(350) The Persistent Pain Transcriptome: Distinct Transcriptional Signatures of Post-Surgical and Inflammatory Models Define Convergent Pathways to the Transition to Hyperalgesia

Abstract

Most models of induced hyperalgesia display stereotyped behavioral responses to modalities such as heat and low threshold mechanical stimuli. Despite this, the nociceptive apparatus and the subsequent subjective experiences that define hyperalgesia differ greatly, as do accompanying symptoms of the associated pain state. Based on several recent in-depth studies of the activation patterns of primary afferents, we predicted that divergent activation paradigms could trigger distinct plastic events at second-order neurons that converge to sensitize the spinal circuits to evoked stimuli. The spinal circuits engaged by inflammatory and post-surgical pain states can be elucidated based on multiplex labeling and time course evaluations of the transcriptional signatures using deep sequencing. These experiments revealed a population of neurons apparently undetected by single-cell and single-nucleus sequencing methods because of its sparse representation in the superficial laminae of the dorsal horn. Investigations into the character and connectivity of these second order spinal neurons revealed that they participate similarly in at least two models of hyperalgesia. These models are driven by different transcriptional machinery at the level of the dorsal spinal cord, and the most transcriptionally evident neurons express very high levels of both the opioid peptide dynorphin and receptors that may be involved in phenotypic switching during hyperalgesia. We identified multiple cell populations, representing opponent processes acting to promote and abrogate hyperalgesia. Surprisingly, both neural and glial substrates of plasticity were divergent between the models, but converged at the pathway level. Examples of convergent pathways included immune-like activation and upregulation of the dynorphin precursor gene, whereas the activation of neuronal genes was divergent. These investigations outline a multidisciplinary strategy for identification of targets for analgesia and hyperalgesia research, and identify a set of neuronal receptors for future analgesic target development.