The development of persistent pain conditions in the setting of tissue or nerve injury results to a great extent from significant reorganization of CNS circuits. These changes contribute to a central sensitization/hyperexcitability state that underlies allodynia and hyperalgesia, the hallmarks of persistent pain conditions. Many studies have focused on the injury-induced sprouting of primary afferents and on the physiological properties of altered """"""""pain"""""""" response neurons in the spinal cord dorsal horn, but there is little information about the tissue and nerve-injury-induced local and long distant circuit changes that occur, in the spinal cord and at more rostral sites. Recently, we developed a transgenic mouse in which wheat germ agluttinin (WGA) synthesis, anterograde transport and transneuronal labeling of complex circuits can be triggered from neurons in any region of the brain or spinal cord, during development or in the adult. In the present proposal, we will use these mice and others that we will generate to study the development and adult organization of CNS circuits engaged by small diameter primary afferent nociceptors and to study their modifications after tissue or nerve injury. Through a highly novel modification of this transneuronal tracing method, in which the tracer is induced in primary afferent neurons only if their peripheral axon has been transected, we also propose to study nerve injury-induced reorganization of CNS nociceptive circuits. Both the normal circuits and the reorganization of circuits engaged by small and large diameter axons will be studied in these experiments. Finally, through the development of BAC transgenics, we propose to begin a detailed analysis of the circuits that arise from neurochemically distinct primary afferent nociceptors. Taken together, these studies will provide an entirely new anatomical perspective on the circuits that process the nociceptive messages resulting in acute and persistent pain.
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