D'Agostino, Giuseppe (2010) A role for PPAR-alpha in the Central Nervous System in pain and inflammation control. [Tesi di dottorato] (Unpublished)

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Peroxisome proliferator-activated receptor alpha (PPAR-alpha) is a ligand activated transcription factor belonging to the nuclear hormone receptors and suggested to be involved in inflammation and pain control. Little is known about its role at CNS level. We report that spinal and dorsal root ganglia PPAR-alpha expression is modulated by a peripheral inflammatory or a painful stimulus, and central administration of endogenous or synthetic PPAR-alpha agonists reduces both pain perception and inflammatory hyperalgesia in mice. Under inflammatory pain state, central PPAR-alpha activation modulates NF-kB nuclear signalling along sciatic nerve, dorsal root ganglia and spinal cord. Moreover, we evidence that PPAR-alpha receptor may physically reduce NF-kB activation during the early phase of pain signalling. In vivo co-immunoprecipitation experiments reveal a physical interaction between PPAR-alpha and NF-kB complex subunits. This interaction was strongly and rapidly increased in lumbar spinal cord of mice subjected to the formalin nociception test. To understand if the enhanced interaction would function as a reducer of pain-evoked intracellular machinery, we used an in vitro approach. In SH-SY5Y neuroblastoma cells substance P stimulation induced the PPAR-alpha/NF-kB interaction in few minutes, similarly to that observed in vivo. GW7647, a synthetic PPAR-alpha agonist (and a pain-reducing compound), increases this complex formation. We conclude that i) PPAR-alpha-mediated reduction of persistent pain may likely rely on reduction of the NF-kB activity and inflammatory central sensitizer synthesis, ii) while the contribution to acute pain responses may be in part related to constitutive activity of both these transcription factors in neurons of the nociceptive system.

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