title: Prenatal alcohol exposure potentiates chronic neuropathic pain, spinal glial and immune cell activation and alters sciatic nerve and DRG cytokine levels.
abstract: A growing body of evidence indicates that prenatal alcohol exposure (PAE) may predispose individuals to secondary medical disabilities later in life. Animal models of PAE reveal neuroimmune sequelae such as elevated brain astrocyte and microglial activation with corresponding region-specific changes in immune signaling molecules such as cytokines and chemokines. The aim of this study was to evaluate the effects of moderate PAE on the development and maintenance of allodynia induced by chronic constriction injury (CCI) of the sciatic nerve in adult male rat offspring. Because CCI allodynia requires the actions of glial cytokines, we analyzed lumbar spinal cord glial and immune cell surface markers indicative of their activation levels, as well as sciatic nerve and dorsal root ganglia (DRG) cytokines in PAE offspring in adulthood. While PAE did not alter basal sensory thresholds before or after sham manipulations, PAE significantly potentiated adult onset and maintenance of allodynia. Microscopic analysis revealed exaggerated astrocyte and microglial activation, while flow cytometry data demonstrated increased proportions of immune cells with cell surface major histocompatibility complex II (MHCII) and β-integrin adhesion molecules, which are indicative of PAE-induced immune cell activation. Sciatic nerves from CCI rats revealed that PAE potentiated the proinflammatory cytokines interleukin (IL)-1β, IL-6 and tumor necrosis factor-alpha (TNFα) protein levels with a simultaneous robust suppression of the anti-inflammatory cytokine, IL-10. A profound reduction in IL-10 expression in the DRG of PAE neuropathic rats was also observed. Taken together, our results provide novel insights into the vulnerability that PAE produces for adult-onset central nervous system (CNS) pathological conditions from peripheral nerve injury.
authors.affiliation: Department of Neurosciences, School of Medicine, University of New Mexico Health Sciences Center, Albuquerque, NM 87131-0001, USA.
authors.forename: Shahani
authors.initials: S
authors.lastname: Noor
authors.affiliation: Department of Neurosciences, School of Medicine, University of New Mexico Health Sciences Center, Albuquerque, NM 87131-0001, USA.
authors.forename: Joshua J
authors.initials: JJ
authors.lastname: Sanchez
authors.affiliation: Department of Neurosciences, School of Medicine, University of New Mexico Health Sciences Center, Albuquerque, NM 87131-0001, USA; Department of Anesthesiology and Critical Care Medicine, University of New Mexico Health Sciences Center, Albuquerque, NM 87131-0001, USA.
authors.forename: Arden G
authors.initials: AG
authors.lastname: Vanderwall
authors.affiliation: Department of Neurosciences, School of Medicine, University of New Mexico Health Sciences Center, Albuquerque, NM 87131-0001, USA.
authors.forename: Melody S
authors.initials: MS
authors.lastname: Sun
authors.affiliation: Department of Pediatrics, University of New Mexico Health Sciences Center, Albuquerque, NM 87131-0001, USA.
authors.forename: Jessie R
authors.initials: JR
authors.lastname: Maxwell
authors.affiliation: Department of Neurosciences, School of Medicine, University of New Mexico Health Sciences Center, Albuquerque, NM 87131-0001, USA.
authors.forename: Suzy
authors.initials: S
authors.lastname: Davies
authors.affiliation: Department of Neurosciences, School of Medicine, University of New Mexico Health Sciences Center, Albuquerque, NM 87131-0001, USA; Department of Pediatrics, University of New Mexico Health Sciences Center, Albuquerque, NM 87131-0001, USA.
authors.forename: Lauren L
authors.initials: LL
authors.lastname: Jantzie
authors.affiliation: Department of Anesthesiology and Critical Care Medicine, University of New Mexico Health Sciences Center, Albuquerque, NM 87131-0001, USA.
authors.forename: Timothy R
authors.initials: TR
authors.lastname: Petersen
authors.affiliation: Department of Neurosciences, School of Medicine, University of New Mexico Health Sciences Center, Albuquerque, NM 87131-0001, USA; Department of Pediatrics, University of New Mexico Health Sciences Center, Albuquerque, NM 87131-0001, USA.
authors.forename: Daniel D
authors.initials: DD
authors.lastname: Savage
authors.affiliation: Department of Neurosciences, School of Medicine, University of New Mexico Health Sciences Center, Albuquerque, NM 87131-0001, USA. Electronic address: EMilligan@salud.unm.edu.
authors.forename: Erin D
authors.initials: ED
authors.lastname: Milligan
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism*; D000431:Ethanol / Q000008:administration & dosage*; D005260:Female; D005727:Ganglia, Spinal / Q000378:metabolism* / Q000503:physiopathology; D006930:Hyperalgesia / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D017628:Microglia / Q000378:metabolism*; D009437:Neuralgia / Q000378:metabolism* / Q000503:physiopathology; D010147:Pain Measurement; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000378:metabolism* / Q000503:physiopathology; D051381:Rats; D020318:Rats, Long-Evans; D012584:Sciatic Nerve / Q000378:metabolism* / Q000503:physiopathology; D013116:Spinal Cord / Q000378:metabolism / Q000503:physiopathology
chemical_list: D016207:Cytokines; D000431:Ethanol
keywords: Astrocytes; Chronic constriction injury; Fetal alcohol spectrum disorder; Inflammatory cytokines; Microglia; Neuroimmune interactions; Neuropathic pain; Prenatal alcohol exposure; Sciatic nerve; Spinal glia; β-Integrin adhesion molecules