Peripheral neuropathic pain arises from diverse changes in the peripheral and central nervous systems that include a reciprocal interaction between the immune and nervous systems. We find from a microarray expression profile analysis that immunologic gene activation in microglia in the dorsal horn is a major common feature of rodent peripheral neuropathic pain models and includes most prominently a local induction of components of the complement cascade in the spinal cord. Blocking the complement cascade by depleting its components in rat spinal cord or in mutant mice reduces, moreover, pain hypersensitivity in neuropathic pain models. Based on this, we hypothesize that peripheral nerve injury results in production by injured sensory neurons of a signal that is transported to the central terminals of the afferents in the dorsal horn/spinal nucleus of the trigeminal where it acts on microglia to induce complement genes. Activation of the classical complement cascade pathway locally in the superficial dorsal horn results in production of C5a anaphylatoxin and assembly of the membrane attack complex (MAC). C5a, we hypothesize, acts via the C5a receptor to alter microglial and neuronal function, while MAC, we propose, is specifically assembled on those neurons that do not express CD59, an endogenous inhibitor of MAC assembly, and by increasing calcium influx in the neurons, increases their excitability and vulnerability to apoptosis. To test this hypothesis we propose to determine: 1) Which peripheral stimuli;activity, inflammation or axonal damage, induce complement genes in microglia in the dorsal horn 2) Which cytokines and chemokines induce complement genes in microglia, 3) The role of the complement cascade in producing neuropathic pain and specifically whether C5a or assembly of the MAC is the prime effector of the pain, and 4) If complement activation alters excitability in dorsal horn neurons sufficiently to produce excitotoxic apoptosis. We will use this information to devise and test novel treatment strategies for somatic and facial neuropathic pain based either on blocking complement gene induction in microglia or complement cascade activation in the nervous system.
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