Neuropathic pain is related to central glial activation, and this activation depends on nerve inputs from the site of injury and release of various enodgenous mediators. Various immune cells migrate into the central nervous system and produce inflammatory mediators that enhance central glial responses to injury.

Cytokines and glia 

Cytokines such as interleukin-1beta released from glia may facilitate pain transmission via coupling to glutamate receptors. This  neuron-glia interacton plays an important role in glial activation, and cytokine production froms one of the factors leading to neuropathic phenomena, such as hyperalgesia and hyperpathia. ^[1]

Activation of satellite glia in sensory ganglia may also play an important role in the development of the neuropathic symptoms such as hyperalgesia and allodynia. Chemical mediators derived from both neurons and satellite glia  also results in changes in central pain-signaling neurons, central sensitization. The focus of the present review is on the contribution of the activation of satellite glia in sensory ganglia ^[2]

Neuron-glia bidirectional relationships thus are involved in the modulation of synaptic activity and pain facilitation. ^[3] 

In the National Headache Foundation’s 7, theh Headache Research Summit October 16, 2009 there is a clear article of Linda Watkins, PhD , title:- Listening and Talking to Neurons: Clinical Implications of Glial Dysregulation of pain and Opioid actions. 

Here some verbatim quotes from her review: 

Concepts of chronic pain and opioid actions have evolved in recent years.  Among the 

most important developments has been the recognition that proinflammatory activation 

of glia—microglia and astrocytes—in the central nervous system (CNS) can be 

beneficial or harmful, depending on the conditions under which activation occurs.  Glial 

activation is beneficial when it helps to resolve CNS immune challenges and facilitate 

neuroprotection.  In chronic pain states and during opioid exposure, however, activated 

glia are proinflammatory, and they enhance pain and contribute to opioid tolerance, 

dependence, reward, and respiratory depression.1-4   

Astrocytes, developmentally derived from the neuroectoderm, are the most abundant 

glial cell type in the CNS.2  In addition to their neuron-supportive functions, astrocytes 

also directly alter neuronal communication because they completely encapsulate 

synapses and are in close contact with neuronal somas.5  Resident microglia are bone 

marrow-derived hematopoietic cells that invade the CNS during embryonic development 

and are never replenished.2  Resident microglia are known to survey the CNS and to 

proliferate rapidly on activation, exerting both inflammatory and anti-inflammatory 

effects.6 

Recognition that activation of microglia and astrocytes is critical to pain enhancement is 

based on evidence from cell culture, anatomy, and in vivo studies.1,7  Cell culture 

studies provided the first evidence that spinal cord glia are responsive to pain-related 

neurotransmitters when they showed that the spinal cord is one of the few CNS sites 

where substance P activates astrocytes.  Anatomy studies characterized the process of 

glial activation—(a) peripheral nerve injury triggers spinal amplification; in the spinal 

cord dorsal horn (b), glia and other immunocompetent cells amplify pain signals by 

releasing microglial and astrocyte activators (c)1—and demonstrated that drugs used for 

neuropathic pain block glial activation.  

Several laboratories have reported activation of glia and release proinflammatory 

products in response to opioids.8-10  In vivo, opioid-induced glial activation has been 

inferred from morphine-induced upregulation of microglial and astrocytic activation 

markers [30,31] and release of proinflammatory cytokines and chemokines9,11-13; 

enhanced morphine analgesia by glial activation inhibitors11,14,15 and proinflammatory 

cytokine blockers9,16; and opioid-induced selective activation of microglial p38 MAPK 

and enhanced morphine analgesia by p38 MAPK inhibitors.17  In vitro studies have 

confirmed that opioids act directly on glia.14,18-20  

Opioids were once assumed to affect glia only through opioid receptors.  But it is now 

known that the effects can occur via non-stereoselective activation of toll-like receptor 4 

(TLR4), a glial receptor that also reverses neuropathic pain and mitigates opioid 

dependence and reward.1  Moreover, a novel antagonism of TLR4 by (+)- and (–)- 

isomer opioid antagonists appears to potentiate antiallodynic and morphine analgesia.  

TLR4, one of multiple receptor-mediated activation pathways, facilitates glial activation 

and neuroexcitability under conditions of chronic pain and in response to opioids.1  

It appears that glia-targeting agents have begun to make an important transition from 

experimental compounds to approved medications.  Robust evidence in rodent 

models21,22 has prompted the US Food and Drug Administration to clear ibudilast and 

propentofylline for Phase 2 clinical trials in neuropathic pain, with ibudilast also being 

cleared for evaluation as an opioid adjuvant.  Ibudilast, a known TLR4 signaling 

inhibitor,1 has been used for the treatment of asthma and post-stroke dizziness, and 

propentofylline has been tested in humans as far as Phase 3 trials for treating 

Alzheimer’s disease. 

 Research has shown that glia are key contributors to pathological and chronic pain 

mechanisms, a discovery that may soon yield safe, effective medications that enhance 

the ability of opioids to relieve pain while reducing their risk of side effects and abuse.  

Given the high prevalence of chronic pain and the partial efficacy of currently available 

treatment options, new strategies to manipulate neuron-glia interactions in pain 

processing hold considerable promise. 

Source: http://www.headaches.org/pdf/HeadacheResearchSummit/Linda_Watkins.pdf

References 

1. Watkins LR, Hutchinson MR, Rice K, Maier SF.  The "toll" of opioid-induced glial 

activation:  improving the clinical efficacy of opioids by targeting glia.  Trends 

Pharmacol Sci.  2009;30:581–591. 

2. Milligan ED, Watkins LR.  Pathological and protective roles of glia in chronic pain.  

Nature Neuroscience Reviews.  2009;10:23–36. 

3. Watkins LR, Hutchinson MR, Ledeboer A, Wieseler-Frank J, Milligan ED, Maier SF. 

Norman Cousins Lecture.  Glia as the "bad guys":  implications for improving clinical 

pain control and the clinical utility of opioids.  Brain Behav Immun. 2007;21:131–146. 

4. Hutchinson MR, Bland ST, Johnson KW, Rice KC, Maier SF, Watkins LR.  Opioid- 

induced glial activation:  mechanisms of activation and implications for opioid 

analgesia, dependence, and reward.  Scientific World Journal.  2007;7:98–111.  

5. Haydon PG.  Glia:  listening and talking to the synapse.  Nat Rev Neurosci.  

2001;2:185–193.     

6. Romero-Sandoval EA, Horvath RJ, Deleo JA.  Neuroimmune interactions and pain:  

focus on glial-modulating targets.  Curr Opin Investig Drugs.  2008;9:726–734.  

7. Watkins LR, Maier SF. Glia and pain:  past, present and future.  In Merskey H et al, 

eds.  The Paths of Pain 1975-2005.  Seattle, WA; IASP Press; 2005:165–176.  

8. Watkins LR, Hutchinson MR, Johnston IN, Maier SF.  Glia:  novel counter-regulators 

of opioid analgesia.  Trends Neurosci.  2005;28:661–669. 

9. Hutchinson MR, Coats BD, Lewis SS, et al.  Proinflammatory cytokines oppose 

opioid-induced acute and chronic analgesia.  Brain Behav Immun.  2008;22:1178– 

1189. 

10. Tawfik VL, LaCroix-Fralish ML, Nutile-McMenemy N, DeLeo JA.  Transcriptional and 

translational regulation of glial activation by morphine in a rodent model of 

neuropathic pain.  J Pharmacol Exp Ther.  2005;313:1239–1247. 

11. Hutchinson MR, Lewis SS, Coats BD, et al. Reduction of opioid withdrawal and 

potentiation of acute opioid analgesia by systemic AV411 (ibudilast).  Brain Behav 

Immun.  2009;23:240–250.  

12. Johnston IN, Milligan ED, Wieseler-Frank J, et al.  A role for proinflammatory 

cytokines and fractalkine in analgesia, tolerance, and subsequent pain facilitation 

induced by chronic intrathecal morphine.  J Neurosci.  2004;24:7353–7365.  

13. Raghavendra V, Tanga FY, DeLeo JA, et al.  Attenuation of morphine tolerance, 

withdrawal-induced hyperalgesia, and associated spinal inflammatory immune 

responses by propentofylline in rats.  Neuropsychopharmacology.  2004;29:327– 

334.   

14. Hutchinson MR, Northcutt AL, Chao LW, et al.  Minocycline suppresses morphine- 

induced respiratory depression, suppresses morphine-induced reward, and 

enhances systemic morphine-induced analgesia.  Brain Behav Immun.  

2008;22:1248–1256. 

15. Cui Y, Liao XX, Liu W, et al.  A novel role of minocycline:  attenuating morphine 

antinociceptive tolerance by inhibition of p38 MAPK in the activated spinal microglia.  

Brain Behav Immun.  2008;22:114–123. 

16. Shavit Y, Wolf G, Goshen I, Livshits D, Yirmiya R.  Interleukin-1 antagonizes 

morphine analgesia and underlies morphine tolerance.  Pain.  2005;115:50–59.  

National Headache Foundation’s 7th Headache Research Summit October 16, 2009 

Linda Watkins, PhD - Listening and Talking to Neurons: Clinical Implications 

of Glial Dysregulation of pain and Opioid actions 

17. Cui Y, Chen Y, Zhi JL, Guo RX, Feng JQ, Chen PX.  Activation of p38 mitogen- 

activated protein kinase in spinal microglia mediates morphine antinociceptive 

tolerance.  Brain Res.  2006;1069:235–243. 

18. Narita M, Miyatake M, Narita M, et al.  Direct evidence of astrocytic modulation in the 

development of rewarding effects induced by drugs of abuse.  

Neuropsychopharmacology.  2006;31:2476–2488.  

19. Horvath RJ, DeLeo JA.  Morphine enhances microglial migration through modulation 

of P2X4 receptor signaling.  J Neurosci.  2009;29:998–1005.  

20. Takayama N, Ueda H.  Morphine-induced chemotaxis and brain-derived 

neurotrophic factor expression in microglia.  J Neurosci.  2005;25:430–435.     

21. Ledeboer A, Hutchinson MR, Watkins LR, Johnson KW.  Ibudilast (AV-411).  A new 

class therapeutic candidate for neuropathic pain and opioid withdrawal syndromes.  

Expert Opin Investig Drugs.  2007;16:935–950.  

22. Watkins LR, Maier SF.  Glia:  a novel drug discovery target for clinical pain.  Nat Rev Drug Discov.  2003;2:973–985.    

Jan M. Keppel Hesselink, MD, PhD, september 2010

Referenties