Transfer of SSRIs and SNRIs across the placenta was substantial. Neonates developed mild behavioral symptoms in the early perinatal period but these were self-limiting and similar for both SSRIs and the SNRI venlafaxine.

With a widespread Opioid Epidemic and profound biopsychosocial implications, chronic pain is a multi-faceted public health issue requiring urgent attention. The treatment of chronic pain is particularly important to anesthesiologists given our unique role as perioperative physicians and pain medicine specialists. The present review details the recent shift from a neuronal theory of chronic pain to one that includes complex neuron-glia interactions. In particular we highlight microglia, the myeloid-lineage cells of the central nervous system, as initiators of a post-injury neuroimmune response that contributes to the acute to chronic pain transition. We discuss everadvancing preclinical studies, wherein significant success has been made through pharmacologic and genetic modulation of microglia, and we emphasize where these approaches have made the transition to the clinical realm. Furthermore, we highlight the most current, novel efforts to visualize glial activation in vivo using positron emission tomography (PET) and improve the

Complex regional pain syndrome (CRPS) is a chronic pain disorder with a clear acute-to-chronic transition. Preclinical studies demonstrate that toll-like receptor 4 (TLR4), expressed by myeloid-lineage cells, astrocytes, and neurons, mediates a sexdependent transition to chronic pain; however, evidence is lacking on which exact TLR4-expressing cells are responsible. We used complementary pharmacologic and transgenic approaches in mice to more specifically manipulate myeloid-lineage TLR4 and outline its contribution to the transition from acute-to-chronic CRPS based on three key variables: location (peripheral vs central), timing (prevention vs treatment), and sex (male vs female). We demonstrate that systemic TLR4 antagonism is more effective at improving chronic allodynia trajectory when administered at the time of injury (early) in the tibial fracture model of CRPS in both sexes. In order to clarify the contribution of myeloid-lineage cells peripherally (macrophages) or centrally (microglia), we rigorously characterize a novel spatiotemporal transgenic mouse line, Cx3CR1-Cre ERT2-eYFP ;TLR4 fl/fl (TLR4 cKO) to specifically knock out TLR4 only in microglia and no other myeloid-lineage cells. Using this transgenic mouse, we find that early TLR4 cKO results in profound improvement in chronic, but not acute, allodynia in males, with a significant but less robust effect in females. In contrast, late TLR4 cKO results in partial improvement in allodynia in both sexes, suggesting that downstream cellular or molecular TLR4-independent events may have already been triggered. Overall, we find that the contribution of TLR4 is time-and microglia-dependent in both sexes; however, females also rely on peripheral myeloid-lineage (or other TLR4 expressing) cells to trigger chronic pain.

Supplemental Figure 1. Time activity curves (TACs) from dynamic PET scans for (A) spinal cord and (B) whole brain at 7 days post-fracture do not exhibit differences in tracer kinetic trajectory using mixed model statistical tests.