Peripheral tissue inflammation can lead to maladaptive plasticity in the spinal cord and brain which contributes to persistent pain. The intensity and quality of pain is determined by the net balance between the activities of pronociceptive systems with compensatory endogenous inhibitory systems, namely spinal opioid signaling. Interestingly, a small set of studies indicate that endogenous opioid inhibition f acute nociception persists even after the initial signs of hyperalgesia have subsided. For example, opioid receptor antagonists reinstate allodynia. This raises two intriguing questions. First, opioid receptor subtypes and neural circuits remain unclear. Second, does a latent nociceptive sensitization persist in the absence of overt behavioral signs of hypersensitivity? My preliminary data show that naltrexone, when intrathecally administered weeks to months after intraplantar CFA, reinstated behavioral signs of hypersensitivity and induced dorsal horn ERK phosphorylation. Both were blocked by spinal antagonism of NMDA receptors. My central hypothesis is that peripheral inflammation induces prolonged signaling of CNS opioidergic-circuits (Aim 1) that mask pronociceptive NMDA and AMPA signaling (Aim 2). This F31 proposal attempts to better characterize the mechanisms that underlie the latent sensitization that is masked by endogenous opioid activity.
Aim 1 tests the hypothesis that spinal opioidergic signaling tonically masks nociceptive sensitization.
Aim 1 A investigates ?-, ?-, and ?-opioid receptor subtypes with the use of selective antagonists.
Aim 1 B and 1C test mechanisms of constitutive receptor signaling and tonic opioid release with the use of ex vivo spinal cord slice GTP ?S35 binding assay and intrathecal sequestering opioid peptide antiserum, respectively.
Aim 1 D tests the hypothesis that opioid receptor blockade disinhibits tonic afferent nociception.
In Aim 2 I will test the idea that glutamatergic signaling drives the hypersensitivity that follows spinal opioid receptor blockade, with a focus on spinal NMDA (Aim 2A) and AMPA/kainate-receptors (Aim 2B). By better understanding long-lasting opioid antinociception, this project could pave the way for future strategies to enhance endogenous opioid analgesia in humans with chronic pain, and thus has the long-term potential to reveal novel targets to prevent the transition for acute to chronic pain. This F31 award will help me achieve my goals that will enable me to successfully compete for strong post-doctoral positions and ultimately, a successful career in research science and teaching beginning with a tenure-track position in a strong medical research university environment:

Public Health Relevance

Sensitization of pain pathways, in the setting of tissue inflammation, leads to a state of hypersensitivity that is counteracted by compensatory endogenous inhibitory systems. This project aims to understand the mechanisms by which the spinal opioid system masks long-lasting glutamatergic sensitization. Therapeutic strategies designed to enhance this endogenous opioid signaling may reduce the occurrence of persistent pain.

National Institute of Health (NIH)
National Institute on Drug Abuse (NIDA)
Predoctoral Individual National Research Service Award (F31)
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Special Emphasis Panel (ZRG1-F02B-M (20))
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Babecki, Beth
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University of Kentucky
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Taylor, Bradley K; Corder, Gregory (2014) Endogenous analgesia, dependence, and latent pain sensitization. Curr Top Behav Neurosci 20:283-325
Corder, G; Doolen, S; Donahue, R R et al. (2013) Constitutive ?-opioid receptor activity leads to long-term endogenous analgesia and dependence. Science 341:1394-9