Grants and Contracts Details
Description
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 of 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 1A investigates ì-,
ä-, and ê- opioid receptor subtypes with the use of selective antagonists. Aim 1B and 1C test mechanisms of
constitutive receptor signaling and tonic opioid release with the use of ex vivo spinal cord slice GTPãS35
binding assay and intrathecal sequestering opioid peptide antiserum, respectively. Aim 1D 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:
Status | Finished |
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Effective start/end date | 3/1/12 → 8/4/13 |
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