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

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 affective or emotional dysregulation in this population. How SCD physiologically manifests within brain circuitry to mediate this link is currently unknown. In the current study, we utilized a transgenic mouse model of SCD to measure protein kinase A (PKA)-mediated phosphorylation of the 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 mice (HbSS-BERK) expressing human sickle hemoglobin display significant mechanical and thermal hyperalgesia and exhibit reductions in GluR1 phosphorylation compared to littermate controls (HbAA-BERK) in the PAG, PFC, and hippocampus. This neuroadaptation is indicative of reduced excitatory transmission potential in these pain-associated areas. In comparison, GluR1 phosphorylation is unchanged in the dorsal striatum, a brain region not traditionally associated with pain or negative emotionality. Our data are consistent with other preclinical pain models that have linked chronic, peripheral pain conditions with compromised excitatory brain signaling. These results make a strong case for greater appreciation and investigation into mechanisms of possible affective disorder in individuals suffering from SCD.