Astrocytes and Chronic Pain Mechanisms—The Role of Histamine, IL-1β and NGF

Abstract

ABSTRACTIn exaggerated pain states, the activated astrocytes release several signalling molecules involved in cellular mechanisms of chronic pain. Among them, nerve growth factor (NGF) and interleukin (IL)-1β are both recognized as potent algogens. We previously showed that histamine is a potent stimulator of NGF production in rat cortical astrocytes in primary culture. Since histamine and IL-1β have common interactions in different physiological responses, in the present work we were interested to elucidate the molecular mechanisms involved in the interactions between histamine, IL-1β and NGF that could contribute to the processing of chronic pain. As an experimental model we used cultured rat cortical astrocytes. NGF and IL-1β levels in the culture medium were measured by ELISA. IL-1β mRNA expression was determined by RT PCR.The results showed that the co-treatment of the cultured astrocytes with histamine and IL-1β significantly increased NGF secretion in comparison to the secretion observed with either histamine, or IL-1β alone. The histamine and IL-1β effect on NGF secretion was additive, dose-dependent and increased with increased concentrations of either histamine, or IL-1β. The additive effect of histamine and IL-1β on NGF secretion was strongly suppressed by histamine H1 receptor antagonist/inverse agonist mepyramine, protein kinase C (PKC) inhibitors (GF 109203X, Go 6976), and mitogen-activated protein kinase kinase (MAPK)-1 inhibitor (PD 98059); however, they did not influence significantly the NGF secretion evoked by IL-1β alone. Histamine also stimulated the secretion of IL-1β from cultured astrocytes and induced higher expression of IL-1β mRNA in comparison to untreated cells.We concluded that histamine potently interacts with the synthesis and secretion of IL-1β and NGF in astroglial cells, and therefore can contribute to the development and maintenance of chronic pain, mediated by both algogens.