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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. [ABSTRACT FROM AUTHOR]

General anesthesia and monitored sedation are vital to nearly all procedural aspects of modern medicine. Inhaled agents such as halogenated gases have long been an integral aspect of anesthesia. In recent years, the noncompetitive NMDA antagonist and dissociative anesthetic ketamine has seen increasing utilization in general anesthesia, as well as in the treatment of chronic pain and depression. The use of ketamine for such chronic conditions has raised questions into its addictive potential, and its potential role in the treatment of existing addictions. New investigations using high density electrical recordings and other multidimensional techniques have led to a clearer understanding of how these agents work, and how they can be utilized to fill clinical needs. To further study their effects at the molecular level, we used deep RNA sequencing to examine the time course (1hr, 10hr, or 10hr + 24hr recovery) of gene changes induced in the frontal cortex, hippocampus, and amygdala during ketamine or isoflurane administration. When compared to isoflurane, the transcriptional signature of ketamine showed similarities and differences that suggested region-specific gene regulation patterns that highlight the molecular underpinnings of the broad clinical uses of ketamine. The evaluation of brain regions subserving the diverse functions of learning and memory, executive function, and emotional-affective dimensions yielded insight into the neural localization of anesthetic actions and potential vulnerabilities associated with general anesthesia. Our investigation demonstrates unique region-specific and time-dependent transcriptional signatures that bridge molecular and systems level findings to expand current understanding of the shifts in neuronal activity associated with general anesthetics and their downstream effects. [ABSTRACT FROM AUTHOR]