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.