In the last decade, the new understanding of the role played
by neural plasticity and glial cells[1]
over central and peripheral sensitization in chronic pain conditions has
prompted a huge wave of research. Glia has been found to be crucial in the
maintenance of neuronal homeostasis in the central nervous system.[2]
Up to date, numerous studies have shown the critical role of glia in
neuropathic and inflammatory pain due to glia’s interrelationship with neurons.
As Ji R.R, Berta T., and Nedergaard M. suggest in their review article Glia and pain: is chronic pain a gliopathy?
published in PAIN in 2013, glia can
communicate with neurons by “listening” and “talking” to them. Thus, “nerve
injury-induced chronic pain is associated not only with neuropathy but with gliopathy.”[3]
It is increasingly being accepted that chronic pain can manifest not only by
neural plasticity but by dysfunction of glial cells.
This new understanding can lead to non-symptomatic therapy
intervention for “gliopathy,” however, as the article affirms, it is still not
clear what type of drugs could be designed because it is difficult to target
only glial cells without affecting neurons, and to eliminate glial cells with
glia-selective toxins could cause adverse effects due to their supportive and
protective roles. Theoretically, as the authors explain, it should be more
effective for pain relief to target both neurons and glia; recent studies have
shown that lipid mediators not only inhibit glial activation and inflammation
but also TRP (Transient Receptor Potential) channels and reverse synaptic
plasticity in neurons. As they propose, these endogenous lipid mediators, given
their potency and safety, could be developed for preventing and treating
chronic pain, via targeting both neuronal and non-neuronal (immune and glial) mechanisms.
Another
important factor in relation to glia is the influence that the immune system
has in the modulation of chronic pain. Glia produces immune factors (specifically
microglia) which are thought to play an important role in nociceptive
transmission. Hence, to Mika et al, “pain may now be considered a neuro-immune disorder,
since it is known that the activation of immune and immune-like glial cells in the
dorsal root ganglia and spinal cord results in the release of both pro- and
anti-inflammatory cytokines, as well as algesic and analgesic mediators.”[4]
Following this notion, they propose several pathways as new treatments for
neuropathic pain. Firstly, they explain that it could be directed towards drugs
that seek targets such as anti-inflammatory factors. Secondly, a novel
alternative suggested is a pharmacological attenuation of glial and immune cell
activation. Thirdly, they think that other way could be to decrease
pro-nociceptive agents such as transcription factor synthesis, kinase synthesis
and protease activation. Lastly they suggest that, since it is known that
opioid-induced glial activation opposes opioid analgesia, some glial
inhibitors, which are safe and clinically well tolerated, could be used as potential
co-analgesic agents for opioid treatment of neuropathic pain.
As it can be seen form these proposals and the evidence on
glia’s role in chronic pain, the stimulation and optimization of endogenous
analgesics and anti-inflammatory factors seems to be a challenging although
promising pathway for improving neuropathic conditions. Many of the studies
that are currently focusing on endogenous and non-endogenous opioids and cannabinoids
as well as lipid mediators for the treatment of chronic pain, will benefit from
the research on glial cells addressed here. The way is open for a new era in
the understanding and intervention of chronic pain that may move away from the solely
symptomatic approach towards a more decisive and effective treatment of pain as
a disease. Regardless of the original trigger agent, it has become widely
accepted that pain can become a condition which outlives its original cause,
and from being physiologically nociceptive can acquire a neuropathic quality.
Whether it may be considered a gliopathy,
a neuro-immune disorder, or some
other, it is clear that due to the unusual characteristics of neuropathic pain,
it demands different methods for management, whether pharmacological or
non-pharmacological. Pain needs to be addressed for itself, and the
alternatives proposed by the authors of the articles reviewed here are a further
step in reversing the unsatisfactory results of its management.
The following video is a TED talk given by Elliot Krane called: The mystery of chronic pain, which I
think captures the spirit of this new frontier in the neuroscience of pain.
TED2011 · 8:14 · Filmed Mar 2011
[1] From the Central Nervous System (CNS): microglia, astrocytes, and oligodendrocytes;
and from the Peripheral Nervous System (PNS): satellite glial cells in the
dorsal root ganglia and trigeminal ganglia, and Schwann cells in peripheral
nerves.
[2] Cf. Joanna Mika, Magdalena Zychowska, Katarzyna
Popiolek-Barczyk, Ewelina Rojewska, Barbara Przewlocka (2013). Importance of
glial activation in neuropathic pain. European
Journal of Pharmacology 716. p.p.106–119.
[3] Ru-Rong Ji, Temugin Berta, Maiken Nedergaard (2013). Glia
and pain: Is chronic pain a gliopathy? PAIN 154 p.p.S10–S28.
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