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 |
Mechanism |
Dev stage |
AV411 (ibudilast) [1] |
astrocyte inhibitor |
II |
Etanercept |
Gia modulator |
II |
Palmitoylethanolamide (PEA) |
Mast cell stabilizing PPAR agonist, NF-kappa-B |
on market |
Cannabis[2] |
CB 1/2 agonist |
on market |
Cannabinoids |
CB 2 agonist |
preclinical |
propentofylline [3] |
glia modulator |
on market Japan |
pentoxifylline |
glia modulator, TNF-alpha blocker |
on market as Trental |
Low Dose Naltrexone |
glia modulator |
on market |
gamma-linolenic acid[4] |
oligodendroglia differentiator |
on market |
NESS400[5] |
CB 2 agonist |
preclinical |
anti-biotic |
on market/preclinical |
|
IL-1 receptor antagonist [9] |
IL-1 receptor antagonist |
preclinic |
IL-17 antagonism KO [10] |
IL-17 antagonism |
preclinic target |
antagonism |
preclinic target |
|
dexmedetomidine [15] |
gia modulator |
|
P2X4 [16] |
modulator |
preclinic target |
P2X7R antagonist [17] |
OxATP or BBG |
preclinic |
fractalkine (FKN) [18] |
antagonism |
preclinic target |
R-flurbiprofen [19] |
CB and FAAH inhibition |
|
GRK2 [20] |
G-protein-coupled receptor |
preclinical |
epoxide hydrolase (sEH) |
prelinical |
|
JNJ 42160443 |
NGF inhbitor |
phase III |
PH-797804 |
p38 Kinase Inhibitor |
phase II |
inhibitor of iNOS |
phase II |
|
IL-17 [10] |
IL-17 antagonism |
target |
SB203580 |
selective p38 MAPK inhibitor, regulates the expression of pro-inflammatory cytokines |
preclinical |
non selective gap junction inhibitor |
preclinical |
More glia cells on each neuron
Glia 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]
, and David J. Kopsky, October 2010, rev Oct 2011,
‘Glia modulators for neuropathic pain’
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[1] Cho Y, Crichlow GV, Vermeire JJ, Leng L, Du X, Hodsdon ME, Bucala R, Cappello M, Gross M, Gaeta F, Johnson K, Lolis EJ. | Allosteric inhibition of macrophage migration inhibitory factor revealed by ibudilast. | Proc Natl Acad Sci U S A. | 2010 Jun 22;107(25):11313-8. Epub 2010 Jun 8.
[2] Rivers JR, Ashton JC. | The development of cannabinoid CBII receptor agonists for the treatment of central neuropathies. | Cent Nerv Syst Agents Med Chem. | 2010 Mar;10(1):47-64.
[3] Sweitzer S, De Leo J. | Propentofylline: glial modulation, neuroprotection, and alleviation of chronic pain. | Handb Exp Pharmacol. | 2011;(200):235-50.
[4] van Meeteren ME, Baron W, Beermann C, Dijkstra CD, van Tol EA. | Polyunsaturated fatty acid supplementation stimulates differentiation of oligodendroglia cells. | Dev Neurosci. | 2006;28(3):196-208.
[5] Luongo L, Palazzo E, Tambaro S, Giordano C, Gatta L, Scafuro MA, Rossi FS, Lazzari P, Pani L, de Novellis V, Malcangio M, Maione S. | 1-(2',4'-dichlorophenyl)-6-methyl-N-cyclohexylamine-1,4-dihydroindeno[1,2-c]pyrazole-3-carboxamide, a novel CB2 agonist, alleviates neuropathic pain through functional microglial changes in mice. | Neurobiol Dis. | 2010 Jan;37(1):177-85. Epub 2009 Oct 3.
[6] Guasti L, Richardson D, Jhaveri M, Eldeeb K, Barrett D, Elphick MR, Alexander SP, Kendall D, Michael GJ, Chapman V. | Minocycline treatment inhibits microglial activation and alters spinal levels of endocannabinoids in a rat model of neuropathic pain. | Mol Pain. | 2009 Jul 1;5:35.
[7] Chen S, Hui H, Zhang D, Xue Y. | The combination of morphine and minocycline may be a good treatment for intractable post-herpetic neuralgia. | Med Hypotheses. | 2010 Dec;75(6):663-5. Epub 2010 Sep 9.
[8] Chang YW, Waxman SG. | Minocycline attenuates mechanical allodynia and central sensitization following peripheral second-degree burn injury. | J Pain. | 2010 Nov;11(11):1146-54. Epub 2010 Apr 24.
[9] Wang KC, Wang SJ, Fan LW, Cai Z, Rhodes PG, Tien LT. | Interleukin-1 receptor antagonist ameliorates neonatal lipopolysaccharide-induced long-lasting hyperalgesia in the adult rats. | Toxicology. | 2011 Jan 11;279(1-3):123-9. Epub 2010 Oct 19.
[10] Kim CF, Moalem-Taylor G. | Interleukin-17 contributes to neuroinflammation and neuropathic pain following peripheral nerve injury in mice. | J Pain. | 2011 Mar;12(3):370-83.
[11] Saito O, Svensson CI, Buczynski MW, Wegner K, Hua XY, Codeluppi S, Schaloske RH, Deems RA, Dennis EA, Yaksh TL. | Spinal glial TLR4-mediated nociception and production of prostaglandin E(2) and TNF. | Br J Pharmacol. | 2010 Aug;160(7):1754-64.
[12] Buchanan MM, Hutchinson M, Watkins LR, Yin H. | Toll-like receptor 4 in CNS pathologies. | J Neurochem. | 2010 Jul;114(1):13-27. Epub 2010 Apr 6.
[13] Bettoni I, Comelli F, Rossini C, Granucci F, Giagnoni G, Peri F, Costa B. | Glial TLR4 receptor as new target to treat neuropathic pain: efficacy of a new receptor antagonist in a model of peripheral nerve injury in mice. | Glia. | 2008 Sep;56(12):1312-9.
[14] Watkins LR, Hutchinson MR, Rice KC, Maier SF. | The "toll" of opioid-induced glial activation: improving the clinical efficacy of opioids by targeting glia. | Trends Pharmacol Sci. | 2009 Nov;30(11):581-91. Epub 2009 Sep 15.
[15] Xu B, Zhang WS, Yang JL, Lû N, Deng XM, Xu H, Zhang YQ. | Evidence for suppression of spinal glial activation by dexmedetomidine in a rat model of monoarthritis. | Clin Exp Pharmacol Physiol. | 2010 Oct;37(10):e158-66. doi: 10.1111/j.1440-1681.2010.05426.x.
[16] Horvath RJ, Romero-Sandoval EA, De Leo JA. | Inhibition of microglial P2X4 receptors attenuates morphine tolerance, Iba1, GFAP and mu opioid receptor protein expression while enhancing perivascular microglial ED2. | Pain. | 2010 Sep;150(3):401-13. Epub 2010 Jun 22.
[17] Chu YX, Zhang Y, Zhang YQ, Zhao ZQ. | Involvement of microglial P2X7 receptors and downstream signaling pathways in long-term potentiation of spinal nociceptive responses. | Brain Behav Immun. | 2010 Oct;24(7):1176-89. Epub 2010 Jun 8.
[18] Staniland AA, Clark AK, Wodarski R, Sasso O, Maione F, D'Acquisto F, Malcangio M. | Reduced inflammatory and neuropathic pain and decreased spinal microglial response in fractalkine receptor (CX3CR1) knockout mice. | J Neurochem. | 2010 Aug;114(4):1143-57. Epub 2010 May 28.
[19] Bishay P, Schmidt H, Marian C, Häussler A, Wijnvoord N, Ziebell S, Metzner J, Koch M, Myrczek T, Bechmann I, Kuner R, Costigan M, Dehghani F, Geisslinger G, Tegeder I. | R-flurbiprofen reduces neuropathic pain in rodents by restoring endogenous cannabinoids. | PLoS One. | 2010 May 13;5(5):e10628.
[20] Eijkelkamp N, Heijnen CJ, Willemen HL, Deumens R, Joosten EA, Kleibeuker W, den Hartog IJ, van Velthoven CT, Nijboer C, Nassar MA, Dorn GW 2nd, Wood JN, Kavelaars A. | GRK2: a novel cell-specific regulator of severity and duration of inflammatory pain. | J Neurosci. | 2010 Feb 10;30(6):2138-49.
[21] Inceoglu B, Jinks SL, Ulu A, Hegedus CM, Georgi K, Schmelzer KR, Wagner K, Jones PD, Morisseau C, Hammock BD. | Soluble epoxide hydrolase and epoxyeicosatrienoic acids modulate two distinct analgesic pathways. | Proc Natl Acad Sci U S A. | 2008 Dec 2;105(48):18901-6. Epub 2008 Nov 21.
[22] Inceoglu B, Jinks SL, Schmelzer KR, Waite T, Kim IH, Hammock BD. | Inhibition of soluble epoxide hydrolase reduces LPS-induced thermal hyperalgesia and mechanical allodynia in a rat model of inflammatory pain. | Life Sci. | 2006 Nov 10;79(24):2311-9. Epub 2006 Aug 2.
[23] De Alba J, Clayton NM, Collins SD, Colthup P, Chessell I, Knowles RG. | GW274150, a novel and highly selective inhibitor of the inducible isoform of nitric oxide synthase (iNOS), shows analgesic effects in rat models of inflammatory and neuropathic pain. | Pain. | 2006 Jan;120(1-2):170-81. Epub 2005 Dec 19.
[24] LaBuda CJ, Koblish M, Tuthill P, Dolle RE, Little PJ. | Antinociceptive activity of the selective iNOS inhibitor AR-C102222 in rodent models of inflammatory, neuropathic and post-operative pain. | Eur J Pain. | 2006 Aug;10(6):505-12. Epub 2005 Aug 24.
[25] Kim CF, Moalem-Taylor G. | Interleukin-17 contributes to neuroinflammation and neuropathic pain following peripheral nerve injury in mice. | J Pain. | 2011 Mar;12(3):370-83.
[26] Roh DH, Yoon SY, Seo HS, Kang SY, Han HJ, Beitz AJ, Lee JH. | Intrathecal injection of carbenoxolone, a gap junction decoupler, attenuates the induction of below-level neuropathic pain after spinal cord injury in rats. | Exp Neurol. | 2010 Jul;224(1):123-32. Epub 2010 Mar 11.
[27] Chiang CY, Li Z, Dostrovsky JO, Sessle BJ. | Central sensitization in medullary dorsal horn involves gap junctions and hemichannels. | Neuroreport. | 2010 Feb 17;21(3):233-7.
[28] Gao YJ, Ji RR | Targeting astrocyte signaling for chronic pain | Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics | 2010 Oct;7(4):482-93. | 10 Oct 2010
[29] Sabato AF. | Idiopathic breakthrough pain: a new hypothesis. | Clin Drug Investig. | 2010;30 Suppl 2:27-9. doi: 10.2165/1158410-S0-000000000-00000.
[30] O'Callaghan JP, Miller DB. | Spinal glia and chronic pain. | Metabolism. | 2010 Oct;59 Suppl 1:S21-6.
[31] Beggs S, Salter MW. | Microglia-neuronal signalling in neuropathic pain hypersensitivity 2.0. | Curr Opin Neurobiol. | 2010 Aug;20(4):474-80.
[32] Scholz J, Woolf CJ. | The neuropathic pain triad: neurons, immune cells and glia. | Nat Neurosci. | 2007 Nov;10(11):1361-8.
[33] Garrison CJ, Dougherty PM, Kajander KC, Carlton SM. | Staining of glial fibrillary acidic protein (GFAP) in lumbar spinal cord increases following a sciatic nerve constriction injury. | Brain Res. | 1991 Nov 22;565(1):1-7.
[34] Colburn RW, Rickman AJ, DeLeo JA. | The effect of site and type of nerve injury on spinal glial activation and neuropathic pain behavior. | Exp Neurol. | 1999 Jun;157(2):289-304.
[35] Zhuang ZY, Wen YR, Zhang DR, Borsello T, Bonny C, Strichartz GR, Decosterd I, Ji RR. | A peptide c-Jun N-terminal kinase (JNK) inhibitor blocks mechanical allodynia after spinal nerve ligation: respective roles of JNK activation in primary sensory neurons and spinal astrocytes for neuropathic pain development and maintenance. | J Neurosci. | 2006 Mar 29;26(13):3551-60.
[36] Dierks RE, Newman JA, Pomeroy BS. | Characterization of avian mycoplasma. | Ann N Y Acad Sci. | 1967 Jul 28;143(1):170-89.
[37] Sweitzer SM, Colburn RW, Rutkowski M, DeLeo JA. | Acute peripheral inflammation induces moderate glial activation and spinal IL-1beta expression that correlates with pain behavior in the rat. | Brain Res. | 1999 May 22;829(1-2):209-21.
[38] Mika J. | Modulation of microglia can attenuate neuropathic pain symptoms and enhance morphine effectiveness. | Pharmacol Rep. | 2008 May-Jun;60(3):297-307.
[39] Zhang J, De Koninck Y. | Spatial and temporal relationship between monocyte chemoattractant protein-1 expression and spinal glial activation following peripheral nerve injury. | J Neurochem. | 2006 May;97(3):772-83. Epub 2006 Mar 8.
[40] Miyoshi K, Obata K, Kondo T, Okamura H, Noguchi K. | Interleukin-18-mediated microglia/astrocyte interaction in the spinal cord enhances neuropathic pain processing after nerve injury. | J Neurosci. | 2008 Nov 26;28(48):12775-87.
[41] Haydon PG. | GLIA: listening and talking to the synapse. | Nat Rev Neurosci. | 2001 Mar;2(3):185-93.
[42] Rohlmann A, Laskawi R, Hofer A, Dobo E, Dermietzel R, Wolff JR. | Facial nerve lesions lead to increased immunostaining of the astrocytic gap junction protein (connexin 43) in the corresponding facial nucleus of rats. | Neurosci Lett. | 1993 May 14;154(1-2):206-8.
[43] Abe M, Takahashi M, Ono K, Hiraoka M. | [Cancer and radiotherapy. (4). Hypoxic cell sensitizers and hyperthermia combined with radiation in cancer treatment]. | Iyodenshi To Seitai Kogaku. | 1982 Jun;20(3):203-9.