Injury and inflammation leads to debilitating and persistent hyperalgesia. This hyperalgesia reflects sensitization of peripheral nerve terminals evoked by a rapid expression of proinflammatory factors as well as a facilitation of spinal nociceptive processing. Studies of peripheral systems have now begun to suggest that tissue injury triggers not only inflammation, but also a well-orchestrated series of events that lead to reversal of the inflammatory state. In this regard, lipoxins represent a unique class of lipid mediators that can function as """"""""braking signals"""""""" in inflammation. Lipoxin A4 (LXA4) is generated via the lipoxygenase pathway during cell-cell interactions. LXA4 binds to a G protein-coupled receptor (ALXR), reducing chemokine and cytokine production and stimulating monocytes and macrophages to nonphlogistic activity. The resolving and anti-inflammatory role of peripheral lipoxin raises the provocative hypothesis that similar systems may also down regulate injury induced spinal facilitation. In preliminary work, intrathecal LXA4 and LXA4 analogues indeed had potent antihyperalgesic effects in inflammation-evoked hyperalgesia. In a subsequent pilot study, ALXR expression was detected throughout na?ve rat spinal parenchyma and was unexpectedly found to be co-localized with astrocytes. Current work suggests that spinal astrocytes sustain inflammatory and neuropathic pain states though an enhancement of neuronal excitability. This linkage opens the possibility that lipoxins regulate spinal nociceptive processing though their effects upon astrocytic activation. This proposed work will: i) characterize the effects of intrathecally delivered structurally-related lipoxin molecules in a model of inflammatory pain; ii) determine the spinal distribution and regulation of the enzymes necessary for lipoxin synthesis, iii) determine if ALXR expression varies with progression of inflammation induced painful conditions and iv) start examining the possible molecular mechanism by which ALXR activation may control astrocyte activation. Targeting mechanisms that counter-regulate the spinal consequences of inflammation suggests a novel endogenous mechanism by which persistent pain can be controlled. Moreover, these studies will additionally inform us regarding the expanding role of spinal non-neuronal cells in persistent pain states. Current medication for chronic pain relief is surprisingly limited. Lipoxins represent a novel class of anti- inflammatory agents that may offer a new therapeutic strategy by which pain can be reduced.
The aim of this proposal is to investigate the role of lipoxins in conditions associated with persistent inflammatory pain. ? ? ?
