Reduced Glutamate Channel Phosphorylation in Pain‐Related Brain Areas in a Transgenic Model of Sickle Cell Disease

Abstract

Sickle cell disease (SCD) is associated with chronic, debilitating pain beginning in childhood and persisting throughout life. SCD patients also tend to exhibit elevated rates of depression and anxiety disorders, indicating a possible connection between recurring pain episodes and later affective or emotional dysregulation in this population. How SCD physiologically manifests within brain circuitry to mediate this link is currently unknown, although we hypothesize that alterations in glutamate plasticity in central pain centers is implicated. In the current study, we utilized a transgenic mouse model of SCD to measure protein kinase A (PKA)‐mediated phosphorylation of the excitatory AMPA glutamate receptor channel subunit GluR1 in specific brain regions associated with central nociception and the emotional dimension of pain, including the periaqueductal gray (PAG), prefrontal cortex (PFC), and hippocampus. Transgenic sickle cell mice (HbSS‐BERK) expressing human sickle hemoglobin displayed significant mechanical and thermal hyperalgesia across multiple tests of nociceptive sensitivity compared to healthy controls (HbAA‐BERK, expressing normal human adult hemoglobin). In addition, HbSS mice also exhibited reductions in GluR1 subunit phosphorylation in the PAG, PFC, and hippocampus relative to HbAA mice. This neuroadaptation is indicative of diminished excitatory transmission potential in these pain‐ and emotion‐associated brain areas. Moreover, our data are consistent with other preclinical pain models that have linked chronic, peripheral pain conditions with compromised excitatory signaling in central brain regions. These results make a strong case for greater appreciation and investigation into mechanisms linking pain sensitivity with possible affective disorder in individuals suffering from SCD. Our future plans include survey and functional magnetic resonance imaging (fMRI) studies of adolescent and young adult SCD patients to compare how our preclinical findings in HbSS mice associate with pain symptoms and brain activity in this patient population.Support or Funding InformationR01HL103733R00AA020839