Neurites again

You already know from a prior article that injured or cut nerves leading to the brain send out many sprouts or neurites, which chemically are bad news, releasing many pain chemicals which affect nerve signal going to the brain.

The two main exciter neurotransmitters in the brain are glutamate and aspartate, two of the “acidic” amino acids. Pain chemicals tend to be peptides or short chains of amino acids. (Proteins are long chains of amino acids).

One of the peptides under study of late is peptide neurotransmitter N-acetylaspartylglutamate (NAAG), which as the name reveals contains both glutamate and aspartate. An enzyme which degrades NAAG has the logical name of NAAG peptidase. “ase” means an enzyme which breaks something apart. Naming of such enzymes is done by naming the substance acted upon first and then adding “ase”; hence, NAAG peptidase. If you break apart NAAG peptide, you would make available a lot of glutamate and aspartate and could expect bad things to happen, painwise.

Yamamoto et al writing in Eur J Neurosci. 2007 Jan;25(1):147-58 in the article ” Local administration of N-acetylaspartylglutamate (NAAG) peptidase inhibitors is analgesic in peripheral pain in rats.

You already know that neurites are sites of tremendous pain chemical synthesis and possibly the nexus of the origin of central pain. It would therefore not be surprising to learn that there is plenty of NAAG around neurites. It must be remembered that glutamate has specific receptors. Those associated with pain have been called type II metabotropic glutamate receptors or mGluRs (you can learn what metabotropic means by using SEARCH at this site).

Yamamoto and some other Chinese anesthesiologists have found that, “The peptide neurotransmitter N-acetylaspartylglutamate (NAAG) selectively activates group II metabotropic glutamate receptors (mGluRs). Systemic administration of inhibitors of the enzymes that inactivate NAAG results in decreased pain responses in rat models of inflammatory and neuropathic pain. These effects are blocked by a group II mGluR antagonist. This research tested the hypothesis that some analgesic effects of NAAG peptidase inhibition are mediated by NAAG acting on sensory neurite mGluRs at the site of inflammation.

In short, NAAG peptidase inhibition should help pain, and apparently, it does.

Yamamoto was looking at peripheral nerve injury and was taken by the idea that LOCAL administration of NAAG peptidase inhibitor could inhibit pain at doses which would have no CNS effect. This concept could probably bring NAAG peptide inhibitor to the market for peripheral nerve pain rather quickly. We are more interested in how it could be exploited in the area of the neurites. Could it, for example, be a candidate for use in a pump?