Could the following article (*) be helpfull?

FOS-reactivity was measured in the dorsal horn after spinal nerve ligation.

(*) J Pain. 2013 Aug;14(8):845-53. doi: 10.1016/j.jpain.2013.02.011..Descending facilitation maintains long-term spontaneous neuropathic pain.

Wang R1, King T, De Felice M, Guo W, Ossipov MH, Porreca F.

Not really, but thank you anyway!

I am more interested about neural circuitry or schematic representation of connectivity patterns between superficial dorsal horn internerons and descending projections.

Any help?

Could this be helpful?: role of intraspinal (astro)glia (in GCT?)

I came across the description of the inhibitory role of astroglia in "tripartite synapses" (pre- & postsynaptic membrane engulfed by glial envelope), while forming a functional unit with other astroglia-cells into a "syncythial territory". The idea would be that within a glial territory a single afferent activating synapse would be inhibited, but if a second synapse would also be active, the whole syncythium would be inhibited, therefore forming a territory of sensitized hyperacitivity (desinhibition of afferent signals) within the dorsal horn.

However other glia articles do not concord with the above view.

There are articles of (astro)glia in the dorsal horn, the PAG and dorsomedial nucleus (hypothalamic).

There are articles of influence of (astro)glia in neuropathia.

There are articles of (astro)glia and rVMM (1).

There is a suggestion for descending painfacilitation rVMM:5HT -> dorsal horn/(5HT)3-R whereby glia is involved (2).

(1) Neuroscience. 2013 Jun 25;241:10-21. doi: 10.1016/j.neuroscience.2013.03.008.

Effects of restraint stress on glial activity in the rostral ventromedial medulla.

Imbe H1, Kimura A, Donishi T, Kaneoke Y.

(2) J Neurosci. 2011 Sep 7;31(36):12823-36. doi:10.1523/JNEUROSCI.1564-11.2011.Spinal 5-HT(3) receptor activation induces behavioral hypersensitivity via a neuronal-glial-neuronal signaling cascade.Gu M1, Miyoshi K, Dubner R, Guo W, Zou S, Ren K, Noguchi K, Wei F.

Dear Jean,

First of all, thank you very much for all your support.

I didn't find the articles you referred (the second one has been retracted: http://www.jneurosci.org/content/32/50/18270.short)

On the other hand, let me make myself clearer (please, see the attachment)

As you can see, this is a schematic representation of a potential polisynaptic pathway composed by interneurons of the superficial dorsal horn (islet, vertical, etc.). Now, what do we know about descending projections from PAG/RVM system? Does those projections synapse islet, vertical or central cells? Are those synapses excitatory or inhibitory?

Thank you so much!

Larry W. Swanson did extensive tracings to determine afferents and efferents of nuclei in rodent brain, and made atlasses. I do not know if the brainstem was included (PAG ? R.Magnus? subnucleus ret.dors.?). That's what I found:

Work

Foundational model of structural connectivity in the nervous system with a schema for wiring diagrams, connectome, and basic plan architecture

As co-author

Mihail Bota, Larry W. Swanson (2006). "A new module for on-line manipulation and display of molecular information in the brain architecture management system". Neuroinformatics 4: 275-298. doi: 10.1385/NI:4:4:275.

Mihail Bota, Larry W. Swanson (2008). "BAMS neuroanatomical ontology: design and implementation". Frontiers in Neuroinformatics 2: 2. doi: 10.3389/neuro.11.002.2008.

Mihail Bota, Hong-Wei Dong, Larry W. Swanson (2005). "Brain architecture management system". Neuroinformatics 3(1): 15-48. PMID: 15897615.

Mihail Bota, Larry W. Swanson (2010). "Collating and curating neuroanatomical nomenclatures: principles and use of the Brain Architecture Knowledge Management System (BAMS)". Frontiers in Neuroinformatics missing volume: missing pages. doi: 10.3389/fninf.2010.00003.

Mihail Bota, Hong-Wei Dong, Larry W. Swanson (2003). "From gene networks to brain networks". Nature Neuroscience 6(8): 795-799.

Mihail Bota, Larry W. Swanson (2007). "Online workbenches for neural network connections". The Journal of Comparative Neurology 500: 807-814.

PS: my son Ruben is researcher at UNAM (Mex-city), we do some work together, we wish you good luck !

Islet cells/ Subst.Gel./ IIa, IIb:

1) J Physiol. 2014 Feb 15;592(Pt 4):759-76. doi: 10.1113/jphysiol.2013.264937.

Morphological, biophysical and synaptic properties of glutamatergic neurons of the mouse spinal dorsal horn.

Punnakkal P1, von Schoultz C, Haenraets K, Wildner H, Zeilhofer HU.

+++ 2) J Physiol. 2007 May 1;580(Pt.3):815-33.

Differential wiring of local excitatory and inhibitory synaptic inputs to islet cells in rat spinal lamina II demonstrated by laser scanning photostimulation.

Kato G1, Kawasaki Y, Ji RR, Strassman AM.

Vertical cell (VGlut1)/ activating projection N: (Todd)

Mol Pain. 2014 Jan 17;10(1):3. doi: 10.1186/1744-8069-10-3.

A putative relay circuit providing low-threshold mechanoreceptive input to lamina I projection neurons via vertical cells in lamina II of the rat dorsal horn.

Yasaka T1, Tiong SY, Polgár E, Watanabe M, Kumamoto E, Riddell JS, Todd AJ.

Physiol. 2007 Oct 15;584(Pt 2):521-33. Epub 2007 Aug 23.

Morphology of inhibitory and excitatory interneurons in superficial laminae of the rat dorsal horn.

Maxwell DJ1, Belle MD, Cheunsuang O, Stewart A, Morris R.

Dear Jean,

Again, thank you very much for all your support!

Let me start to looking for those articles (I hope they are available for free, because I don't receive economic founding). Last year I succesfully downloaded the one from Maxwell (2007).

Best regards!

Intrigued by the neuroïd model, may I ask:

would it be helpful or possible to build into the model the Wind-up phenomenon of the highly convergent Wide Dynamic Range (projection) Neuron (WDR) in the dorsal horn?

Is it your understanding that the WDR-neuron is monosynaptically influenced by primary C-afferents, the Wind up phenomenon happening without interference of an interneuron of Gate Control?

Am I correct there is no computational model available hitherto in which the WDR-neuron is involved? but you introduced a convergent model for the retina? could you apply this for a WDR-neuron?

My interest in the question is that the convergence of the WDR-neuron explains referred interoceptive pain which could be influenced by acupuncture needling of the primary cutaneous receptive field of the concerned WDR-neuron.

Let me answer you backwards

Theoretically, I could build a cutaneous receptive-field model. In fact, I built a Neuroid-based retina model. But I am more interested in Lamina I nociceptive-specific projection neurons, than in WDR projection neurons. It has been proposed that information conveyed via the innocuous mechanoreceptive pathway may gain access to nociceptive pathway in neuropathic pain conditions. Now, I think that this is so because specific alterations in stimulus-response functions of inhibitory (and excitatory) neurons of superficial dorsal horn.

Can you see where i am pointing?

Let me try :-)

There are experiments with (chronic) constriction of the sciatic nerve, leading to allodynia, sensitization or neuropathy:

according Fig.6 Abeta-fibers would not be able any longer to suppress C-afferents for pain (shaded area dissappears).

In this sense you would not need descending pain facilitation to explain central sensitization. There are two interneurons (II & EI) instead of just one Gate-cell as Melzack and Wall suggested.

Yes I woud!

It has been showed that the PAG-RVM system receives ascendant projections from lamina I. In turn, lamina I receives descending projections from RVM. This sinergic combination suggests a feedback control of noxious information at spinal cord level. As an Engineer, I strongly believe that feedforward and feedback mechanisms may have some influence on sensory information processing, so as functional differences between neural elements which compose sensory circuits.

With respect to ABeta fibers, you're right! Under physiological conditions, these fibers modulate painful experience, whether increasing (initially) or decreasing (later) the sensation intensity, as Melzack & Wall originally postulate. But, under pathological conditions (neural damage), these fibers not only lose their modulating role, but also gain access to nociceptive pathways, partially due to loss of inhibitory control at the spinal cord level.

I would like to build a "new Gate control system" to provide a more realistic representation of the neural circuitry of the dorsal horn and, therefore, to analize how the mechanisms which I mentioned above, influence the transmision (and ultimately, the perception) of the sensory information, specially that which is commonly related to pain.

Thank you Erick :-).

May I ask another question concerning Abeta-fibers? and PAG-rVMM feedback.

Spinal nerve ligation or sciatic constriction supposedly mimick peripheral damage. The reasoning is very segmental in terms of the recruited neurons in the superficial laminae (I&II). This segmental reasoning could explain Südeck atrophy (also called: algo-neurodystrophy or complex regional pain syndrome) in which the Abeta-fibers are involved. It makes feedback loop comprehensible via PAG-rVMM for the involved spinal segments.

Would it be possible to make a GC-model that could explain a more generalized sensitization: plurisegmental, extrasegmental or even generalized. I am thinking of bilateral small fiber pathology in diabetic neuropathy (of the inferior limbs e.g.), nocturnal restless legs syndrome or fibromyalgia in the whole body. Is there evidence in the literature of a spreading or escalating mechanism? On spinal level, on PAG- or VMM-level?

Thank you Jean!

With respect to complex regional pain syndrome (formlely known as "reflex sympathetic dystrophy" or "caulsalgia") I didn't hear or read anything about the contribution of ABeta fibers to this pathology. On the other hand, I read years ago about noradrenergic sprouting (Ruocco et al., 2000) and up-regulation of noradrenergic receptors exhibited by intact primary afferents, after peripheral nerve injury (Drummond et al., 1996; Ali et al., 1999). It is supposed that this is so because Nerve Growth Factors, which are released in response to peripheral nerve damage.

I enjoy this transatlantic conversation very much, Erick :-).

- A possible spreading or escalating mechanism would be through collateralization of the afferents (tract of Lissauer): one or two segments above and bellow the segment of entry. But do we have an idea about spreading other than intensity of impact?

- But there is something else: astroglia (astrocytes).

They have long been considered as merely structural support and feeding elements for the neurons, which were considered to be the only transmission elements. Astroglia have myelin extensions surrounding capillaries and synapses (e.g. between primary afferent and second order neurons of superficial laminae). The synapses are called therefore tripartite. The astrocyte reuptakes Glutamate, protecting the synapse from excitotoxicity. When this fails there would be hyperexcitability in the sense of neuropathy. Second thing is that they can be involved in the inflammatory proces via the topical blood vessels.

Another characteristic is that they are interconnected between each other via Junction Gaps (connexons), transmitting a wave of Ca++ efflux through a syncythial territory. All the neuron synapses within the territory become therefore synchronized: activity of one synapse facilitates activity of the others within the same territory. This mechanism could explain the spreading or escalation independent from the segmental entry. Do we have an idea about the size and (longitudinal or transverse) extension of the astrocytic territories?

I'm enjoying this too!

I think that we know very little about glial contribution in pain states. These cells are more than, as you pointed, merely support structures. But unfortunately, we are strictly focused on neurons.

It would be interesting to study astrocytes, oligodendrocytes, schwann cells in detail, and their influence on neural dynamics, even from a computational point of view. Perhaps we could introduce a new RG topic... something like "how the glial cells influence the computational capabilities of sensory pathways?"

What do you think, Jean?

Excellent idea Erick, go ahead !

Could you have a look into this review "Computational quest for understanding the role for astrocyte signaling in transynaptic transmission and plasticity" from 2012. I got it by courtesy of Alfredo Pereira jr. who wrote highly updated articles on the subject of astroglia. If you start the topic on RG he will follow us.

I'm glad you like it!

I will go out of town for this weekend. Then, please give me a copule of days to read the article and start the topic on RG.

Agree?

OK, have a nice WE !

Remind me afterwards, in response to your initial question,

about the relationship between rVMM: NA-> alfa2R/astrioglia.

I'm back!

Let's get started with the three functional classes of neurons from RVM, that is, ON-, OFF- and Neutral cells.

RVM provides serotonergic input to superficial dorsal horn, but serotonin (5-HT) was found exclusively in a subset of neutral cells (Potrevic, 1994), whose role in nociceptive modulation remains unclear. On the other hand, GAD67 immunoreactivity was found in most OFF-cells and less frequently in ON-cells, suggesting that the majority of the OFF-cells are GABAergic, and some ON-cells (Clayton, 2006). However, the neurons that receive that descending projections from RVM, as well as their connectivity patterns, are still unknown...

OK,

OFF cells are antinociceptive, by GABA-inhbition in the dorsal horn. They also present Mu-receptors activating the OFF cells. They also present CCK2-Rs desactivating them, leading to hyperalgesia (pain by disinhibition). This should be a direct inhibition of the axon of the primary afferent. If I understand it correctly,

ON cells would be serotonergic, but in the dorsal horn the effect depends on the subtype of the serotonine receptor (5HT3-R pain facilitating and 5HT7-R pain inhibiting). So the ON cell would target a 5HT3-R neuron in the dorsal horn. Am I correct sofar?

-> possibility could be to identify some target neurons (not the interneurons?) according the subtype of 5HT-R, (for the ON cells)?

As you mentioned above, Serotonine effect (pronociceptive or antinocicpeptive) depends on the subtype of the 5-HT receptor. That is one more reason why the role of this neurotransmitter remains unclear....

Perhaps you're right, assuming that ON-cells from RVM are serotonergic, to be consistent with their pronociceptive role, those cells should target DH neurons expresing the 5-HT7 receptor... but which ones? Islet? Vertical? Central?

Do you know the updated compilation by Zeilhofer (2012)?

Fast Synaptic Inhibition in Spinal Sensory Processing and Pain Control

Hanns Ulrich Zeilhofer , Hendrik Wildner , Gonzalo E. Yévenes

Physiological ReviewsPublished 1 January 2012Vol. 92no. 193-235DOI: 10.1152/physrev.00043.2010

I found the integral version: (pasted)

http://physrev.physiology.org/content/92/1/193

However targeted cells remain elusive. I was impressed with staining photo's of laminar distribution of GABA-cells and Glycine-cells (fig.6 & 7). And also the overview of transcription factors determining the specification of dorsal horn inhibitory interneurons (chapter VIII).

Yes I do... I refer that compilation in the original question (see above). On the other hand, you are right again... the targets of descending projections remain elusive...

No studies seem to be available to adress this issue!

I'm just an Engineer, but I think the "paired" patch-clamp technique used by Lu & Perl (2003, 2005, 2007, 2013), would be helpful to determine RVM's target neurons at the superficial dorsal horn.