Glia modulators for neuropathic pain

Since 1994 when Meller and colleagues for the first time demonstrated that by inhibiting astrocyte functions, neuropathic pain did not emerge, many glia modulators have been explored as new inroads in the treatment of neuropathic pain.

Some specifically inhibit cytokines (like Il-18), others enhance anti-inflammatory cytokines, such as Il-10, and again others stabilize mast cell degranulation and are PARR agonists, such as Palmitoylethanolamide (PEA).

A summary

Substance or target
Dev stage
 AV411 (ibudilast)  [1]
astrocyte inhibitor
Gia modulator
 Palmitoylethanolamide (PEA)
Mast cell stabilizing PPAR agonist, NF-kappa-B 
on market
CB 1/2 agonist
on market
CB 2 agonist
glia modulator
on market Japan
glia modulator, TNF-alpha blocker
on market as Trental
Low Dose Naltrexone
glia modulator
on market
gamma-linolenic acid[4]
oligodendroglia differentiator
on market
CB 2 agonist
minocycline [6][7][8]
on market/preclinical
IL-1 receptor antagonist [9]
IL-1 receptor antagonist
IL-17 antagonism KO [10]
IL-17 antagonism
preclinic target
Toll-like receptor 4 [11][12][13][14]
preclinic target
dexmedetomidine [15]
gia modulator
P2X4 [16]
preclinic target
P2X7R antagonist [17]
fractalkine (FKN) [18]
preclinic target
R-flurbiprofen [19]
CB and FAAH inhibition
GRK2 [20]
G-protein-coupled receptor
epoxide hydrolase (sEH) inhibitors[21][22]
epoxide hydrolase (sEH)
JNJ 42160443
NGF inhbitor
phase III
p38 Kinase Inhibitor
phase II
KD7040 [23][24]
inhibitor of iNOS
phase II
IL-17 [10]
IL-17 antagonism
selective p38 MAPK inhibitor,  regulates the expression of pro-inflammatory cytokines
non selective gap junction inhibitor


More glia cells on each neuron

freeimages-1-1424913-INP.jpg Glia modulators for neuropathic painGlia cells and astrocytes are more and more widely recognized as important new targets, even to treat break through pain.[28][29][30][31]

On each neuron in the CNS many more glia cells can be found. And also a single astrocyte enwraps 4 to 6 neuronal somata and contacts 300 to 600 neuronal dendrites [32]

Thus glia cells and neurons are intensively intermingled. Activated astrocytes are mainly referred to glial fibrillary acidic protein (GFAP) up regulation and astrogliosis (hypertrophy of astrocytes).

Astrocyte activation as been found in many pain states such as in chronic constriction injury,[33] after spinal nerve ligation,[34][35] and due to tissue injury and/or inflammation.[36][37]

Pharmacological attenuation of glia activation therefore represents a novel approach for controlling neuropathic pain. It has also been found that old molecules, such as propentofylline, pentoxifylline, fluorocitrate and minocycline.

They decrease microglial activation and inhibit pro inflammatory cytokines, thereby suppressing the development of neuropathic pain.[38] 

Although many networks within gliopathic pain exist, we give an example of two factors, Il-18 and the gap junction. 

Example: Il-18 

Astroglial reaction after nerve injury is more persistent than microglial reaction.[39] Microglial reaction is usually prior to astrocyte reaction. Interestingly, after nerve injury, the cytokine and its receptor Il-18 is upregulated on astrocytes and microglia.[40] By blocking Il-18 the allodynia due to the nerve injury diminishes.

Gap Junctions 

Glia cells are interconnected with gap junctions (tubes in which ions flow from one cell to the other.[41] When a nerve injury occurs, one component of gap junctions (connexin Cx43) is increasingly expressed.[42] Inhibition of gap junction function by carbenoxolone produces analgesia in pain models.[43]

Jan M. Keppel Hesselink, MD, PhD, and David J. Kopsky, October 2010, rev Oct 2011, Prof. dr. J.M. Keppel Hesselink
‘Glia modulators for neuropathic pain’

Watch here our video’s about Neuropathy.

Propentofylline, a glia modulator

Visceral pain: a forgotten topic
Is Tapentadol better than Tramadol?
Vitamin D and the influence on chronic pain


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