title: Loss of dopamine D1 receptors and diminished D1/5 receptor-mediated ERK phosphorylation in the periaqueductal gray after spinal cord lesion.
abstract: Neuropathic pain resulting from spinal cord injury is often accompanied by maladaptive plasticity of the central nervous system, including the opioid receptor-rich periaqueductal gray (PAG). Evidence suggests that sensory signaling via the PAG is robustly modulated by dopamine D1- and D2-like receptors, but the effect of damage to the spinal cord on D1 and D2 receptor protein expression and function in the PAG has not been examined. Here we show that 21days after a T10 or C6 spinothalamic tract lesion, both mice and rats display a remarkable decline in the expression of D1 receptors in the PAG, revealed by western blot analysis. These changes were associated with a significant reduction in hindpaw withdrawal thresholds in lesioned animals compared to sham-operated controls. We investigated the consequences of diminished D1 receptor levels by quantifying D1-like receptor-mediated phosphorylation of ERK1,2 and CREB, events that have been observed in numerous brain structures. In naïve animals, western blot analysis revealed that ERK1,2, but not CREB phosphorylation was significantly increased in the PAG by the D1-like agonist SKF 81297. Using immunohistochemistry, we found that SKF 81297 increased ERK1,2 phosphorylation in the PAG of sham animals. However, in lesioned animals, basal pERK1,2 levels were elevated and did not significantly increase after exposure to SKF 81297. Our findings provide support for the hypothesis that molecular adaptations resulting in a decrease in D1 receptor expression and signaling in the PAG are a consequence of SCL.
authors.affiliation: University of Maryland School of Dentistry, Department of Endodontics, Periodontics & Prosthodontics, 650 W. Baltimore Street, Baltimore, MD 21201, USA.
authors.forename: Pamela J
authors.initials: PJ
authors.lastname: Voulalas
authors.affiliation: University of Maryland School of Dentistry, Department of Endodontics, Periodontics & Prosthodontics, 650 W. Baltimore Street, Baltimore, MD 21201, USA.
authors.forename: Yadong
authors.initials: Y
authors.lastname: Ji
authors.affiliation: University of Maryland School of Medicine, Department of Diagnostic Radiology, Baltimore, MD 21201, USA.
authors.forename: Li
authors.initials: L
authors.lastname: Jiang
authors.affiliation: University of Maryland School of Dentistry, Department of Neural and Pain Sciences, 650 W. Baltimore Street, Baltimore, MD 21201, USA.
authors.forename: Jamila
authors.initials: J
authors.lastname: Asgar
authors.affiliation: University of Maryland School of Dentistry, Department of Neural and Pain Sciences, Baltimore, MD 21201, USA; Kyung Hee University, School of Dentistry, Department of Oral Medicine, Seoul, Republic of Korea.
authors.forename: Jin Y
authors.initials: JY
authors.lastname: Ro
authors.affiliation: University of Maryland School of Dentistry, Department of Endodontics, Periodontics & Prosthodontics, 650 W. Baltimore Street, Baltimore, MD 21201, USA; University of Maryland School of Medicine, Department of Anatomy and Neurobiology, 650 W. Baltimore Street, Baltimore, MD 21201, USA. Electronic address: rmasri@umaryland.edu.
authors.forename: Radi
authors.initials: R
authors.lastname: Masri
mesh_terms: D000818:Animals; D001552:Benzazepines / Q000494:pharmacology; D050882:CREB-Binding Protein / Q000378:metabolism; D004195:Disease Models, Animal; D018491:Dopamine Agonists / Q000494:pharmacology; D005260:Female; D020935:MAP Kinase Signaling System / Q000502:physiology*; D008297:Male; D008822:Mice, Transgenic; D010487:Periaqueductal Gray / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D010766:Phosphorylation; D020318:Rats, Long-Evans; D017207:Rats, Sprague-Dawley; D055647:Rats, Transgenic; D017447:Receptors, Dopamine D1 / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D013119:Spinal Cord Injuries / Q000378:metabolism* / Q000473:pathology
chemical_list: D001552:Benzazepines; D018491:Dopamine Agonists; D017447:Receptors, Dopamine D1; C067113:SK&F 81297; D050882:CREB-Binding Protein
keywords: SKF 81297; behavior; extracellular signal regulated kinase; hyperalgesia; neuropathic pain; spinal cord injury