Unexplained pain: "Pain-initiating function of glial cells identified"

[natasa778]

The sensation of pain occurs when neural pathways conduct excitation generated by tissue damage to the spinal cord, where the nociceptive information is extensively pre-processed. From there, the information is transmitted to the human brain, where the sensation of "pain" is finally created. This is the general belief. However, researchers from the Division of Neurophysiology at MedUni Vienna's Center for Brain Research have now discovered that pain is not just a matter of nerves but that non-neuronal cells, the glial cells, are also involved in clinically relevant pain models and their activation is sufficient to amplify pain. The study has now been published in the leading journal Science...

...
At the same time, however, when they are activated – by pain processes, for example ¬– glial cells are themselves able to release messenger substances, such as inflammatory cytokines. Glial cells therefore have two modes: a protective and a pro-inflammatory mode. "The activation of glial cells results in a pain-amplifying effect, as well as spreading the pain to previously unaffected parts of the body. For the very first time, our study provides a biological explanation for this and for other hitherto unexplained pain phenomena in medicine,"

http://medicalxpress.com/news/2016-11-pain-initiating-function-glial-cells.html

paper: http://science.sciencemag.org/content/early/2016/11/04/science.aah5715

 

[Woolie]

Thanks for posting, @natasa778.

I just want to point out that we should be cautious about articles that include statements like this (my bolding):

The sensation of pain occurs when neural pathways conduct excitation generated by tissue damage to the spinal cord...

The reason is that there are a lot of peripheral pain phenomena that have nothing to do with tissue damage. Extremes of cold and heat can be very painful, even without "tissue damage". Local inflammation (for example, when a wound gets infected) is often much more painful that the "tissue damage" that led to it. Labor pains during childbirth and severe period pain are other nice examples. Immune activity can be painful - for example, the muscle aches that accompany severe flu are usually attributed to antibody complexes circulating within the system. Not. tissue damage.

If anyone tries to claim that all pain that isn't caused by tissue damage must be "central" (ie. generated in the brain), they have set up a false dichotomy.

At worst, this kind of reasoning can be used to justify a lot of bullshit about how people with chronic pain need psychotherapy.

 

[Woolie]

I just read the paper. I'm pretty much a layperson when it comes to this area, but my reading of it was this. Its about glial cells in the spinal cord, which can "remember" pain for a short while, and even amplify it. The new contribution this study makes is that this memory/amplification effect may have a "spreading" effect, so that the experience of pain appears to "spread" to areas outside the affected site.

The spread is still narrow, though. And the duration is a couple of hours max, at least from what I can tell. Yet the paper ends with the usual far-flung claims about how this line of research could help us understand chronic pain, and every manner of psychiatric condition under the sun.

Could others with more expertise perhaps comment?

 

[lansbergen]

@Woolie as an aside. Did you ever disinfect an open wound with hydrogenperoxide? If so can you imagine how painfull high endogenous hydrogenperoxide can be?

 

[natasa778]

Few more papers on the role of glial cells in (chronic) pain, published in the last few months

Minocycline Effects on IL-6 Concentration in Macrophage and Microglial Cells in a Rat Model of Neuropathic Pain

Microglial role in the development of chronic pain
Resveratrol attenuates inflammatory hyperalgesia by inhibiting glial activation in mice spinal cords

 

[natasa778]

Also this one

Glial contributions to visceral pain: implications for disease etiology and the female predominance of persistent pain

Dysregulation of healthy glial activity contributes to the development of persistent pain

... under certain conditions, glial reactivity is not advantageous and can instead be detrimental to neuronal function, such as during the manifestation of persistent pain.

In response to strong or persistent receptor stimulation, microglia switch from a surveillance state to an active response state, and astrocytes transition from a regulatory to reactive state.11 Under these circumstances, the release of proinflammatory mediators by glia can contribute to ongoing nociception, by inducing long-lasting plastic changes of synaptic connectivity that enhances the transmission of ascending nociceptive information. As such, glia and their products are sufficient to create exaggerated pain. This has been shown where intrathecal transfer of highly reactive microglia alone, or injection or induction of their proinflammatory products (such as interleukin (IL)-1β and tumor necrosis factor-α (TNFα)) into naive animals, can induce symptoms of neuropathic pain.17, 18, 19

The downstream effects of enhanced glial reactivity are strengthened by the fact that immune mediators, including those released by glia, are substantially more potent in modulating neuronal signaling compared with classical neurotransmitters on a per molecule basis.11 Glial proliferation, morphological changes and increases in protein expression can persist for months after initial injury, even beyond tissue healing.20, 21 Moreover, proinflammatory mediators and glial-derived neurotransmitters can reciprocally stimulate glia in an autocrine and paracrine manner, thereby amplifying a positive feedback loop of unfavorable activity.22, 23, 24

they go on to speculate that female sex hormone modulation of glial reactivity could be contributing to the female predominance of persistent pain ...


PS note the major role of purinergic receptors/ATP signalling in the above...

 

[Woolie]

Also this one

Glial contributions to visceral pain: implications for disease etiology and the female predominance of persistent pain



they go on to speculate that female sex hormone modulation of glial reactivity could be contributing to the female predominance of persistent pain ...


PS note the major role of purinergic receptors/ATP signalling in the above...

@natasa778, if you know about this work, maybe you could do an everyman's summary for us?

I am troubled by it. In the excerpt you quote it states:

..... injection or induction of their proinflammatory products (such as interleukin (IL)-1β and tumor necrosis factor-α (TNFα)) into naive animals, can induce symptoms of neuropathic pain.https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5048206/#bib19

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5048206/#bib19
Okay, so these products, on their own can induce pain. That seems like a pretty good explanation on its own for the higher incidence of many pain syndromes in women, right there. Given that women are much more susceptible to autoimmune illnesses. What's left - which consists largely of menstrual syndromes - well those might not occur very often in those without a uterus! There's also no mention of the persistent pain syndromes that are actually more common in men, such as back pain.

This is the interesting new idea:

intrathecal transfer of highly reactive microglia alone.... can induce symptoms of neuropathic pain.https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5048206/#bib19

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5048206/#bib19
So the idea is, you can also induce pain just by transferring the reactive microglia to another animal. That's a "central" pain phenomenon, if you mean central as anywhere in the CNS. But still not that central. The effect persists for a limited period (couple of months max).

Okay, so glial cells can enhance and prolong the sensation of peripherally-induced pain. But only for a short time. Then all goes back to normal if there isn't any peripheral pain stimulus.

One problem is that this mechanism cannot account for relapsing-remitting pain, which is the more common presentation in most of the conditions mentioned.

But my big problem is that, it doesn't lead anywhere in terms of interventions. Even if you coudl somehow tranpslant glial cells form a healthy indivudal, that might reduce the intensity of the pain experience a bit, for a while. But then the peripheral factors that initially triggered the pain response will still be in place. So the cycle would just start all over again. We need to target those peripheral factors to really relieve the pain.

Also, one of the subtitles in the article is this:

Persistent pain arises from central sensitization

(no, we don't know that. They justify this claim on the basis of the false dichotomy error I mentioned earlier: If there's no tissue damage then the pain must be central. Not true, you might have persistent peripheral factors, such as the persistent production of inflammatory cytokines, and these mechanisms might have nothing to do with the CNS).

I don't think the approach is going to lead to much in the way of help for people with pain, and I also worry that it could be misused by psychosocial advocates to justify all sorts of dodgy claims and treatments

 

[lansbergen]

(no, we don't know that. They justify this claim on the basis of the false dichotomy error I mentioned earlier: If there's no tissue damage then the pain must be central. Not true, you might have persistent peripheral factors, such as the persistent production of inflammatory cytokines, and these mechanisms might have nothing to do with the CNS).

For instance: superoxide production as an early immune response and if the agent is hard or impossible to destroy, ongoing production.