GRK2 deficiency is a pain

Abstract

G protein-coupled receptor (GPCR) kinase (GRK)2 regulates the responsiveness of many GPCRS, e.g. CCR1, CCR2, CCR5, neurokinin-1 receptor, and metabotropic glutamate receptors, which are involved in the development of allodynia (pain due to a stimulus which does normally not provoke pain) and hyperalgesia (an increased response to a painful stimulus). During several inflammatory processes, the amount of cellular GRK2 is modulated in leukocytes, which has consequences for GPCR function. In general, a reduction in GRK2 expression correlates with enhanced receptor signaling, whereas an increase in GRK2 associates with decreased receptor function. In addition, the amount of cellular GRK2 determines the course and outcome of the disease. The experiments performed in this thesis focused on: 1. the expression of spinal cord neuronal GRK2 during neuropathic pain, 2. the consequences of low GRK2 on pain perception, 3. the mechanism of GRK2-mediated regulation of GPCR signaling. We demonstrated a reduction of neuronal GRK2 in the spinal cord dorsal horn during two models of nerve injury-induced mechanical allodynia: chronic constriction injury (CCI) of the sciatic nerve in rats and L5 spinal nerve transection (SNT) in mice. In addition, we reported that interleukin (IL)-1 type 1 receptor knock-out (IL-1R-/-) mice did not show a reduction in spinal cord GRK2 during L5 SNT and also did not develop mechanical allodynia in this model. Furthermore, chronic IL-1 1β treatment of ex vivo cultured spinal cord slices resulted in a decrease in GRK2. These data demonstrate a role for IL-1 1β signaling in downregulating spinal cord GRK2 during mechanical allodynia. Moreover, we showed that low GRK2 lead to increased mechanical allodynia and thermal hyperalgesia in animals with paw inflammation. No changes in pain perception were observed in naive GRK2+/- mice compared to wild type (WT) mice. Finally, we reported that GRK2 not only plays a role in neurons, but also in astrocytes by regulating GPCR (chemokine) signaling in primary cultures of astrocytes via interaction with intracellular signaling molecules. Further elucidation of the function of GRK2 during states of increased pain perception might uncover new opportunities for the treatment of patients with chronic pain.