The Leaf THE LEAF Sept-Oct 17 | Page 26

Glycine Receptors Glycine receptors (GlyRs) are ligand-gated ion channels which inhibit nerve activation. GlyRs are expressed in spinal interneurons, where they regulate pain transmission to the brain. Anandamide is capable of directly binding to GlyRs and increasing channel activation. Anandamide does not bind the main agonist site nor can it activate GlyRs by itself. Like with 5-HT3 receptors, anandamide acts as an allosteric modulator. It binds a different site on the GlyR and enhances activation by glycine. This is another mechanism, independent of the CB1 and CB2 receptors, that endocannabinoids may reduce pain by acting at the spinal level. Peroxisome Proliferator-Activated Receptors Peroxisome proliferator-activated receptors (PPARs) are fundamentally different than the receptors described above. Rather than sit within the cell membrane, PPARs reside within the cell and can directly bind to DNA sequences and change transcription of targeted genes. There are three isoforms of PPAR: α, β, and γ. Anandamide and 2-AG are potentially able to activate PPARα, but activation is much stronger by the endocannabinoids OEA and PEA. Anandamide and 2-AG may also be able to activate PPARγ. PPARs regulate cellular functions in almost every tissue. Some of the effects of endocannabinoids which may be at least partially attributed to either PPARα or PPARγ activation include neuroprotection against ischemia and neurodegeneration, reduced nicotine addiction, analgesia, anti-tumour effects, vasorelaxation, weight reduction, and reduced inflammation. Interestingly, there are already approved drugs which act through PPARα activation (for treatment of cholesterol disorders and triglyceride metabolism) and through PPARγ activation (for treatment of insulin resistance and to decrease blood glucose levels.) Other Possible Endocannabinoid Targets Other potential targets for endocannabinoids have been identified. However, it is not clear if these play a significant role in the effects of endocannabinoids. These include voltage-gated ion channels, NMDA receptors, acetylcholine receptors, and glycine transporters.