Chronic pain remains intractable as currently available therapeutics offer limited relief to limited numbers of patients. It is known that microglia & astrocytes contribute to chronic pain, by releasing neuroexcitatory substances which maintain hyperexcitabllity of spinal neurons within pain transmission pathways. However, there are other spinal cell types likely to contribute to this facilitation of neuronal hyperexcitabllity. Oligodendrocytes (OLG) & endothelial cells (EC) exist in close contact with neurons, microglia, astrocytes, & immune cells, which are known to be involved in creating & maintaining exaggerated pain states. OLG are close partners to neurons & may act as first-line responders to endogenous danger signals released by injured neurons. EC form the blood-brain barrier, & are thus intermediaries between the central nervous & systemic circulation. The proposed research will determine whether spinal OLG & EC are activated to release neuroexcitatory substances in rat models of exaggerated pain caused by chronic constriction injury of a peripheral nerve, & chronic administration of morphine or the chemotherapeutic paclitaxel. Expression of putative activation markers, upregulation of proinflammatory signaling molecules, & release of neuroexcitatory substances will be assayed in spinal OLG & EC from rats with ongoing exaggerated pain, utilizing immunohistochemistry, real time-PCR, & ex vivo culture experiments. These experiments may redefine current understanding of the functioning of OLG & EC within the spinal microenvironment, & thus contribute to the NINDS 'Neural Environment' program area. Also, these experiments may facilitate design of novel analgesics that provide effective pain relief while minimizing side effects such as potential for addiction, & thus contribute to NIDA's mission. PUBLIC HEALTH RELEVANCE: Chronic pain remains poorly treated by currently available drugs, & the proposed research aims to study two cells types as potential novel contributors to changes in central nervous system excitability that underiie chronic pain. These two cell types are oligodendrocytes & endothelial cells, which are important in normal physiology as the cells providing myelination within the central nervous system & maintenance of the blood- brain barrier, respectively. These studies will provide critical insight into how a nervous system that is generating chronic pain is different from a normal nervous system, & may facilitate development of novel therapeutics for pain relief