Neuronal and microglial mechanisms of neuropathic pain

Neuronal and microglial mechanisms of neuropathic pain | Mol Brain. 2011

Neuropathic pain is generally defined as a chronic pain state resulting from peripheral and/or central nerve injury

Neuronal mechanisms of neuropathic pain, especially synaptic plasticity, are the major focus of many investigators.

N-methyl-D-aspartate (NMDA) receptor dependent synaptic plasticity at the spinal and cortical levels is believed to contribute to enhanced sensory responses after injury.

Glial cells, including astrocytes and microglia, have recently been implicated in neuropathic pain. These glial cells form close interactions with neurons and thus may modulate nociceptive transmission under pathological conditions.  

In this review, we present recent progress in the study of neuronal and microglial mechanisms underlying neuropathic pain. We propose that activity-dependent neuronal plasticity is a key target for treatment in neuropathic pain.

Glial mechanisms for neuropathic pain

Our understanding of pathological pain has evolved from solely neuronal mechanisms to neuron-glial interactions. In particular, astrocytes and microglia act as possible modulators of neuropathic pain by releasing a number of cytokines and chemokines.

Astrocytes and microglia play different roles in relation to neuronal activity; however, they do have some overlapping functions in mediating CNS innate immune response.

Both astrocytes and microglia are activated in neuropathic pain, and their activation leads to pro-inflammatory responses with pathological effects, such as neuronal hyperexcitability, neurotoxcity and chronic inflammation. The roles of astrocytes in neuropathic pain have been summarized in a number of recent reviews. Here we will focus on the role of microglia in neuropathic pain

Targeting microglia for neuropathic pain

The therapeutic benefits of targeting microglial molecules may reside in the fewer side effects on acute pain sensation, as most of these molecules are upregulated predominantly in activated microglia.

A few immunosuppressive compounds are being developed to attenuate microglial activation and inflammation and have proven to be effective in animal models of neuropathic pain

For example, minocycline, a second-generation tetracycline antibiotic, selectively targets microglia to globally inhibit metabolism. At a cellular level, this drug suppresses the expression of inducible nitric oxide synthase, the production of pro-inflammatory cytokines, and p38 phosphorylation in microglia; at the behavioral level, it is therapeutically effective in animal models of neuropathic pain

Minocycline can cross the blood-brain barrier and is under clinical investigation as a treatment for multiple sclerosis and amyotrophic lateral sclerosis

However, it should be noted that minocycline also has a variety of side effects, including fever, stomach pain, effects on vision, drowsiness, and even psychiatric problems

Microglia and inflammatory pain

Recent studies have shown that activation of microglial cells in the spinal cord may contribute to inflammatory pain.

the involvement of microglia in inflammatory pain is dependent on the inflammatory stimulus administered.

Conclusions and future directions

After two decades of searching, there is still a lack of effective treatments for neuropathic pain.

Understanding neuronal and glial mechanisms in neuropathic pain offers hope of developing painkillers targeting NMDA receptors or microglia-related molecules

Or, we could continue using opioids. Those that suggest we use should use other medications, like these described, clearly don’t care much about our ability to think. They assume this is a necessary sacrifice, when it can be easily avoided by giving opioids.

One obvious challenge for most treatments is their side effects on cognition. NMDA receptors play important roles in various cognitive functions, while microglia survey the microenvironment in the brain. Therefore, the use of such drugs for neuropathic pain is likely to require balancing a gain and loss of brain function.

It may be inevitable that some cognitive functions must be sacrificed in order to control severe pain in some patient populations.

What? It seems bizarre that we are being urged to “sacrifice some cognitive functions” just so we can get some pain control without using opioids.

Recent studies from both human and animal consistently demonstrate that forebrain areas are important for processing pain perception and the unpleasantness of somatosensory stimuli.

Therefore, selectively targeting NMDA receptors in the forebrain would provide new insights into treatment of neuropathic pain

Also see Microglial Regulation of Neuropathic Pain | J Pharmacol Sci 2013

 

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