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The transient receptor potential (TRP) channel of the vanilloidtype 1 (the “capsaicin receptor”) is involved in thermosensation, pain transduction and inflammation. It is expressed in sensory fibers of Aδ and C-type, in dorsal root and trigeminal ganglia and in perivascular neurons, often together with TRP channels of the ankyrin type-1 (TRPA1, the “mustard receptor”). Whilst TRPV1 is activated by high temperatures, low pH (as during inflammatory conditions) and inflammatory mediators, TRPA1 is activated by cold and irritants. TRPV1 activation in sensory neurons leads to release of vasodilatory peptides, thus contributing to neurogenic inflammation. TRPV1 is also expressed in central neurons of the periaqueductal grey (PAG) and rostral ventrolateral medulla (RVM), where it modulates the descending pathway of antinociception. Contrary to its role in the spinal cord and sensory afferents, TRPV1 in the PAG-RVM contributes to descending antinociception by enhancing both glutamatergic signalling/OFF neuron activity in the RVM and μ-opioid receptor-mediated analgesia. TRPV1 is expressed in the prefrontal cortex, where it also participates in neuropathic pain. In both central and sensory neurons, TRPV1 is often co-expressed with cannabinoid CB1 receptors (the Δ9-tetrahydrocannabinol [THC] receptors), with which it shares two endogenous agonists, anandamide and NADA. CB1 receptor activation by these and other endocannabinoids plays a major role in the peripheral and central control of pain. TRPV1 and CB1 can either act in concert or oppose each other at modulating neurotransmitter release and pain. Furthermore, plant cannabinoids, such as THC, cannabidiol or cannabichromene, activate and subsequently desensitize TRPV1 and/or TRPA1 channels, and this property allows these compounds to influence pain and inflammation. These interactions suggest that the “endovanilloid/endocannabinoid” system is a major player in the pathophysiology of pain.
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.
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