title: Immature spinal cord neurons are dynamic regulators of adult nociceptive sensitivity.
abstract: Chronic pain is a debilitating condition with unknown mechanism. Nociceptive sensitivity may be regulated by genetic factors, some of which have been separately linked to neuronal progenitor cells and neuronal differentiation. This suggests that genetic factors that interfere with neuronal differentiation may contribute to a chronic increase in nociceptive sensitivity, by extending the immature, hyperexcitable stage of spinal cord neurons. Although adult rodent spinal cord neurogenesis was previously demonstrated, the fate of these progenitor cells is unknown. Here, we show that peripheral nerve injury in adult rats induces extensive spinal cord neurogenesis and a long-term increase in the number of spinal cord laminae I-II neurons ipsilateral to injury. The production and maturation of these new neurons correlates with the time course and modulation of nociceptive behaviour, and transiently mimics the cellular and behavioural conditions present in genetically modified animal models of chronic pain. This suggests that the number of immature neurons present at any time in the spinal cord dorsal horns contributes to the regulation of nociceptive sensitivity. The continuous turnover of these neurons, which can fluctuate between normal and injured states, is a dynamic regulator of nociceptive sensitivity. In support of this hypothesis, we find that promoters of neuronal differentiation inhibit, while promoters of neurogenesis increase long-term nociception. TrkB agonists, well-known promoters of nociception in the short-term, significantly inhibit long-term nociception by promoting the differentiation of newly produced immature neurons. These findings suggest that promoters of neuronal differentiation may be used to alleviate chronic pain.
authors.affiliation: MGH Center for Translational Pain Research, Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Gabriel
authors.identifier: http://orcid.org/0000-0002-2811-905X
authors.initials: G
authors.lastname: Rusanescu
authors.affiliation: MGH Center for Translational Pain Research, Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Jianren
authors.initials: J
authors.lastname: Mao
mesh_terms: D000375:Aging / Q000502:physiology*; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D019208:Brain-Derived Neurotrophic Factor / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002908:Chronic Disease; D003251:Constriction, Pathologic; D004815:Epidermal Growth Factor / Q000494:pharmacology; D016222:Fibroblast Growth Factor 2 / Q000494:pharmacology; D008297:Male; D058953:Neural Stem Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D055495:Neurogenesis / Q000187:drug effects; D009474:Neurons / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D059225:Nociception / Q000187:drug effects / Q000502:physiology*; D017207:Rats, Sprague-Dawley; D013116:Spinal Cord / Q000166:cytology*; D013997:Time Factors
chemical_list: D015415:Biomarkers; D019208:Brain-Derived Neurotrophic Factor; D016222:Fibroblast Growth Factor 2; D004815:Epidermal Growth Factor
keywords: 7,8-dihydroxyflavone; BDNF; adult neurogenesis; chronic pain; neuronal differentiation; neurotrophins; nociception; peripheral nerve injury