pain.
abstract: The pleiotropic cytokine tumor necrosis factor-alpha (TNFalpha) is implicated in the development of persistent pain through its actions in the periphery and in the central nervous system (CNS). Activation of the alpha(2)-adrenergic receptor is associated with modulation of pain, possibly through its autoregulatory effect on norepinephrine (NE) release in the CNS. The present study employs a chronic constriction nerve injury (CCI) pain model to demonstrate the interactive role of presynaptic sensitivity to TNFalpha and the alpha(2)-adrenergic autoreceptor in the pathogenesis of neuropathic pain. Accumulation of TNFalpha is increased initially in a region of the brain containing the locus coeruleus (LC) at day 4 post-ligature placement, followed by an increase in TNFalpha in the hippocampus at day 8 post-ligature placement, coincident with hyperalgesia. Levels of TNFalpha in the thoraco-lumbar spinal cord are also increased at day 8 post-ligature placement. Concurrently, alpha(2)-adrenergic receptor and TNFalpha-induced inhibition of NE release are increased, and stimulated NE release is decreased in superfused hippocampal slices isolated at day 8 post-ligature placement. Stimulated NE release is also decreased in spinal cord slices (lumbar region) from animals undergoing CCI, although in contrast to that which occurs in the hippocampus, alpha(2)-adrenergic receptor inhibition of NE release is not changed. These results indicate an important role that TNFalpha plays in adrenergic neuroplastic changes in a region of the brain that, among its many functions, appears to be a crucial link in the conscious perception of pain. We predict that neuroplastic changes, involving increased functional responses of alpha(2)-adrenergic autoreceptors and increased presynaptic sensitivity to TNFalpha, culminate in decreased NE release in the CNS. These neuroplastic changes provide a mechanism for the role of CNS-derived TNFalpha in the pathogenesis of persistent pain.
authors.affiliation: Department of Pathology, State University of New York at Buffalo, School of Medicine and Biomedical Sciences, 204 Farber Hall, 3435 Main Street, Buffalo, NY 14214, USA.
authors.forename: W C
authors.initials: WC
authors.lastname: Covey
authors.forename: T A
authors.initials: TA
authors.lastname: Ignatowski
authors.forename: P R
authors.initials: PR
authors.lastname: Knight
authors.forename: R N
authors.initials: RN
authors.lastname: Spengler
mesh_terms: D000316:Adrenergic alpha-Agonists / Q000494:pharmacology; D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology; D000818:Animals; D001921:Brain / Q000166:cytology / Q000378:metabolism*; D002908:Chronic Disease; D003000:Clonidine / Q000494:pharmacology; D003243:Consciousness / Q000502:physiology*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004558:Electric Stimulation; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D006930:Hyperalgesia / Q000503:physiopathology; D019329:Idazoxan / Q000494:pharmacology; D008297:Male; D009473:Neuronal Plasticity / Q000502:physiology*; D010148:Intractable Pain / Q000503:physiopathology*; D010468:Perceptual Disorders / Q000503:physiopathology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018341:Receptors, Adrenergic, alpha-2 / Q000187:drug effects* / Q000378:metabolism*; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism* / Q000494:pharmacology
chemical_list: D000316:Adrenergic alpha-Agonists; D000317:Adrenergic alpha-Antagonists; D018341:Receptors, Adrenergic, alpha-2; D014409:Tumor Necrosis Factor-alpha; D003000:Clonidine; D019329:Idazoxan