A New Target for Neuropathic Pain-glucocorticoid Receptor in Spinal Cord Dorsal Horn
|School||Zunyi Medical College,|
|Keywords||glucocorticoid receptor Spinal cord astrocytes calcium|
Glucocorticoids (GC) affect virtually all organs that regulate metabolism, growth, development and neuronal functions. Recent studies show that central GR contributed to the development and maintenance of neuropathic pain after peripheral nerve injury. At present, the study of mechanisms of GR action in this process is mainly focus on dorsal spinal cord neurons. Several studies show that GR in dorsal spinal cord neurons can regulate the expression and funcation of some neurotransmitter receptor relative to pain, cellular pathways that may contribute to the development of neuropathic pain behaviors. There is significant evidence that exaggerated pain is regulated by the activation of spinal dorsal horn astrocytes. Astrocytes in spinal cord are activated in response to inflammation or damage to peripheral tissues, peripheral nerves, spinal nerves, or spinal cord. On the other hand, GC have been shown to regulate astrocytic activity. For example, Dexamethasone, corticosterone, and aldosterone were all found to inhibit rat cortical astrocyte proliferation in culture. In addition, Corticosterone or dexamethasone can reverse trimethyltin-induced enhancement of GFAP and IL-1alpha/beta expressions in astrocytes in the rat hippocampus.Whether GC has an effect on dorsal spinal cord astrocytes and then affect sensory transduction of noxious stimuli remains unclear.Recent evidences indicate that activation of spinal astrocytes plays a critical role in nociceptive modulation and persistent pain. Glucocorticoid receptor (GR) is involved in pain transduction and expressed in dorsal spinal cord astrocytes. The research work will provide new ideas for speculating the mechanisms of pathological pain and some evidences for developing effective analgesics that target on astrocytes for clinical treatment of pathological pain. Objective:To investigate the role of spinal glucocorticoid receptor (GR) in the generation and development of neuropathic pain and whether corticosterone (CORT) has an effect on the intracellular calcium concentration ([Ca2+]i) in cultured dorsal spinal cord astrocytes and the relative mechanism.Methods:The SD rats were used in our University Experimental Animal Center.(1). Behavioral methods:The thermal withdrawal latency (TWL) were measured.(2). Morphological methods:immunohistochemistry(3). Cell culture technology:Purification and Culture of Astrocytes.(4).[Ca2+]i measurement:Changes of [Ca2+]i in astrocytes were detected with confocal laser scanning microscopy using fluo-4/AMResult:1. TWL started to decrease at1d after CCI operation. Thermal hyperalgesia persisted until the end of experiment, Immunohistochemistry showed that the expression of GR was markedly enhanced in the ipsilateral dorsal horn on7d and14d after nerve injury. However, repeated intrathecal administration of GR antagonist RU38486markedly suppressed the decrease of TWL after nerve injury.2. CORT induced [Ca2+]i increase in cultured dorsal spinal cord astrocytes within30min.The rapid elevation of [Ca2+]i in astrocytes by CORT was concentration-dependent and could be blocked by pertussis toxin (a blocker of G protein activation,100ng/mL), but not by glucocorticoid receptor antagonist RU38486(10μM) and protein-synthesis inhibitor, cycloheximide (10μg/mL) Furthermore, the effect of CORT was abolished by protein kinase C inhibitor Chelerythrine chloride (10μM), but was not influenced by protein kinase A inhibitor H89(10μM).Conclusion:1. Activation of GR in spinal dorsal horn may be a critical event in the pathogenesis of neuropathic pain and suggest that blocking GR might be a viable therapeutic strategy for treating neuropathic pain.2. A nongenomic pathways may be involved in the effect of CORT on [Ca2+]i in cultured dorsal spinal cord astrocytes and the effect is mediated by a putative pertussis toxin-sensitive G-protein-coupled receptor and the downstream activation of protein kinase C.