title: Neuropathic pain is constitutively suppressed in early life by anti-inflammatory neuroimmune regulation.
abstract: Peripheral nerve injury can trigger neuropathic pain in adults but not in infants; indeed, for unknown reasons, neuropathic pain is rare before adolescence. We show here that the absence of neuropathic pain response in infant male rats and mice following nerve injury is due to an active, constitutive immune suppression of dorsal horn pain activity. In contrast to adult nerve injury, which triggers a proinflammatory immune response in the spinal dorsal horn, infant nerve injury triggers an anti-inflammatory immune response, characterized by significant increases in IL-4 and IL-10. This immediate anti-inflammatory response can also be evoked by direct C-fiber nerve stimulation in infant, but not adult, mice. Blockade of the anti-inflammatory activity with intrathecal anti-IL10 unmasks neuropathic pain behavior in infant nerve injured mice, showing that pain hypersensitivity in young mice is actively suppressed by a dominant anti-inflammatory neuroimmune response. As infant nerve injured mice reach adolescence (postnatal day 25-30), the dorsal horn immune profile switches from an anti-inflammatory to a proinflammatory response characterized by significant increases in TNF and BDNF, and this is accompanied by a late onset neuropathic pain behavior and increased dorsal horn cell sensitivity to cutaneous mechanical and cold stimuli. These findings show that neuropathic pain following early life nerve injury is not absent but suppressed by neuroimmune activity and that "latent" pain can still emerge at adolescence, when the neuroimmune profile changes. The data may explain why neuropathic pain is rare in young children and also why it can emerge, for no observable reason, in adolescent patients.
authors.affiliation: Department of Neuroscience, Physiology and Pharmacology, University College London, London WC1E 6BT, United Kingdom.
authors.forename: Rebecca
authors.initials: R
authors.lastname: McKelvey
authors.affiliation: Departments of Anesthesiology and Neurobiology, Duke University Medical Center, Durham, North Carolina 27710, and.
authors.forename: Temugin
authors.initials: T
authors.lastname: Berta
authors.affiliation: Wolfson Centre for Age Related Diseases, King's College London, London WC2R 2LS, United Kingdom.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Old
authors.affiliation: Departments of Anesthesiology and Neurobiology, Duke University Medical Center, Durham, North Carolina 27710, and.
authors.forename: Ru-Rong
authors.initials: RR
authors.lastname: Ji
authors.affiliation: Department of Neuroscience, Physiology and Pharmacology, University College London, London WC1E 6BT, United Kingdom, m.fitzgerald@ucl.ac.uk.
authors.forename: Maria
authors.initials: M
authors.lastname: Fitzgerald
mesh_terms: D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics / Q000378:metabolism; D006930:Hyperalgesia / Q000276:immunology / Q000378:metabolism / Q000503:physiopathology; D016753:Interleukin-10 / Q000235:genetics / Q000378:metabolism; D015847:Interleukin-4 / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D009437:Neuralgia / Q000276:immunology / Q000378:metabolism* / Q000503:physiopathology; D015213:Neuroimmunomodulation; D051381:Rats; D017207:Rats, Sprague-Dawley; D066148:Spinal Cord Dorsal Horn / Q000254:growth & development* / Q000276:immunology / Q000378:metabolism / Q000503:physiopathology; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D015847:Interleukin-4
keywords: anti-inflammatory; development; dorsal horn; infant; neuropathic; pain