ABSTRACT
The endogenous lipid agent N-arachidonoylethanolamine (anandamide), among other effects, has been shown to be involved in nociceptive processing both in the central and peripheral nervous systems. Anandamide is thought to be synthesised by several enzymatic pathways both in a Ca(2+)-sensitive and Ca(2+)-insensitive manner, and rat primary sensory neurons produce anandamide. Here, we show for the first time, that cultured rat primary sensory neurons express at least four of the five known Ca(2+)-insensitive enzymes implicated in the synthesis of anandamide, and that application of 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine-N-arachidonoyl, the common substrate of the anandamide-synthesising pathways, results in anandamide production which is not changed by the removal of extracellular Ca(2+). We also show that anandamide, which has been synthesised in primary sensory neurons following the application of 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine-N-arachidonoyl induces a transient receptor potential vanilloid type 1 ion channel-mediated excitatory effect that is not inhibited by concomitant activation of the cannabinoid type 1 receptor. Finally, we show that sub-populations of transient receptor potential vanilloid type 1 ion channel-expressing primary sensory neurons also express some of the putative Ca(2+)-insensitive anandamide-synthesising enzymes. Together, these findings indicate that anandamide synthesised by primary sensory neuron via a Ca(2+)-insensitive manner has an excitatory rather than an inhibitory role in primary sensory neurons and that excitation is mediated predominantly through autocrine signalling. Regulation of the activity of the Ca(2+)-insensitive anandamide-synthesising enzymes in these neurons may be capable of regulating the activity of these cells, with potential relevance to controlling nociceptive processing.
Subject(s)
Action Potentials , Arachidonic Acids/metabolism , Calcium/metabolism , Endocannabinoids/metabolism , Phosphatidylethanolamines/pharmacology , Polyunsaturated Alkamides/metabolism , Sensory Receptor Cells/metabolism , Animals , Arachidonic Acids/biosynthesis , Cells, Cultured , Endocannabinoids/biosynthesis , Ganglia, Spinal/cytology , Ganglia, Spinal/enzymology , Ganglia, Spinal/metabolism , Group IB Phospholipases A2/genetics , Group IB Phospholipases A2/metabolism , Lysophospholipase/genetics , Lysophospholipase/metabolism , Male , Mice , Mice, Inbred C57BL , Phosphatidylethanolamines/chemistry , Phosphoric Diester Hydrolases/genetics , Phosphoric Diester Hydrolases/metabolism , Protein Tyrosine Phosphatase, Non-Receptor Type 22/genetics , Protein Tyrosine Phosphatase, Non-Receptor Type 22/metabolism , Rats , Rats, Sprague-Dawley , Sensory Receptor Cells/enzymology , Sensory Receptor Cells/physiology , TRPV Cation Channels/genetics , TRPV Cation Channels/metabolismABSTRACT
A recent focus meeting on Controlling Acute Inflammation was held in London, April 27-28, 2006, organized by D.W. Gilroy and S.D. Brain for the British Pharmacology Society. We concluded at the meeting that a consensus report was needed that addresses the rapid progress in this emerging field and details how the specific study of resolution of acute inflammation provides leads for novel anti-inflammatory therapeutics, as well as defines the terms and key components of interest in the resolution process within tissues as appreciated today. The inflammatory response protects the body against infection and injury but can itself become dysregulated with deleterious consequences to the host. It is now evident that endogenous biochemical pathways activated during defense reactions can counter-regulate inflammation and promote resolution. Hence, resolution is an active rather than a passive process, as once believed, which now promises novel approaches for the treatment of inflammation-associated diseases based on endogenous agonists of resolution.