Targeting Tiam1-mediated synaptic plasticity for the relief of opioid tolerance

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PROJECT SUMMARY/ABSTRACT The major objective of this proposal is to identify Tiam1-mediated synaptic plasticity as the molecular mechanism underlying opioid tolerance and validate Tiam1 as a promising therapeutic target in the relief of tolerance. Opioid pain medications remain the gold standard for the treatment of moderate to severe perioperative and chronic pain. However, over time, opioid use can result in tolerance, which is a primary driver for opioid misuse and overdose that directly contribute to increased morbidity and mortality. Opioid action at µ opioid receptors (MORs) expressed by nociceptors not only acutely depresses nociceptive transmission, but can induce glutamate release and brain-derived neurotrophic factor (BDNF) release in the spinal dorsal horn, which initiate downstream events that trigger the molecular, synaptic, and network-level adaptations that drive tolerance. Among these, synaptic plasticity is assumed to be the key determinant in opioid tolerance. However, the molecular mechanisms that trigger synaptic plasticity remain unclear. Rho GTPases, activated by guanine nucleotide exchange factors (GEFs) and inhibited by GTPase-activating proteins (GAPs), play important roles in dendritic spine morphogenesis and synaptic plasticity by controlling actin cytoskeleton remodeling in response to extracellular cues. We and others previously identified the Rac1-GEF Tiam1 as a critical regulator of dendrite, spine, and synapse development, which couples synaptic N-methyl-D-aspartate receptors (NMDARs) and TrkB receptors to Rac1 signaling-mediated actin cytoskeleton remodeling during brain development. In preliminary studies, we found that Tiam1 is activated in the spinal dorsal horn in response to chronic morphine treatment and it modulates synaptic remodeling by promoting chronic morphine-induced actin polymerization and synaptic NMDAR expression. Genetic deletion of Tiam1, deletion of Tiam1 from spinal dorsal horn neurons, or pharmacological blockade of Tiam1 signaling prevents the development of morphine tolerance. Moreover, combination morphine and Tiam1 inhibitor therapy reduce morphine tolerance in completer Freund’s adjuvant (CFA) inflammatory pain management. In this proposal, we will use a multidisciplinary approach to test our central hypothesis that Tiam1 links opioid-induced activation of synaptic NMDARs and/or TrkB receptors to Rac1 signaling in spinal dorsal horn neurons, resulting in synaptic structural and functional plasticity via actin cytoskeleton reorganization and NMDAR stabilization, which together underlies opioid tolerance. Moreover, we will determine whether blocking Tiam1-mediated synaptic plasticity with Tiam1 inhibitor or antisense oligonucleotides (ASOs) produces the long- lasting relief of opioid tolerance. The contribution of this proposed research is significant because it will uncover a previously unknown mechanism that underlies opioid tolerance and will provide a promising therapeutic target for the long-lasting relief of opioid tolerance.