Vanilloid Receptors
Transient receptor potential vanilloid 1
(TRPV1) is an ion channel expressed both on
sensory neurons and in the brain.
In sensory nerves, TRPV1 acts a sensor for
things that could potentially cause tissue
damage. It is activated in response to heat and
proinflammatory substances, sending a pain
signal to the brain. The most famous activator
of TRPV1 is capsaicin, the ingredient found
in chili peppers that causes a burning pain.
Dysregulation of TRPV1 is also involved in
chronic pain.
Interestingly, anandamide is an activator of
the TRPV1 channel. Sensory neurons often
co-express both the CB1 receptor and the
TRPV1 receptor, making the role of
anandamide in generating pain signals
unclear.
TRPV1 plays a very different role in the brain,
where its activation by anandamide seems to
reduce pain.
Serotonin Receptors
There are many different serotonin (5-HT)
receptor subtypes that mediate the different
effects of serotonin. The 5-HT3 subtype is
unique among the 5-HT receptors since it is a
ligand-gated ion channel instead of a GPCR.
The 5-HT3 receptor is most well-known for
mediated nausea and vomiting, particularly
after chemotherapy. Several anti-nausea
drugs work by inhibiting this ion channel. It
also has a role in neuropathic pain.
Anandamide can directly bind to the 5-HT3
receptor and inhibit its activation. However, it
doesn’t work by blocking the main serotonin
binding site on the receptor. Instead, it binds
to a different site and acts as a negative
allosteric modulator. In other words, it
changes the conformation of the receptor to
minimize activation by 5-HT.
This inhibition of 5-HT3 is at least partly
responsible for the analgesic effects of
cannabinoids that are not mediated through
the traditional CB1 or CB2 receptors.