New treatment for Chronic Neuropathic Pain (under development)


Senior Member
This is the paper

A high-affinity, bivalent PDZ domain inhibitor complexes PICK1 to alleviate neuropathic pain, 30 april 2020

Maladaptive plasticity involving increased expression of AMPA-type glutamate receptors is involved in several pathologies, including neuropathic pain, but direct inhibition of AMPARs is associated with side effects.

As an alternative, we developed a cell-permeable, high-affinity (~2 nM) peptide inhibitor, Tat-P4-(C5)2, of the PDZ domain protein PICK1 to interfere with increased AMPAR expression.

The affinity is obtained partly from the Tat peptide and partly from the bivalency of the PDZ motif, engaging PDZ domains from two separate PICK1 dimers to form a tetrameric complex.

Bivalent Tat-P4-(C5)2 disrupts PICK1 interaction with membrane proteins on supported cell membrane sheets and reduce the interaction of AMPARs with PICK1 and AMPA-receptor surface expression in vivo.

Moreover, Tat-P4-(C5)2 administration reduces spinal cord transmission and alleviates mechanical hyperalgesia in the spared nerve injury model of neuropathic pain.

Taken together, our data reveal Tat-P4-(C5)2 as a novel promising lead for neuropathic pain treatment and expand the therapeutic potential of bivalent inhibitors to non-tandem protein–protein interaction domains.

From the introduction
Excitatory communication between neurons in the central nervous system relies almost exclusively on glutamatergic neurotransmission. Concordantly, most neurological and psychiatric diseases, including devastating conditions such as neuropathic pain, feature distinct glutamatergic components, yet very few drugs targeting glutamate neurotransmission have been approved for clinical applications.

An attractive alternative approach to manipulate glutamatergic neurotransmission is to target the synaptic scaffold proteins that orchestrate synaptic signaling complexes and dynamically regulate the surface expression and ion conductance of the ionotropic glutamate receptors in the postsynaptic density.

Tagging @mariovitali @Ben H as this could be a way to tackle some of the glutamate issues some folks have. Way above my pay grade though ;)


Senior Member
I wonder if people with this sort of neuropathic pain are supposed to be sensitive to MSG. I didn't notice any sensitivity when I was having neuropathic pain from ME. LDN worked, so maybe there's a type of neuropathic pain that's due to problems with endorphins.