The rostral ventral medulla (RVM) is a relay area between the periaqueductal gray and the spinal cord. (See prior articles on the PAG using search). The cerebral aqueduct is a communicating channel about 3/4 inch long running in the midbrain between the IIId and IVth ventricles of the brain. See http://www.mrcophth.com/MRCOphth/mrcophthpartoneessay/march1990q4.html
Gray matter immediately around the aqueduct is the PAG.
We have already commented in previous posts that BDNF, which comes from the P2X4 site on the microglia, prevents GABA)A) from attaching to the binding of tyrosine kinase B. Frankly, we think our much earlier article on P2X sites was prescient. However, it is much too contracted to assume that BDNF is the ONLY function of the microglia involved in pain. In fact, as this article shows, we do not yet know all the chemical nor anatomical sites where BNDF functions. There is a rather hot debate going on as to whether BDNF is IT, the nexus of central pain, or merely one of the cast. Many proteins remain to be studied. For now, we are happy that researchers at the University of Maryland, by tagging BDNF have discovered an entirely new pain pathway. The glial cells, formerly known as “supportive cells”, surround neurons and contribute MANY substances, including growth factors, among which is BDNF. Dr. Ren from the Univ. of Maryland has informed painonline that Src inhibitors appear able to block pain (re: Michael Salter’s work). Another author, Dr. Dubner, has also indicated an interest in kinase inhibitors. We expect to post many more articles on this and request that you review some of the article here about kinases, phosphorylation, and protein activation. For the shortest and simplest understanding, read the word “kinase” as something which can activate a chemical by attaching a high energy phosphate bond.
Think of calcium as sitting inside the nerve membrane, waiting to change places with sodium outside the membrane, as part of nerve firing. If the channels which exchange sodium and calcium fail, there is a buildup of calcium, leading to pain. This is an oversimplification, but will inform you why we pay so much attention to calcium.
Guo W and others at the Univ. of Maryland, including Ron Dubner, a well known pain researcher cited here previously, have reported in J Neurosci. 2006 Jan 4;26(1):126-37. a previously unknown pain pathway or mechanism. The recent article by Jeffrey Coull explained how brain derived neurotrophic factor (BDNF) interfered with the binding of GABA(A), a quieter of pain, to one of its receptor, Tyrosine Kinase B (TrkB). [Some call TrkB tropomyosin receptor kinase B, particularly when BDNF effects on vascularization around axonal growth cones is under discussion]. This prevented pain inhibition by GABA.
Now Guo et al have discovered that BDNF containing cells in the PAG release BDNF to cells in the rostral ventral medulla (RVM). The RVM is the linkup pathway between the PAG and the cord. The medulla is just atop the cord, and the RVM is located at the top front of the medulla.
As explained elsewhere here, substitutions in molecules which attach high energy phosphate bonds are known as phosphorylation. BDNF is manufactured by microglia, of which there are a number in the periaqueductal gray. BDNF production in the PAG and phosphorylation (activation) of TrkB in the RVM are upregulated in inflammation. “Upregulated” means the genes which manufacture these proteins increase their output. BDNF effects are expressed in the PAG and RVM through the NMDA receptors at their NR2A subunit. NMDA (a pain exciter) activity requires Ca2+, which in the case of pain neurons travels through CaV2.2 channels which may probably be regulated by T type Calcium channels.
Any inappropriate buildup of Ca2+ leads to chronic pain sensitization. This reaction, the production of PAG BDNF and activation of TrkB involves participation by IP(3) growth factor, Protein Kinase C, and Src a kinase which can activate tyrosine kinase. Via a Parathyroid hormone receptor, PTH leads to tyrosine phosphorylation of the enzyme and activates as well the MAPK kinases and ERK-1 and ERK-2 kinases. (Parathyroid Hormone activates Src, which leads to conformational changes [ie takes Tyrosine from one locus and places in on another, making THAT site active and reshaping the enzyme], via a G protein and Calcium dependent mechanism, resulting in the activation of MAPK and ERK.) See Gentili et al J Endocrinology 2006 Jan;188(1):69-78. The sum total of all of this is nerve hypersensitization. Excess calcium not only gets sensory fibers going, it also fires up muscle fibers, such as in the condition TETANUS aka “lockjaw”, where calcium makes the heart contract so hard that it cannot relax, causing death.
Here is where the going gets tough and the controversy begins. There is a type of pain known as inflammatory pain. However, like many pains, it lacks a precise definition. In our previous articles we indicated that there is a dispute over whether inflammatory pain exactly equals neuropathic pain. We think NOT, but there seems to be a close relation. In other words, while we know the brain meets the criteria for inflammation in CP, based on the type of cells present, what really IS inflammation? Classically it is the presence of certain cells, (listed in the recent prior article here on inflammation in the brain and central pain). The circularity in definition may mislead us into thinking we need look no further than inflammation to understand pain.
Do those cells always express the same proteins and do they always cause identical gene expression when there is inflammation as they do in pain. We do not know. It is estimated that perhaps 100-200 orphan proteins (ie. their function and partners are not yet known) can be identified in the pain neurons which have not yet been characterized. Surely some of them participate in the pain process. Marshall Devor has been especially cautionary in his correspondence that we not automatically assume inflammation (including microglia) is the whole story of pain.
Nevertheless, we know that inflammation does occur in Central Pain, that acids are formed, and that pain results. For now, it is entirely allowed to call this inflammatory pain. Since this definition is based on the cells which migrate to the brain and on the acids and cytokines which form, which also form in inflammation, the evidence would seem overwhelming that inflammation is pretty much the story of pain hypersensitization.
However, we respect Dr. Devor so much that we are inclined to agree with him that we should not assume the work has all been done, and await study of the other proteins present in pain situations. Guo et al’s study illustrates that we may perhaps just be beginning to identify all the pain pathways. It now seems possible to us that certain compounds such as imatinib mesylate, a tyrokine kinase inhibitor may have some place in pain treatment. Dasatinib inhibits Src and may also find a role. We are a very long way from knowing exactly which type of pain travels along this new RVM pathway, but eventually we will probably find that this chemical transfer is the substrate for a specific symptom. We may not know, until we block it, precisely the pain type in which it participates.
The multiplicity of such anatomical relationships makes it easy to understand why all central pain is not identical. We thank Guo and his colleagues for their work. As time goes by, we love the dentists more and more for their very high grade research and contributions on pain.
Special thanks to Drs. Ren and Dubner for commenting on their work for us.