Dynamic regulation of the endocannabinoid system: implications for analgesia

Abstract

The analgesic effects of cannabinoids are well documented, but these are often limited by psychoactive side-effects. Recent studies indicate that the endocannabinoid system is dynamic and altered under different pathological conditions, including pain states. Changes in this receptor system include altered expression of receptors, differential synthetic pathways for endocannabinoids are expressed by various cell types, multiple pathways of catabolism and the generation of biologically active metabolites, which may be engaged under different conditions. This review discusses the evidence that pain states alter the endocannabinoid receptor system at key sites involved in pain processing and how these changes may inform the development of cannabinoid-based analgesics.

Figure 1

Proposed biosynthetic pathways for the generation of AEA from its arachidonoyl containing NAPE (NArPE) precursor. NAPEs are formed from phosphatidyl choline and phosphatidyl ethanolamine membrane precursors by an as yet uncharacterised N-acyl transferase enzyme. The most widely accepted route of AEA biosynthesis is via NAPE-PLD [142,143]. This enzyme is also responsible for the generation of other NAEs including OEA and PEA from their corresponding NAPE precursor. The serine hydrolase αβh4 can generate lysoNAPE and glycerophospho-N-acyl ethanolamine (GpNAE), including glycerophospho-N-arachidonoyl ethanolamine (GpAEA), glycerophospho-N-oleoyl ethanolamine (GpOEA) and glycerophospho-N-palmitoyl ethanolamine (GpPEA) intermediates that are subsequently hydrolysed by a metal dependant phosphodiesterase to produce AEA, OEA and PEA, respectively. In mouse brain, this enzyme has been identified as GDE1 [144]. LPS induced synthesis of AEA involves the generation of phosphorylated AEA (pAEA) via PLC which is then converted to AEA by phosphatases. In mouse brain, this phosphatase has been identified as PTPN22 [83]. Whether this third pathway contributes to the synthesis of other NAEs such as OEA and PEA remains to be determined.

Figure 2

Proposed metabolic pathways for the breakdown of AEA and 2-AG via hydrolase and oxygenase pathways.

Figure 3

A: The endocannabinoid AEA and related NAEs PEA and OEA are broken down by FAAH, 2-AG is primarily metabolized by MAGL. AEA is a ligand at CB₁, CB₂ and TRPV1 receptors and the nuclear receptor PPAR-α. OEA and PEA are ligands for PPAR-α. 2-AG is a ligand at CB₁and CB₂. Both AEA and 2-AG can be metabolized by COX2, LOX and CYP450 to form biologically active metabolites, some of which are ligands for CB₁, CB₂ and PPAR-α. B: Under pathological conditions, such as inflammatory or neuropathic pain, the presence of infiltrating immune cells or the activation of microglia provides another source of endocannabinoid synthesis and catabolism, as well as providing additional/or alternative receptor sites of action of the endocannabinoids, NAEs and their metabolites.