Over the past 15 years, our laboratory has been particularly involved in the study the role of CGRP in pain and tolerance to the anti-nociceptive effects of opiates. CGRP is the most abundant peptide (far more than the neurokinins) expressed in primary afferents making it an interesting therapeutic target. Our findings indicate that a peptide CGRP antagonist can markedly delay or fully block the development of tolerance to opiates in acute models of pain in rodents. Intracellular mechanisms likely involve MAP kinases and CREB, but not PKC and akt kinases. We now wish to establish if this CGRP peptide antagonist can be similarly effective in chronic models of pain, and in the development of tolerance to opiates in these models. A collaboration with chemists is also planned to develop non-peptide CGRP antagonists that will be more amenable to clinical studies. Using molecular approaches (DNA chip arrays and proteomics) we also propose to study families of genes that are altered post-CGRP antagonists treatments, results from such experiments possibly uncovering new therapeutic targets.