Sandra M. Garraway

Garraway explored how primary afferent stimulation impacted plasticity, in the form of long term potentiation (LTP) or long term depression (LTD), of the DDH neurons.[5] LTP and LTD had only just been identified in the spinal cord, and Garraway discovered that LTP and LTD can also be induced in the DDH neurons with even lower frequency afferent stimulation.[5] She also found that in rats aged P9-16, only LTP could be produced.[5] These findings shed light on potential mechanisms of prolonged pain sensation, or chronic pain, as LTD and LTP present forms of long lasting cellular memory.[5] Garraway then explored the descending serotonergic projections that modulate the DDH neurons.[6] She used an in vitro slice preparation of DDH neurons and applied various serotonin receptor ligands to assess the effects of modulation at each serotonin receptor subtype in the primary afferent neurons.[6] She found that the afferents are in fact modulated by several serotonin receptors and that 5-HT1A modulation facilitates evoked responses whereas 5-HT7 depressed evoked responses.[6] Her work was one of the first identifications of the presence and effects of 5-HT7 receptors in the spinal cord and her results showed promise in using selective serotonin receptor targeting in the modulation of pain.[6] Garraway then further characterized monoamine transmitter effects in the spinal cord in comparison with the actions of acetylcholine.[7] She found dopamine, serotonin, and norepinephrine depressed postsynaptic potentials and did not modify the passive membrane properties of neurons whereas acetylcholine lead to increased EPSP amplitude.[7] Further, Garraway found that the addition of both serotonin and norepinephrine simultaneously could evoke even greater depression than either in isolation.[7]

After completing her graduate studies in 2000, Garraway moved to the United States to pursue her postdoctoral training at the State University of New York at Stony Brook.[8] Studying under Lorne Mendell, she explored the implications of brain-derived neurotrophic factor (BDNF) on central sensitization and exaggerated pain states.[9] Garraway found that BDNF signalling in the dorsal horn led to facilitation, and the initiation of this facilitation was dependent on NMDA receptor signalling and phospholipase C.[9] Garraway then explored how spinal injury impacted the effects of BDNF on lamina II neurons.[10] She found that after neonatal spinal injury, BDNF was no longer able to facilitate dorsal-root EPSCs.[10] After discovering that NMDA receptor dysfunction was not the cause for decreased responses, she elucidated that expression of dysfunctional trkB might be contributing to the decline in BDNF effects after injury.[10]

Garraway then completed a second postdoctoral fellowship in New York City, at the Weill Cornell Medical College.[8] She worked in the Department of Pharmacology and became an instructor of Pharmacology as well. Garraway studied under the mentorship of Charles Inturrisi, exploring methods of chronic pain management and biological mechanisms of pain with which to target.[3] She first designed and tested a novel small interfering RNA that knocked down expression of the NR1 subunit of the NMDA receptor.[11] This led to decreased mechanical allodynia after injection of an inflammatory agent.[11] She then tested the efficacy of the siRNA on formalin-induced phase 2 nociceptive responses, and it was able to significantly reduce them.[12] Both of her results show that vector-derived siRNAs targeting the NR1 subunit of the AMPA receptor might be beneficial in the treatment of pain by reducing expression of genes mediating pain sensation in the spinal cord.[12]

After discovering a role for spinal cord BDNF signaling in pain sensitization in her postdoc, Garraway explored whether the behavioral correlates of pain were associated with cellular changes mediated by BDNF.[20] She found that nociceptive stimulation decreased expression of BDNF, TrkB, and ERK2 in the dorsal spinal cord.[20] Garraway and her colleagues then found that BDNF signalling mediates the protective and restorative effects of instrumental training in models where pain is controllable.[21] After instrumental training, where rats learned to not flex their hind limb to prevent pain, there were increases in BDNF and increased plasticity. Further, when BDNF was injected during uncontrollable pain stimulation, it blocked allodynia and enabled rats to learn to not extend their hind legs.[21] Overall, her results and work point to the importance of BDNF in beneficial plasticity in pain models and the potential importance of BDNF in plasticity and recovery after spinal cord injury.[21]

Garraway also explores the role of Tumor Necrosis Factor alpha (TNFa) signalling in the development and maintenance of chronic pain.[22] In 2015, she discovered increases in TNFa expression after nociceptive stimulation post spinal cord injury and that downstream TNFa signalling may induce apoptosis in neurons and microglia.[22]  In 2019, Garraway and her colleagues found that peripheral inflammation increases the onset of mechanical hypersensitivity after spinal cord injury and that TNFa is involved in the early onset sensitization process.[23]