 |
Neuronal and Neural-Glial Signaling Mechanisms in Pain Neuroplasticity
Summary: Michael Salter is interested in identifying and characterizing the cellular and molecular signaling processes that cause neuroplasticity and in applying this knowledge to the management of chronic pain in humans.
Chronic pain has been labeled the silent health crisis, afflicting tens of millions of people worldwide. It is known that pain causes more disability than cancer and heart disease, and the annual monetary cost of treatment and lost productivity hovers around $100 billion in the United States alone. Once considered simply a response to disease or injury, we now recognize that chronic pain is a group of mechanistically separable nervous system disorders produced and maintained by a variety of abnormal cellular signaling processes. Aberrations in cell signaling occur not only in neurons but also in glial cells and in the interactions between neurons and glia in the central nervous system. We are interested in the molecular mechanisms that produce the abnormalities in signaling that lead to chronic pain. We are using molecular, biochemical, electrophysiological, behavioral, and genetic approaches to understand these mechanisms. One of our aims is to develop tools to interfere with or correct the abnormal signaling. Such tools may form the basis for novel mechanism-based therapeutics for chronic pain.
NMDA receptor upregulation in pain plasticity. The N-methyl D-aspartate (NMDA) receptor is one of the principal types of receptor for the neurotransmitter glutamate and mediates the vast majority of excitatory synaptic transmission in the central nervous system. By virtue of their permeability to Ca2+, NMDA receptors have critical roles in numerous physiological and pathological processes in the CNS; in particular, NMDA receptors are strongly implicated in the pathogenesis of chronic pain. Our previous studies have shown that the activity of NMDA receptors is strongly upregulated by phosphorylation by the protein tyrosine kinase Src and that this upregulation is critical for enhancing excitatory synaptic transmission. The NMDA receptor is a multiprotein complex that comprises core receptor subunits, which contain the ligand-binding sites and form the ion conductance pathway and various associated scaffolding and regulatory proteins. Recently, we discovered that Src is anchored to the NMDA receptor complex by interacting with an adaptor protein ND2. Our future work is directed to characterizing Src-ND2-NMDA receptor interactions. By developing molecules that interfere with these interactions, we will be able to dissociate Src from the receptor complex, thereby preventing the upregulation. We will test the hypothesis that such molecules, when administered to animals, will reverse behavioral, electrophysiological, and biochemical signs of pain plasticity.
Microglia-neuron signaling in nerve-injury-induced pain plasticity. Glial cells were historically considered to play primarily housekeeping roles in the nervous system. However, this view has changed radically in the last half decade, particularly regarding the role of microglia in pain resulting from peripheral nerve injury. In the healthy central nervous system, microglia are not dormant as once thought, but act as sentries that react rapidly to various stimuli that threaten physiological homeostasis. Our studies have shown that microglia in the dorsal horn of the spinal cord play a causal role in neuropathic pain behaviors that result from peripheral nerve injury, and we have discovered a neuron-microglia-neuron signaling pathway within the dorsal horn that is critical for establishing and maintaining these pain behaviors. The pathway begins with the P2X4 receptor, a subtype of purinergic receptor, which is upregulated in dorsal horn microglia after peripheral nerve injury. The receptors are tonically stimulated by extracellular ATP leading to release of brain-derived neurotrophic factor (BDNF). BDNF suppresses inhibition of output neurons in the dorsal horn pain-processing network, suppression of which comes about by raising the concentration of chloride ions within these neurons. Our future work is directed to determining the molecular mechanisms in microglia by which stimulating P2X4 receptors leads to release of BDNF. We aim to develop molecules that inhibit this release of BDNF and test these molecules in models of pain plasticity. We are also interested in discovering genes that regulate the P2X4 receptor-BDNF-chloride ion signaling pathway.
Major gaps remain in our ability to treat chronic pain. This is particularly the case for neuropathic pain, which is typically resistant to all forms of therapy presently available. Therefore, there is a critical need for novel therapies. We believe that providing new insights into cell signaling aberrations in neuroplasticity will be a foundation for developing novel mechanism-based strategies for treating pain. The signaling pathways we are studying are implicated in numerous processes in the CNS ranging from development and learning, to epilepsy, schizophrenia, stroke, and neurodegeneration. The implications of our work thus extend beyond chronic pain to broad areas of CNS function and dysfunction.
Last updated January 2007
|
|
|
|
