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1 Acta Neurobiologiae Experimentalis

1 2011

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Regulation on spinal nociceptive TRPV1/CB1 processing as therapeutic opportunities in a rat model of neuropathic pain

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Starowicz K. , Zychowska M. , Mrugala M. , Makuch W. , Korostynski M. , Slezak M. , Petrosino S. , Di Marzo V. , Przewlocka B.

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Anandamide (AEA) has emerged as a multifunctional lipid mediator of various stimuli. Latest reports suggest a role for AEA as an endovanilloid ligand, however, no data exist on the potential role of endogenous AEA upregulation in the spinal cord in neuropathic pain model. Rats chronically implanted with intrathecal (i.t.) catheters underwent sciatic nerve ligation (CCI model). The effect of selective inhibitor of AEA enzymatic hydrolysis, URB597 and the involvement of TRPV1 or cannabinoid CB1 receptors, were investigated. Measurements of allodynia and hyperalgesia were made 7 days after CCI and the levels of AEA in the spinal cord of CCI rats were determined. The spinal endovanilloid/endocannabinoid system was studied by means of qRT-PCR and western blott analysis in CCI rats. Finally, the distribution of TRPV1 and endovanilloid degradation enzymes were compared in the rat lumbar spinal cord. Depending on the administered dose, URB597 (10 – 200 μg/rat) reduced pain via CB1 or TRPV1 receptors. URB597 (10 – 100 μg) dose-dependently enhanced spinal AEA levels. Surprisingly those were reduced by 200 μg of URB597 suggesting an indirect effect of an endovanilloid/endocannabinoid AEA action at TRPV1. Alterations in lypoxygenases (LOX) mRNA support the idea of alternative ways of AEA metabolism. LOX-mediated production of hydroperoxides was associated with increased phospholipase A2 acitvity. Finally, baicalein by blocking the 12-LOX activity reduced the URB597 (200 μg) analgesic effect in CCI rats. We suggest that i.t. AEA reduces neuropathic pain by acting as an endovanilloid, on the he spinal cord TRPV1/ CB1 neurons. When endogenously up-regulated with URB597, AEA exerts analgesia via both receptors. Dependent on efficiency of FAAH a secondary route of AEA metabolism plays a role in CCI model. Moreover spinal lipoxygenase metabolites contribute to the AEA-mediated nociception in CCI model suggesting a complex interplay these systems in vivo. Supported by 0152/B/2008/35.