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Morning Plenary II: Sex and Pain: It’s Not Always about the Differences
Plenary
Session Description
Speaker: Mike Salter
Advances in transcriptomics in the dorsal horn of the spinal cord have led to cataloging diverse cellular pathways and transcriptomic alterations in response to peripheral nerve injury, but have focused on phenomenology and classifying transcriptomic changes. Recently, we took a purposeful approach of exploring the possibility of identifying pain-relieving drugs by simultaneously looking not just between sexes in a single species but between sexes in two species. Surprisingly, given the massive emphasis on sex differences across biomedical sciences we found that there are many more commonalities than differences between sexes and across species in the gene expression changes produced in the spinal dorsal horn. The key was then determining whether there was a way to use this information to make testable predictions about drug response. We used pathway analysis to define the molecular network of proteins encoded by the genes in which transcript expression had changed. Because of the power of our four-way analysis we not only identified known pathways – which validated our analyses – but we discovered connections and hubs not seen previously. With this information we developed a workflow through mining the database of FDA-approved drugs and interrogating this with the common nodes and hubs we had identified. The top hit from this analysis was fostamatinib, the molecular target of which is the non-receptor tyrosine kinase SYK, which our analysis had identified as a key node in the interactome. We found that intrathecally administrating the active metabolite of fostamatinib, R406, and another SYK inhibitor P505-15, reversed pain hypersensitivity and, as our analysis predicted, did this in both sexes. Thus, we identified and showed the efficacy of agents that could not have been previously predicted to have analgesic properties.
Learning Objectives:
1. Upon completion, the participant will be better able to understand processing, plasticity and transmission of nociceptive information in the central nervous system.
2. The participant will be better able to appreciate the critical role of glia-neuron interactions in the pathological pain neuroplasticity.
3. The participant will be better able to understand sex differences and sex similarities in mechanisms underlying pain.