title: PKCδ-targeted intervention relieves chronic pain in a murine sickle cell disease model.
abstract: Pain is a life-long symptom in sickle cell disease (SCD) and a predictor of disease progression and mortality, but little is known about its molecular mechanisms. Here, we characterized pain in a targeted knockin mouse model of SCD (TOW mouse) that exclusively expresses human alleles encoding normal α- and sickle β-globin. TOW mice exhibited ongoing spontaneous pain behavior and increased sensitivity to evoked pain compared with littermate control mice expressing normal human hemoglobins. PKCδ activation was elevated in the superficial laminae of the spinal cord dorsal horn in TOW mice, specifically in GABAergic inhibitory neurons. Functional inhibition and neuron-specific silencing of PKCδ attenuated spontaneous pain, mechanical allodynia, and heat hyperalgesia in TOW mice. Furthermore, we took a hematopoietic stem cell transplantation approach to generating a SCD model in PKCδ-deficient mice. Neither spontaneous pain nor evoked pain was detected in the mice lacking PKCδ despite full establishment of SCD phenotypes. These findings support a critical role of spinal PKCδ in the development of chronic pain in SCD, which may become a potential target for pharmacological interventions.
authors.forename: Ying
authors.initials: Y
authors.lastname: He
authors.forename: Diana J
authors.initials: DJ
authors.lastname: Wilkie
authors.forename: Jonathan
authors.initials: J
authors.lastname: Nazari
authors.forename: Rui
authors.initials: R
authors.lastname: Wang
authors.forename: Robert O
authors.initials: RO
authors.lastname: Messing
authors.forename: Joseph
authors.initials: J
authors.lastname: DeSimone
authors.forename: Robert E
authors.initials: RE
authors.lastname: Molokie
authors.forename: Zaijie Jim
authors.initials: ZJ
authors.lastname: Wang
mesh_terms: D000483:Alleles; D000755:Anemia, Sickle Cell / Q000235:genetics* / Q000628:therapy*; D000818:Animals; D059350:Chronic Pain / Q000378:metabolism*; D004195:Disease Models, Animal; D005260:Female; D005786:Gene Expression Regulation; D055879:Gene Knock-In Techniques; D020868:Gene Silencing; D006801:Humans; D006930:Hyperalgesia / Q000378:metabolism; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009474:Neurons / Q000378:metabolism; D051745:Protein Kinase C-delta / Q000235:genetics* / Q000378:metabolism
chemical_list: C497259:Prkcd protein, mouse; D051745:Protein Kinase C-delta