title: CaMKIIα underlies spontaneous and evoked pain behaviors in Berkeley sickle cell transgenic mice.
abstract: Pain is one of the most challenging and stressful conditions to patients with sickle cell disease (SCD) and their clinicians. Patients with SCD start experiencing pain as early as 3 months old and continue having it throughout their lives. Although many aspects of the disease are well understood, little progress has been made in understanding and treating pain in SCD. This study aimed to investigate the functional involvement of Ca/calmodulin-dependent protein kinase II (CaMKIIα) in the persistent and refractory pain associated with SCD. We found that nonevoked ongoing pain as well as evoked hypersensitivity to mechanical and thermal stimuli were present in Berkeley sickle cell transgenic mice (BERK mice), but not nonsickle control littermates. Prominent activation of CaMKIIα was observed in the dorsal root ganglia and spinal cord dorsal horn region of BERK mice. Intrathecal administration of KN93, a selective inhibitor of CaMKII, significantly attenuated mechanical allodynia and heat hyperalgesia in BERK mice. Meanwhile, spinal inhibition of CaMKII elicited conditioned place preference in the BERK mice, indicating the contribution of CaMKII in the ongoing spontaneous pain of SCD. We further targeted CaMKIIα by siRNA knockdown. Both evoked pain and ongoing spontaneous pain were effectively attenuated in BERK mice. These findings elucidated, for the first time, an essential role of CaMKIIα as a cellular mechanism in the development and maintenance of spontaneous and evoked pain in SCD, which can potentially offer new targets for pharmacological intervention of pain in SCD.
authors.affiliation: Department of Biopharmaceutical Sciences.|Sickle Cell Center, Chicago, IL, USA.
authors.forename: Ying
authors.initials: Y
authors.lastname: He
authors.affiliation: Department of Biopharmaceutical Sciences.
authors.forename: Yan
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Department of Biopharmaceutical Sciences.
authors.forename: Xuebi
authors.initials: X
authors.lastname: Tian
authors.affiliation: Department of Biopharmaceutical Sciences.
authors.forename: Cheng
authors.initials: C
authors.lastname: Yang
authors.affiliation: Department of Biopharmaceutical Sciences.
authors.forename: Jian
authors.initials: J
authors.lastname: Lu
authors.affiliation: Department of Biopharmaceutical Sciences.
authors.forename: Chun
authors.initials: C
authors.lastname: Xiao
authors.affiliation: Sickle Cell Center, Chicago, IL, USA.|Division of Hematology and Oncology, Department of Medicine, University of Illinois, Chicago, IL, USA.
authors.forename: Joseph
authors.initials: J
authors.lastname: DeSimone
authors.affiliation: Department of Biobehavioral Nursing Science, University of Florida, Gainesville, FL, USA.
authors.forename: Diana J
authors.initials: DJ
authors.lastname: Wilkie
authors.affiliation: Department of Biopharmaceutical Sciences.|Sickle Cell Center, Chicago, IL, USA.|Division of Hematology and Oncology, Department of Medicine, University of Illinois, Chicago, IL, USA.|Jesse Brown Veteran's Administration Medical Center, Chicago, IL, USA.
authors.forename: Robert E
authors.initials: RE
authors.lastname: Molokie
authors.affiliation: Department of Biopharmaceutical Sciences.|Sickle Cell Center, Chicago, IL, USA.
authors.forename: Zaijie Jim
authors.initials: ZJ
authors.lastname: Wang
mesh_terms: D000755:Anemia, Sickle Cell / Q000150:complications* / Q000235:genetics; D000779:Anesthetics, Local / Q000627:therapeutic use; D000818:Animals; D001596:Benzylamines / Q000627:therapeutic use; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000235:genetics / Q000378:metabolism*; D003216:Conditioning, Operant / Q000502:physiology; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D005557:Formaldehyde / Q000633:toxicity; D005727:Ganglia, Spinal / Q000378:metabolism / Q000473:pathology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D006454:Hemoglobins / Q000235:genetics / Q000378:metabolism; D006930:Hyperalgesia / Q000209:etiology; D007249:Inflammation / Q000139:chemically induced / Q000150:complications; D008012:Lidocaine / Q000627:therapeutic use; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010146:Pain / Q000188:drug therapy / Q000209:etiology*; D017288:Pain Threshold / Q000187:drug effects / Q000502:physiology; D010812:Physical Stimulation / Q000009:adverse effects; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism; D013449:Sulfonamides / Q000627:therapeutic use; D000096926:Benzenesulfonamides
chemical_list: D000779:Anesthetics, Local; D001596:Benzylamines; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D004791:Enzyme Inhibitors; D005557:Formaldehyde; D006454:Hemoglobins; D008012:Lidocaine; D013449:Sulfonamides; C072105:KN 93; D000096926:Benzenesulfonamides