Longterm potentiation and nociception

As I scanned through Edge.org's question for 2012, I came upon this: Todd Sacktor's essay on "Elementary Particles of Memory", his contribution to the question,  2012: What is your favorite deep, elegant, or beautiful explanation? 

Excerpt:

The key molecule maintaining LTP is a persistently active enzyme, called PKMzeta. Together with the molecules maintaining LTD that are still being determined, these elementary molecules store most forms of memory. Without the persistent strengthening of synapses by PKMzeta, the ongoing physiological process of LTP at the synapse collapses, and most long-term memories are erased. The animal returns to a "blank slate," with just its genetic inheritance of behavior.

LTP= longterm potentiation. It's a process by which synaptic connections between neurons are strengthened. 

LTP is a persistent strengthening of synaptic connections triggered by a brief episode of high-frequency activity of those connections... The key molecule maintaining LTP is a persistently active enzyme, called PKMzeta... PKMzeta is an unusual form of protein kinase. Once made when LTP is triggered, PKMzeta is active all the time, rather than being turned on and off in response to other molecules. When mutations occur in genes for kinases that render them active all the time, they promote uncontrolled growth in cells, leading to cancer. However, the change in the gene that encodes PKMzeta also restricts the formation of the persistently active kinase to neurons. Because mature neurons are tethered to thousands of other neurons through their synapses, they cannot possibly divide and are remarkably resistant to forming cancers (most brain tumors in adults originate from glial cells, which readily divide). By restriction to cells that communicate but cannot divide, a mutation signaling continual growth, potentially deadly to an organism, was used to maintain long-term memory.

Isn't that remarkable. Here is a paper by him, from 2008: 

PKMzeta, LTP maintenance, and the dynamic molecular biology of memory storage.

ABSTRACT: How memories persist is a fundamental neurobiological question. The most commonly studied physiological model of memory is long-term potentiation (LTP). The molecular mechanisms of LTP can be divided into two phases: induction, triggering the potentiation; and maintenance, sustaining the potentiation over time. Although many molecules participate in induction, very few have been implicated in the mechanism of maintenance. Understanding maintenance, however, is critical for testing the hypothesis that LTP sustains memory storage in the brain. Only a single molecule has been found both necessary and sufficient for maintaining LTP--the brain-specific, atypical PKC isoform, protein kinase Mzeta (PKMzeta). Although full-length PKC isoforms respond to transient second messengers, and are involved in LTP induction, PKMzeta is a second messenger-independent kinase, consisting of the independent catalytic domain of PKCzeta, and is persistently active to sustain LTP maintenance. PKMzeta is produced by a unique PKMzeta mRNA, which is generated by an internal promoter within the PKCzeta gene and transported to the dendrites of neurons. LTP induction increases new PKMzeta synthesis, and the increased level of PKMzeta then enhances synaptic transmission by doubling the number of postsynaptic AMPA receptors (AMPAR) through GluR2 subunit-mediated trafficking of the receptors to the synapse. PKMzeta mediates synaptic potentiation specifically during the late-phase of LTP, as PKMzeta inhibitors can reverse established LTP when applied several hours after tetanization in hippocampal slices or 1 day after tetanization in vivo. These studies set the stage for testing the hypothesis that the mechanism of LTP maintenance sustains memory storage. PKMzeta inhibition in the hippocampus after learning eliminates the retention of spatial memory. Once the PKMzeta inhibitor has been eliminated, the memory is still erased, but new spatial memories can be learned and stored. Similar results are found for conditioned taste aversion when the inhibitor is injected in the insular neocortex. Thus PKMzeta is the first molecule found to be a component of the long-term memory trace.

Hmn. Insular cortex. That little brainpart, important in pain processing, in salience processing, shows up again. 

Anyway.

So... find something that messes with LTP and maybe.. "memory" could be erased? ... but I am way ahead of myself. Let me start again. 

A few days ago, this story came out of Nature | News: High-dose opiates could crack chronic pain. People in Vienna have found a way to reverse longterm potentiation in spinal cord synapses, at least in rat models. Here is the abstract of their paper,  Erasure of a Spinal Memory Trace of Pain by a Brief, High-Dose Opioid Administration:

Painful stimuli activate nociceptive C fibers and induce synaptic long-term potentiation (LTP) at their spinal terminals. LTP at C-fiber synapses represents a cellular model for pain amplification (hyperalgesia) and for a memory trace of pain. μ-Opioid receptor agonists exert a powerful but reversible depression at C-fiber synapses that renders the continuous application of low opioid doses the gold standard in pain therapy. We discovered that brief application of a high opioid dose reversed various forms of activity-dependent LTP at C-fiber synapses. Depotentiation involved Ca²⁺-dependent signaling and normalization of the phosphorylation state of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors. This also reversed hyperalgesia in behaving animals. Opioids thus not only temporarily dampen pain but may also erase a spinal memory trace of pain.

So, what they did was, took rats, gave them 'chronic pain', i.e., allowed longterm potentiation to develop in their spinal cord synapses such that the second-order neurons conveying nociceptive afferent information to the rats' poor little brains, presumably their insular cortices, along with some other destinations probably, got way better at their jobs. Then, the researchers figured out what dose, and what kind, of opioid it took to reverse all the longterm potentiated changes. It turned out to be something called remifentanil, a "potent ultra short-acting synthetic opioid analgesic drug",  "given to patients during surgery to relieve pain and as an adjunct to anesthetic."

(A bit further down in the Wikipedia link is this interesting comment: 

Doses listed in the package insert from its manufacturer are much higher than those used in actual clinical practice

Huh. Gee, why not use it according to directions?)

Yes, pain would be a good thing to be helped to forget. Great place to start. 

There are only three neurons between anywhere on the surface of a vertebrate (or beneath its surface, I suppose..), and said vertebrate's brain. Clearly the junctions are the right place to target. Clearly opioids can help with pain, both prevention and, apparently, according to this, cure. It looks as though Sacktor may have been looking at the second link in the chain. The Vienna people looked at the first link.

I looked in the Vienna paper to see if PKMzeta figured in at all - the authors say they took a look:

We thus asked whether PKMz in spinal cord also plays a role for the maintenance phase of LTP (22, 23) after LFS. PKMz inhibitor ZIP had, however, no obvious effect on the maintenance of LFS-induced LTP within the observation period of 6 hours (fig. S2D).

22. M. N. Asiedu et al., J. Neurosci. 31, 6646 (2011).

23. T. C. Sacktor, Nat. Rev. Neurosci. 12, 9 (2011).

 It looks like they didn't see what Sactor found, or else they found something else:

Depending on the type of conditioning stimulation, distinct forms of LTP [longterm potentiation] are induced at C-fiber synapses, which affect different groups of postsynaptic neurons (13, 24) and involve signaling pathways that overlap only partially (13, 24, 25). 
We therefore tested whether OID [opioid-induced depotentiation] can also be achieved for other forms of established spinal LTP. We induced LTP by conditioning high-frequency stimulation (HFS, 100 Hz; fig. S3A) of sciatic nerve fibers or by subcutaneous capsaicin injections (fig. S3C). 
The latter selectively activates nociceptive nerve fibers, which express the transient receptor potential channel subfamily V member 1 (TRPV1). Remifentanil also fully reversed these forms of LTP (after HFS,  depotentiation was from 158 ± 8% to 99 ± 9%, n=12,P<0.001; after capsaicin,  depotentiation was from 170 ± 16% to 100 ± 13%, n=5, P<0.001;fig.S3, B and D), demonstrating that OID applies to various forms of activity-dependent LTP at C-fiber synapses.

My comments inside square brackets.

It's probably worth mentioning that if that first synapse, the one in the dorsal horn, can be affected, then the second-order neuron, the one that not only carries the info straight up but can turn into a signal amplifier blasting the info through the thalamus into all the third-order neurons that go to the sensory cortex, insular cortex, anterior cingulate cortex, like a lawn sprinkler on steroids, or a finger over the end of a garden hose increasing the distance and force of the spray, will be diminished to mere leakage. Then the brain will be able to ignore the ordinary light tapping or tinking of rain (nociception) on the roof, instead of a continuous thunderous pounding driving rainstorm day in and day out. Yes, one could still distract oneself (not register it as "pain") but it would probably be a lot harder than if the noise level could just be turned way down again to ordinary levels.


From the Viennese paper:

LTP is a synaptic model for some forms of hyperalgesia (26). We therefore asked whether OID has any relevance for behaving animals. Sub- cutaneous injections of capsaicin quickly led to mechanical hyperalgesia at the injected hindpaw (Fig. 4). The same dosage regimen of remifentanil that caused OID significantly attenuated capsaicin- induced hyperalgesia (Fig. 4A). Not surprisingly, the behavioral hyperalgesia was reversed only partially by the opioid treatment because additional peripheral and central mechanisms contribute to capsaicin-induced hyperalgesia (27, 28). PP1 inhibitor calyculin A fully blocked the attenuation of hyperalgesia by remifentanil (Fig. 4B), suggesting that depotentiation at nociceptive C fibers may erase a memory trace of pain[sic - at this point it's still only nociception]. LTP is expressed in ascending nociceptive pathways, which are relevant for the aversive components of pain. It will thus be interesting to explore whether opioids may also reverse the tonic-aversive state of pain (29). Taken together, the present and our previous data (3) demonstrate that activation of spinal MORs triggers distinct, bidirectional, and state-dependent synaptic plasticity in naïve versus potentiated C-fiber synapses. Remifentanil activates Ca2+-dependent signaling pathways, leading to activation of PP1 and PKC. At potentiated synapses, this normalizes the phosphorylation state [i.e., reverses the energy efficiency gained, makes them work harder again, makes them more "naive" again] of GluR1 at Ser831 and that of GluR2 at Ser880 and thereby depotentiates synaptic strength in C fibers. The presently identified reversal of synaptic LTP in nociceptive pathways provides a rationale for novel therapeutic strategies to cure rather than to temporarily dampen some forms of pain with opioids.

All "synaptic learning" seems to be about, really, in the case of pain, is a ratcheting of energy efficiency, such that the nociceptive neurons take advantage of a chemically altered "gain" in synaptic "strength" so that they can do their job with less fuel, perhaps. Economy of means. The Vienna people have figured out how to reverse that in a rat model, at the first synapse: it seems to me that Sactor's work has had to do with the second synapse upstairs in the brain, that he has not directly involved himself in LTP of the nociceptive system. 


Anyway, those are just some ramblings I've strung together from two recently read pieces of work that sound like maybe they talk about the same thing, LTP, but when I look close, I can't see that they actually do. I need to read the Vienna paper several more times, but so far it still looks like there's a gap between pain science and other neuroscience. It might help if people doing 'pain' science at the first synapse would stop calling it "pain science" and instead would call it "nociception science."