Argenine Vasopressin and Pain

We print this article not so much because we think you will understand it, but to point out one more reason why pain scientists need MONEY for more research.

Vasopressin (derived from pituitary action) is of longstanding familiarity to doctors because of its known role in elevating blood pressure. It acts by mobilizing calcium, which as you already know is involved in many neuronal functions, both excitatory and inhibitory.

Most AVP study has been in the kidney. There, receptors in the renal cortex (outside) for Argenine Vasopressin (AVP) are known as V(1) receptos while those in the renal medulla (central area) are known as V(2). These same receptors for AVP exist in the brain as well. Stimulating V(1) receptors has been shown to lower signal activity in the hypoglossal nerve (the cranial nerve which supplies the tongue).

Inhibitory molecules are always candidates for pain relief. The possible drug exploiting AVP activity would retain the inhibitory action and eliminate the blood pressure elevating action. This sort of molecular manipulation is not as hard as you may think and is usually accomplished by altering binding characteristics of the molecule to prevent binding of the undesired portion by changing a couple of amino acid sequences in the long chain.

Although early information on AVP and pain was done internationally, Yang in China has impressed the world with a stunning series of articles on AVP, showing so far that it is involved with pain inhibition (antinociception) in a shocking number of brain structures. The list is so extensive, some are almost ready to make opiates a minor player by comparison, but this is considerably over the top in our view. However, it may well be that AVP is of major importance and in some cases more important than opiates.

So far, Yang has shown AVP antinociception in the periaqueductal greay, the caudate nucleus (one of the basal nuclei which is just outside the thalamic area), nucleus raphe magnus (learn more about the NRM by using SEARCH at this site), hypothalamic paraventricular nucleus (use SEARCH at this site), and the hypothalamic supraoptical nucleus (the newly discovered RF amide related peptides are rich in the SON, and CGRP plays a regulatory role–a relation to pain is known but poorly studied).

The most controversial and most important article so far by Yang is at Regul Pept. 2006 Sep 27. The reason for the stir is that AVP came in ahead of enkephalin and endorphin in promoting pain relief (elevated threshold for pain) in the periaqueductal gray, which has been known for a very long time to be involved in antinociception. The fact that AVP, a relatively unknown chemical, would even be in the same ballpark with endogenous opiates is stunning. AVP processing is related to enkephalin and endorphin but it is actually the big brother. This puts AVP squarely in the center of the action. We simply must have more information on this potent molecule.

Yang showed fairly conclusively that it is the V(2) receptor which is responsible for pain relief, and not the v(1) receptor. Oh, if only the researchers in America could afford to do this work. Looks like the Chinese are the only ones willing to invest the time, money, and trouble. The study of AVP is funded by Guangdong Bangmin Pharmaceutical Co. Ltd.

It would serve American drug manufacturers right if they were exposed as being asleep at the switch on pain relieving medications. They have for too long merely reworked what they had, messing with making things timed release, etc. and tinkering around like that instead of going to the heart of pain. Way to go China! Looks like the trade deficit may get even bigger.

We began writing on the role of purine receptors some time ago, and you can review those articles here.

As McGaraughty has said, “P2X3/P2X2/3 receptors have emerged as important components of nociception. However, there is limited information regarding the neurochemical systems that are affected by antagonism of the P2X3/P2X2/3 receptor and that ultimately contribute to the ensuing antinociception” As a caveat and to be fair to Abbott pharmaceuticals, McGaraughty et al have shown that antagonism of spinal P2X3/P2X2/3 receptors results in an indirect activation of the opioid system to alleviate inflammatory hyperalgesia and chemogenic nociception.

In the ongoing question of whether opioids can really treat central pain, McGaraughty et al showed that ENDOGENOUS opioids attenuate (lessen)pain induced by the purine receptors in rat models of inflammatory and chemogenic pain but NOT in NEUROPATHIC pain.

We really think the pain centers should take a look at AVP and purine antagonist research before assuming we are not being cooperative if opioids don’t help our central pain. It is too late in the day for scientists to assume opioids are the whole story on pain relief.

If one thinks teleologically about why the body would want to link high blood pressure with pain relief, via AVP, the thought occurs of the “painless soldier”. Blood pressure elevation is a concommitant of stress. Perhaps AVP is how soldiers postpone pain from wounds FOR A TIME. When they are back in the hospital, however, the soldiers hurt like mad. Just ask any VA or MASH unit doc.