Protein kinase C‐beta isoform as a mechanism promoting chronic pain in sickle cell disease

Abstract

Pain is a hallmark symptom in sickle cell disease (SCD). Besides acute painful vaso‐occlusive crises, SCD is also accompanied by intractable chronic pain. This persistent, and often unrelieved, pain starts early in childhood and continues throughout life. The neurobiological mechanisms of chronic pain in SCD remain unclear, which limits effective pain management and the quality of life in patients with SCD. Taking advantage of a humanized mouse model of SCD, this study aimed to investigate protein kinase C (PKC)‐beta isoform mechanism for chronic pain in SCD. We characterized pain phenotypes in the Townes' mouse model (TOW) of SCD that exclusively expresses human alleles encoding normal α‐ and sickle β‐globin. TOW mice exhibited ongoing spontaneous pain as well as hypersensitivity to evoked pain stimuli compared with littermate control mice. We then examined spinal PKCbeta‐mediated signaling and behavioral consequences. Prominent activation of PKCbeta was identified in the superficial laminae of the spinal cord in TOW sickle mice. Functional inhibition and genetic silencing of the PKCbeta attenuated sickle cell pain phenotypes, abolishing PKCbeta activation, spontaneous pain, mechanical allodynia, and heat hyperalgesia in the sickle cell mice. Taken together, these data suggest PKCbeta may be one of the mechanisms for the generation and maintenance of ongoing and evoked pain in SCD. These findings offer new insights into sickle cell pain mechanisms, which may offer new pharmacological interventions.Support or Funding InformationR35 HL140031 and K99 HL133590This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.