GRK Gatekeeper of pain and inflammation
More then 10% of the population suffers from chronic pain. Treatment often fails since individual susceptibility is highly variable. Therefore, better understanding of factors involved in determination whether pain becomes chronic is crucial. In this thesis we investigated the role of two kinases, G protein-coupled receptor kinase (GRK) 2 and 6, as possible factors in regulating pain and inflammation. Both kinases are ubiquitously expressed and restrain G protein-coupled receptor (GPCR) signalling by interfering at various levels of the transduction cascade. In order to investigate the role of GRK2 in pain we used mice partially deficient for GRK2. In addition, mice with a GRK2 reduction in specific cell types only were used. To test the role of GRK2 in pain we looked at the development of hyperalgesia, a state in which painful stimuli are perceived as more painful. Importantly, reduced levels of GRK2 in spinal microglia caused a transition of a transient inflammatory hyperalgesia into a chronic process, a process that was mediated via the MAPkinase p38. Additionally, GRK2 expressed in primary sensory neurons was shown to be important in controlling the magnitude of acute hyperalgesia induced by the chemokine CCL3, but not the cytokine IL-1beta. Finally, GRK2 reduction in primary sensory neurons alters the signalling cascade involved in the induction of hyperalgesia by prostaglandin E2, resulting in prolonged (days) hyperalgesia. In this thesis we also investigated the role of GRK6 in inflammatory hyperalgesia. We found that GRK6 protects against IL-1beta-induced chronic hyperalgesia via a spinal microglia and spinal IL-1 signalling dependent pathway. To test whether these findings would have implications for post-inflammatory hyperalgesia, a condition that is observed in e.g. post-infectious irritable bowel syndrome, we developed an animal model of post-inflammatory hyperalgesia. In this model we observed post-inflammatory hyperalgesia at the behavioural but also at the spinal neuronal level. Using this model we found that GRK6 protects against post-inflammatory visceral hyperalgesia in female mice, without affecting the course of colitis. Finally, we investigated the role of GRK6 in an animal model of an acute transient model of visceral inflammation in male mice that has some resemblances with ulcerative colitis in humans. We found that GRK6 not only protects against acute visceral inflammation via regulation of inflammatory cell chemotaxis, but also protects against the transition of a transient inflammation into a chronic process via regulation of regulatory T-cell function. In conclusion in this thesis we discovered that GRK2 and GRK6 are key gatekeepers of the transition of a transient inflammatory hyperalgesia into a chronic inflammatory hyperalgesia. In addition, we have provided novel evidence that GRK2 also controls the severity of acute inflammatory hyperalgesia induced by GPCR agonists. Furthermore, GRK6 controls the severity of acute colitis and the transition of an acute colitis into a chronic process independently of the severity of acute colitis. These novel data provide important information in the understanding of chronic pain and chronic inflammation and may improve the search for novel therapeutical strategies to treat chronic pain and inflammation.