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.