Which flavor of CP does RTX kill?

[dejerine]

C fibers are the small fibers which sensitize other pain fibers and cause nerve injury pain. Resiniferotoxin (RTX) is being recruited to assasinate C fibers. What does it really kill?

You have heard the story of the three Hindu blind men asked to describe an elephant. This is what Central Pain is like, or more properly, the Central PAINS. The TWO broad categories of CP separate into what are called:
1) spinothalamic (ST) pain (ie. burning to touch or temperature change, as well as gut pain) "ST pain" includes injury to higher tracts which receive ST pain. There are really seven ST tracts, their individual function is unknown.
2) lemniscal pain (muscle pain or lancinating shooting pain). The medial lemniscus is the higher tract which receives posterior column pain.

However, we know little about how the effectiveness of therapies compare between these two groups. The latter apparently has better opiate response, and response to meds in general. In Harrison's Textbook of Medicine, Howard Fields indicates the lemniscal pain also responds better to anticonvulsants (like Neurontin). Where does that leave the dysesthetic burning?

Even animal models are blurred as to which Central Pain is under discussion. Scientists are now looking at therapy which does not differentiate, but simply destroys C fibers, with their VR1 receptors. How much we hope resinoferotoxin (RTX) lives up to expectations.

VR1 is the receptor by which Capsaicin exerts its effect, causing a one dimension burn. Its singular burning is not the same thing as Central Pain burning, which is a complex sensation with other pains thrown in. Capsaicin irritation of C fibers is close enough to CP to bring those injected into the same category as nerve injury pain. There are no skeptics about CP among those who have sacrificed their comfort for our sake by experiencing capsaicin. They give no pontifications about painless soldiers with limbs blown off. Is it irreverent to say sudden explosions cause less pain than CP?

The complete reality of nerve injury pain for capsacin injectees is noteworthy since the thirty minute time period is very brief. Do injectees comprehend what it is like to be blanketed with burning over much or all of the body? Of course not. We are grateful to them and do not tell them they have not experienced CP yet, but they are getting close, if only in one small area of the body.

Capsaicin suppresses the VR1 receptor. Apparently nerve injury causes the VR1 receptor to malfunction. RTX apparently overloads the VR1 receptor by rapid Ca influx and kills the C fiber. Hopefully the effect is limited to C fibers.

Perhaps RTX will kill both ST pain and lemniscal pain. We will take either, with deep gratitude. Lemniscal (posterior column pain) is the most intense of the central pains, but it is intermittent, which may be why many with severe lemniscal pain are still able to function.

Capsaicin causes burning, RTX apparently stops burning akin to capsaicin burn, so presumably the ST pain will respond. Most animal models test solely for painful response to touch or temperature. Only the animal model of Hulsebosch tests for muscle pains, so we must see if muscle pains yield to RTX.

The NIH researchers are showing their stuff. This elegant work compares favorably to anything in the space program. God bless the NIH.

[This message was edited by dejerine on 05-12-04 at 09:24 AM.]

[This message was edited by dejerine on 05-15-04 at 11:12 PM.]

[calico]

Dejerine, I've heard concerns that if one kills a nerve, that the pain may recede but come back worse than before. What do you think of this and RTX?

Calico

[dejerine]

Hi Calico,

Cutting a nerve causes deafferentation. The cut end sends out sprouts. Either the sprouts or the nerve growth factors which cause sprouting have other effects, quite possibly including stimulation of production of Nav 1.3 fetal sodium ion channels, which render the remaining nerve hypersensitive to the point it fires without stimulus.

According to the theory, if you keep cutting the nerve, you cut off the area with sprouts and nerve growth factor being released by glial cells near the cut end. With the new cut, the process begins anew with deafferented pain at the higher level.

Deafferented means the distant nerve cannot reach the brain. Perhaps more importantly the brain cannot properly reach the distal part of the nerve to inhibit it. Jeffrey Coull indicated the failure occurs in inability of injured neurons to manufacture KCC2 (the protein than transports chloride), so that chloride cannot reach the cell membrane, so all stimuli, including stimuli meant to inhibit the cell, are converted to excitation.

Positive feedback circuits which feed on themselves are defined as "torture". The nerve eventually adapts because CP does not continue upward forever, although its peak level is well above normal pain in many people. In others, the peak level is like normal pain, but the threshold for firing is ridiculously low.

In this latter group the CP pain is like the sack of groceries that gets unbelievably heavy after carrying it a while. Few pains cover the entire body, such as inside the mouth and sinuses, in the gut and bladder, muscle spindles, and in the walls of blood vessels, but all these pain sources can be operating in CP.

Thus, while the peak pain does not exceed normal pain, the reach, global extent, variety, and endlessness of the pain more than qualifies to be called "torture". Why else would CP patients have lined up readily for brain ablative therapy if they were not really hurting. Yes, we know all about the painless soldier, but his limbs had not been sensitized prior to being blown off. No doubt if they had, his pain would not only have been present, it would have been above normal. Normal pain (nociception) is unlike Central Pain.

When the first painless investigator having capsaicin injection is found, then we will include painless soldiers in our discussion, but so far they all report serious pain from that small area of the skin, which hurts less than CP, supposedly "really hurting" them. When behaviorists pop off about painless soldiers, we should insist on capsaicin to "educate" them. So far, no one has been thankful for the education, but they quit talking about the painless soldier. Why is it human nature for people to assume they would be braver than someone else when faced with pain? We have a surprise for them. We are endurance experts. We are actually doing great in enduring our CP. Capsaicin can turn scorn to admiration. Now if we could just find some way to inject ALL of the body with capsaicin. Their admiration might even turn to worship.

With RTX, the ENTIRE C fiber is killed, so there is no proximal nerve portion to begin abnormal firing. The animal studies are VERY encouraging.

[This message was edited by dejerine on 05-15-04 at 01:23 AM.]