Neuroimmune Modulation of Chronic Pain after Spinal Cord Injury

Bryan C. Hains, Ph.D.

Yale University School of Medicine

Funded in September, 2006: $200000 for 3 years
LAY SUMMARY . ABSTRACT . BIOGRAPHY . FINDINGS . SELECTED PUBLICATIONS .

LAY SUMMARY

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How Do Immune Microglial Cells Contribute to Chronic Pain after Spinal Cord Injury?

Investigators will explore, at the molecular level, how immune microglial cells in the spinal cord interact with nerve cells to perpetuate chronic pain following spinal cord injury.  The study may accelerate initiation of clinical trials of an experimental drug to block this interaction and prevent or treat this pain.

Following spinal cord injury (SCI), pain-processing sensory neurons undergo electrophysiological changes that result in hyperexcitability of neurons and intractable, chronic pain.  The neurons fire spontaneously without stimulation, respond to non-painful stimuli, and react inordinately to weak stimuli.  Preliminary evidence from the Yale researchers indicates that immune microglial cells that reside in the spinal cord play a key role in maintaining this neuronal hyperexcitability and chronic pain. Following experimental SCI in laboratory animals, microglial cells there proliferate extensively.  They influence how the neurons process sensory information and contribute to maintaining the neurons’ hyperexcited state and chronic pain.  Moreover, the researchers found, by selectively inhibiting microglial activation with the experimental drug minocycline, they can reduce hyperexcitability and pain-related behaviors in animals with SCI.   

Now, the researchers will explore the molecular processes that underlie the immune microglia’s contribution to chronic pain after SCI.  They hypothesize that spinal cord microglia are abnormally activated following SCI by “signaling” molecules. The activated microglia induce changes in sodium channels.  These changes produce sodium currents.  The sodium currents then generate neuronal hyperexcitability.  If this is the case, using the drug minocycline to block the signaling molecules might prevent this process and the resulting intractable pain.

Significance:  This study may reveal the molecular interactions of nerve and immune cells that produce intractable pain following spinal cord injury and lead to clinical trials of an experimental drug to block these interactions.  This would be a significant therapeutic advance.

ABSTRACT

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Neuroimmune Modulation of Chronic Pain after Spinal Cord Injury

The majority of patients with traumatic spinal cord injury (SCI) report moderate to severe chronic pain syndromes that persist indefinitely and are resistant to current therapeutic approaches (Finnerup et al., 2001; Siddall et al., 2003). This study focuses on the interaction between the nervous and immune systems in contributing to chronic pain after SCI. Similar to what is observed clinically (Chang, 2006), we have recently shown that after experimental SCI, neuroimmune cells called microglia undergo morphological and functional activation in the spinal cord and dynamically maintain abnormal hyperexcitability of spinal cord pain processing neurons and pain-related behaviors (Hains and Waxman, 2006). Furthermore, we demonstrated the effectiveness of the microglia-inhibiting drug minocycline in reducing these pain-related phenomena after SCI.

The molecular mechanisms underlying the contribution of microglia to chronic pain after SCI are not yet established, and an understanding of these will improve our ability to treat pain. Thus, our objective is to elucidate mechanisms linking microglia to pain.

Our currently proposed experiments will test the following hypotheses:

Hypothesis 1: Molecular reconfiguration, i.e., the abnormal activation of spinal cord microglia, contributes to the generation of chronic pain following SCI. Using pharmacological, electrophysiological, and immunohistochemical-imaging techniques, Specific Aim 1 will map the temporal and spatial sequence of microglial activation, neuronal hyperexcitability, and pain and, utilizing pharmacological blockade, will determine what role microglia play in the development and/or maintenance of chronic pain.

Hypothesis 2: Specific upstream signaling molecules trigger the activation of microglia that leads to chronic hyperexcitability of pain-signaling neurons, providing a molecular target that can control or prevent development of this hyperexcitability. Using pharmacological and imaging techniques, Specific Aim 2 will determine the role of p38 and ERK MAP kinases in the activation of microglia after SCI.

Hypothesis 3: Microglial activation induces alterations in sodium channel expression (specifically Nav1.3) that contribute to the generation of pain-related sodium currents and hyperexcitability after SCI. Specific Aim 3 will determine the link between microglial activation and expression of the Nav1.3 sodium channel, pain-related sodium currents, and hyperexcitability, after SCI.

INVESTIGATOR BIOGRAPHIES

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Bryan C. Hains, Ph.D.

Dr. Hains is currently an Assistant Professor of Neurology at Yale University. He joined the Yale faculty after coming as a post-doctoral fellow to work with Dr. Stephen Waxman. He completed his graduate training with Dr. Claire Hulsebosch at the University of Texas Medical Branch, following undergraduate work at Stetson University. Work in his laboratory has focused on understanding molecular mechanisms underlying the generation and maintenance of chronic pain after spinal cord injury (SCI).

FINDINGS

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Lay Results:
Neuroimmune cells called microglia have been demonstrated to contribute to pain after injury to peripheral nerves. After nerve injury, microglia become activated within the spinal cord and contribute to the development phase of pain. In our laboratory, we have very recently shown that after SCI, spinal microglia become activated and contribute, in real-time, to hyperexcitability of pain-processing neurons and chronic pain. We have now elucidated the molecular mechanisms linking microglia to pain by showing that specific upstream mechanisms trigger the activation of microglia.

Scientific Results:
We have characterized the timing of microglial activation in both the spinal cord dorsal horn and thalamus after SCI, and found a correlative relationship between activation and degree of pain (as measured by nociceptive thresholds) that developed in these animals. With selective blockade of microglia with minocycline and other molecules that specifically target microglia, we can reduce neuronal hyperexcitability and pain-related behaviors. We next identified ERK1/2 MAP kinase as an important intracellular signaling molecule that helps to control microglial activation and production of PGE2, a microglia-neuron signaling molecule that once released by activated microglia, signals spinal cord neurons to become hyperexcitable. This is the first clear elucidation of a tightly controlled signaling pathway between microglial cells and neurons in the spinal cord induced by injury.

In addition, we have characterized the activation patterns of microglial cells in the thalamus after SCI. This work has identified a novel signaling mechanism that remotely triggers microglial activation in the ventral posterolateral nucleus (VPL) of the thalamus, a major relay center for nociceptive signals on the way to the brain. We show that SCI causes the release of the chemokine CCL21 in the thalamus of injured animals, which causes microglia to become activated. Our gain and loss of function experiments clarify the role of CCL21 and exclude other cytokines in this process. We are now learning how sodium channels contribute to microglial homing and activation after injury.

SELECTED PUBLICATIONS

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Zhao P., Waxman S.G., and Hains B.C.  Modulation of thalamic nociceptive processing after spinal cord injury through remote activation of thalamic microglia by cysteine cysteine chemokine ligand 21.  J Neurosci. 2007 Aug 15;27(33):8893-902.

Zhao P., Waxman S.G., and Hains B.C.  Extracellular signal-regulated kinase-regulated microglia-neuron signaling by prostaglandin E2 contributes to pain after spinal cord injury.  J Neurosci. 2007 Feb 28;27(9):2357-68.