http://www.pubmedcentral.nih.gov/art...medid=17362934

This is interesting

And here's the article I had found earlier on Neurokinin mediation of edema and inflamation:

Attached Files

Neurokinin mediation of edema and inflamation - MM Campos JB Calixto - Neuropeptides [2000].pdf (162.9 KB, 419 views)

Hi Mike,
It is my understanding that diuretics are dangerous for RSd. the reason I was told is because our edema is caused by fluid ,being held or leaked within the nerve cell. Not the typical tissue swelling. Direutics work for people that have connective tissue disorders etc as the swelling is in the tissues. When you have RSD and take diruetics, it increases muscle spasms and dysfunction.
Not a good thing for us.Jose had good advise on drinking more water. We generally are dehydrated and just the nature of RSD keeps our limbs from being supplied adquetaly with blood flow which also moves water through our bodies.Our edema is very unique like every thing else with this disease. I had so much fluid once in both legs, from the nerve cells, I was hospitalized and they successfully removed seven pounds of fluid from each leg- but with a ketamine infusion and another medicine that starts with an m... mizondian - something like that sorry I cant remember the name-it is listed in Dr. Hoosmands puzzles. Hope this helps. My primary, thinking she was helping put me on a diruetic recently due to my upper back swellling. The spasms almost killed me- she quickly told me to stop taking it. When I told my Rsd doctor this he explained to me why the diruetic was not right for us. I hope this helps. Good luck. cz

What's real interesting here is how when you begin to look at look at the use of Neurokinins in the control of edema, as set forth in the article I posted above, and underlying the neuro-immunolgical model of edema, the first question that comes up is - of course - what's a Neurokinin?

Now, the good folks who give us our little online medical dictionary have an answer for that, "a mammalian decapeptide tachykinin found in the central nervous system. It is similar in structure and action to substance p and neurokinin k. The compound has bronchoconstrictor, smooth muscle constrictor, and hypotensive effects and also activates the micturition reflex."

But that isn't as hard as it seems. First, a decapeptide is defined in turn simply as "an oligopeptide [a peptide of a small number of component amino acids as opposed to a polypeptide] containing 10 amino acids."

But here comes the interesting part. A tachykinin is defined as "Any member of a group of polypeptides, widely scattered in vertebrate and invertebrate tissues, that have in common four of the five terminal amino acids: Phe-Xaa-Gly-Leu-Met-NH2; pharmacologically, they all cause hypotension in mammals, contraction of gut and bladder smooth muscle, and secretion of saliva." Note the key word here: hypotension.

Now consider a somewhat different definition of Neurokinins in the article posted above:

Neurokinins form a family of peptides that include substance P (SP), neurokinin A (NKA) and neurokinin B(NKB). These peptides are largely distributed throughout the central and peripheral nervous system, being localized in capsaicin-sensitive neurons.

"Neurokinin mediation of edema and inflammation," Campos MM, Calixto JB, Neuropeptides 2000 Oct; 34(5): 314 at 314.

And then the following:

The participation of neurokinins and their receptors at inflammatory events has been demonstrated by a great amount of pharmacological and biochemical studies, indicating their importance in most pathological responses. One of the main alterations evoking the increase in neurokinin levels is sensorial nerve damage. The destruction of neuronal terminals may occur following inflammatory chronic diseases or in response to some noxious stimulus, such as the application of chemical agents or burns. The characterization of the main alterations in the neurokinin system may constitute an attractive and relevant alternative for the development of new therapeutic agents. The aim of the present review is to highlight the recent progress in the area of neurogenic inflammation, with an emphasis on the roles exerted by neurokinins in this scenario.

Id at 315.

But then getting back to the the slightly more generic issue of tachykinins, check out the exhaustive survey article, "The Tachykinin Peptide Family," Cinzia Severini et al, Pharmacological Reviews, 54: 285–322, 2002, available online at http://pharmrev.aspetjournals.org [or just send me a PM with your email address for a copy], and it's discussion under the topic heading "Neurogenic Inflammation," at 313-14":

Electrical, mechanical, and chemical stimulation of the C-fibers in sensory neurons causes an axon reflex taking place in the branchings of sensory nerves. The consequence is the neurogenic inflammation: pain, vasodilation (flare), and plasma extravasation.

Antidromic vasodilation is mediated by a neurotransmitter at the sensory nerve endings in the skin. Similarly, plasma extravasation elicited by antidromic stimulation also seemed to be provoked by a mediator released from pain sensitive nerve terminals (Jancso et al., 1967).

Among the many transmitters suggested in this connection were acetylcholine, noradrenaline, ATP, bradykinin, histamine, 5-HT, and prostaglandins. At the present time, SP fulfills the criteria for being accepted as the main mediator for all components of antidromic stimulation (Lembeck and Holzer, 1979; Pernow, 1985).

i. SP is present in the C-fibers of the sensory neurons and is released from these fibers during antidromic stimulation.

ii. Close arterial administration of SP causes vasodilation and plasma extravasation, thus, mimicking the effect of antidromic stimulation.

iii. Capsaicin, which depletes SP in sensory neurons, almost completely blocks vasodilation and neurogenic plasma extravasation.

The above criteria were completed and remarkably strengthened by more recent data:

iv. The nociceptin/orphanin-induced nociceptive response is brought about in mice by SP release from peripheral endings of nociceptive primary afferent neurons (Inoue et al., 1998), supporting the view that also pain in neurogenic inflammation is due to release of SP.

v. In mutant mice with disrupted preprotachykinin A gene, neurogenic inflammation produced by topical application of capsaicin was almost absent, whereas in non-neurogenic paw edema produced by complete Freund’s adjuvant neurogenic inflammation was the same in wild-type and mutant mice (Cao et al., 1998). However, there is some doubt about the fact that SP is the unique direct or indirect (through release of histamine from the mast cells) agent responsible for the vasodilation and plasma extravasation seen in neurogenic inflammation. Two points deserve attention. The first is that SP is costored and coreleased from sensory nerve endings with calcitonin gene-related peptide, which displays a potent edema producing activity; the second is that the histamine-releasing activity of SP, which remarkably contributes to plasma extravasation and edema, has been attributed not to the intact SP molecule but to its N-terminal fragment (1–7). Moreover there are data, which need confirmation, showing that antidromic stimulation may not always release SP but other active agents.

In summing up, there is little doubt that neurogenic inflammation represents the most striking and credible example of a decisive, if not unique, involvement of SP in a physiopathological process.

Then in the same vein, we also have "Neurokinins enhance excitability in capsaicin responsive DRG neurons," Adrian Sculptoreanu and William C. de Groat, Exp. Neurol. 2007 May; 205(1): 92–100 [and once more, I'll be happy to send anyone a copy of this who wants it]:

Abstract

Neurokinins released by capsaicin-responsive (C-R) dorsal root ganglia neurons (DRG) may control firing in these neurons by an autofeedback mechanism. Here we used patch clamp techniques to examine the effects of neurokinins on firing properties of dissociated DRG neurons of male rats. In C-R neurons that generated only a few action potentials (APs, termed phasic) in response to long depolarizing current pulses (600 ms), substance P (SP, 0.5 μM) lowered the AP threshold by 11.0 ±0.3 mV and increased firing from 1.1±0.7 APs to 5.2±0.6 APs. In C-R tonic neurons that fire multiple APs, SP elicited smaller changes in AP threshold (6.0±0.1 mV reduction) and the number of APs (11±1 vs. 9±1 in control). The effects of SP were similar to the effect of heteropodatoxin II (0.05μM) or low concentrations of 4-aminopyridine (50 μM) that block A-type K+ currents. A selective NK2 agonist, [βAla8]-neurokinin A (4–10) (0.5 μM), mimicked the effects of SP. The effects of SP in C-R phasic neurons were fully reversed by an NK2 receptor antagonist (MEN10376, 0.5 μM) but only partially by a protein kinase C (PKC) inhibitor (bisindolylmaleimide, 0.5 μM). An NK3 selective agonist ([MePhe7]-neurokinin B, 0.5 μM), an NK1 selective agonist ([Sar9, Met11]-substance P, 0.5μM) or activation of PKC with phorbol 12, 13-dibutyrate (0.5 μM) did not change firing. Our data suggest that the excitability of C-R phasic afferent neurons is increased by activation of NK2 receptors and intracellular signaling mediated only in part by PKC.

All of which leads me, full circle, back to the thread I posted a couple of weeks ago, "Sodium Channel Blockers Make it Big or The Holy Grail in Pain Science":

Jim Broatch of the RSDSA just forwarded a press release, dated October 3, 2007, in which this work was referred to as meeting "The Holy Grail in pain science is to eliminate pathologic pain without impairing thinking, alertness, coordination, or other vital functions of the nervous system," by the director of the National Institute of Neurological Disorders and Stroke (NINDS) at NIH:

TREATMENT BLOCKS PAIN WITHOUT DISRUPTING OTHER FUNCTIONS

A combination of two drugs can selectively block pain- sensing neurons in rats without impairing movement or other sensations such as touch, according to a new study by National Institutes of Health (NIH)-supported investigators. The finding suggests an improved way to treat pain from childbirth and surgical procedures. It may also lead to new treatments to help the millions of Americans who suffer from chronic pain. The study used a combination of capsaicin -- the substance that makes chili peppers hot -- and a drug called QX-314. This combination exploits a characteristic unique to pain-sensing neurons, also called nociceptors, in order to block their activity without impairing signals from other cells. In contrast, most pain relievers used for surgical procedures block activity in all types of neurons. This can cause numbness, paralysis and other nervous system disturbances.

"The Holy Grail in pain science is to eliminate pathologic pain without impairing thinking, alertness, coordination, or other vital functions of the nervous system. This finding shows that a specific combination of two molecules can block only pain- related neurons. It holds the promise of major future breakthroughs for the millions of persons who suffer with disabling pain," says Story C. Landis, Ph.D., director of the National Institute of Neurological Disorders and Stroke (NINDS) at the NIH, which funds the investigators' research along with the National Institute of Dental and Craniofacial Research (NIDCR) and the National Institute of General Medical Sciences (NIGMS). The study appears in the October 4, 2007, issue of "Nature". [1]

[1] Binshtok AM, Bean BP, Woolf CJ. "Inhibition of nociceptors by TRPV1-mediated entry of impermeant sodium channel blockers." "Nature", October 4, 2007, Vol. 449, No. 7162, pp. 607-610.

http://neurotalk.psychcentral.com/sh...ghlight=sodium

So as soon as they are ready, count me in on the chili peppers. (Unless I try out something else altogether first.)

Mike

Your mention of my article brought me to this forum...there is actually a connection between neurokinins and Na channels in nociceptive (pain) neurons which I am presently investigating. Turns out that neurokinins stimulate Na channles; particularly the tetrodotoxin-resistant subtype (Nav1.9) which has more recently been associated with development of chronic pain; that may account in part for the increase in excitability caused by neurokinins. There is a wide interest in the pharmaceutical industry at present to develop drugs that are selective blockers of this Na channel subtype and it is hope may selectively influence (inhibit) abnormal electrical activity in pain neurons. We have evidence to support this assertion:
"26. Yamane H, de Groat WC, Sculptoreanu A. (2007) Effects of ralfinamide, a Na+ channel blocker, on firing properties of nociceptive dorsal root ganglion neurons of adult rats. Exp Neurol. 208(1):63-72."

To qote the highlight of one of my colleagues (Michael Gold):

Thanks for discussing my articles, I am the guy who did the work, Adrian Sculptoreanu. There are many interesting things still emerging from my early studies..among them Na channels are definitely a target of neurokinin modulation via erk kinase. That could be theoretically why during inflammation phosphorylated channels have higher affinities for certain local anesthetics. The autofeedback mechanism responsible for switching on C-fiber neurons are more complex and may involve several channels that may include TRP in addition to a slew of voltage dependent channels. For example SP and endothelin (released by some tumors) interact synergistically to produce very large increases in depolarizing TRPC currents (non selective cation channels)...so if I had the money to continue this research there are many dfirections it could take. For now I am in Italy enjoying the good weather...

do we have 2 Dr Adrians claiming to be the author worrying