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PKCδ-targeted intervention relieves chronic pain in a murine sickle cell disease model
Ying He, … , Robert E. Molokie, Zaijie Jim Wang
Ying He, … , Robert E. Molokie, Zaijie Jim Wang
Published June 27, 2016
Citation Information: J Clin Invest. 2016;126(8):3053-3057. https://doi.org/10.1172/JCI86165.
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Brief Report Hematology

PKCδ-targeted intervention relieves chronic pain in a murine sickle cell disease model

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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

Ying He, Diana J. Wilkie, Jonathan Nazari, Rui Wang, Robert O. Messing, Joseph DeSimone, Robert E. Molokie, Zaijie Jim Wang

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Figure 1

TOW mice exhibited ongoing spontaneous pain, evoked pain, and activation of spinal PKCδ.

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TOW mice exhibited ongoing spontaneous pain, evoked pain, and activation...
(A) Lidocaine (0.04%, i.t.) induced CPP in TOW (hβS/hβS) SCD mice. TOW mice spent significantly more time in lidocaine-paired chambers, whereas nonsickle control mice showed no chamber preference. (B) Difference scores between test time and preconditioning (pre) time confirmed that hβS/hβS, but not hβA/hβA, mice developed lidocaine CPP. (C) TOW mice displayed significantly reduced paw withdrawal threshold to von Frey filaments when compared with hβA/hβA mice. (D) In response to noxious radiant heat, TOW mice showed significantly shorter paw withdrawal latency compared with hA/hβA mice. Data were analyzed by ANOVA followed by Dunnett’s t test. Two-way ANOVA (pairing vs. treatment) and post hoc Bonferroni’s test were used to analyze CPP data. Difference scores were analyzed by 2-tailed paired t test. ***P < 0.001 vs. hβA/hβA. n = 8/group. (E) Immunohistochemistry showed plasma membrane translocation of PKCδ (indicated by solid arrows) in the superficial lamina region of the dorsal spinal cord in TOW, but not hβA/hβA, mice. PKCδ fluorescent intensity across representative cells (indicated by dashed arrows) is shown. Red, PKCδ; green, NeuN. Scale bars: 20 μm. n = 15 slices from 3 mice.

Copyright © 2021 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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