Neuromodulatory regulation of synaptic plasticity in spinal nociceptive circuits

Project Summary/Abstract
Long-term potentiation (LTP) of primary afferent synapses onto spinal projection neurons (PNs) has
been linked to increased pain sensitivity. The timing rules controlling the generation of LTP in adult PNs can
be persistently relaxed by neonatal tissue damage, which likely contributes to the ability of early life injury to
‘prime’ nociceptive circuits and thereby exacerbate pain after subsequent insult. In the brain, the temporal
window governing this spike timing-dependent plasticity (STDP) is strongly regulated by G protein-coupled
receptor (GPCR) signaling evoked by neuromodulators such as dopamine (DA). This raises the possibility that
neonatal injury facilitates LTP at primary afferent synapses onto adult PNs, and thereby promotes persistent
pain, via long-term changes in spinal neuromodulatory signaling. Unfortunately, it remains unknown how
GPCRs influence STDP at sensory synapses onto PNs. As a result, the cellular and molecular mechanisms
underlying the increased amplification of ascending nociceptive transmission by the adult dorsal horn during
the primed state are poorly understood. The objective of this application is to identify the neuromodulatory
signals that promote the activity-dependent strengthening of sensory synapses onto the key output neurons of
the spinal nociceptive circuit and contribute to the priming of developing pain pathways after early life injury.
The central hypothesis is that ‘non-Hebbian’ LTP at sensory synapses onto spinal PNs is enabled by D1-like
(i.e. D1/D5) dopamine receptor activation, occurring in concert with mGluR5-dependent intracellular Ca2+
release and extracellular signal-regulated kinase (ERK) signaling, which is essential for neonatal priming. The
rationale of the proposed research is that these studies will identify novel molecular strategies to reduce the
signaling gain of the spinal nociceptive network. Guided by strong preliminary data, the central hypothesis will
be tested by pursuing the following specific aims: (1) Elucidate how DA receptor activation shapes STDP in
PNs; (2) Identify the signaling pathways which cooperate with DA receptors to facilitate LTP in PNs; and (3)
Identify the neuromodulators which mediate the priming of spinal nociceptive circuits following neonatal tissue
damage. These aims will be accomplished by using a multidisciplinary experimental approach that includes
electrophysiological characterization of STDP in PNs combined with both reflexive and non-reflexive behavioral
measures of pain. The proposed work is innovative because it will be the first to demonstrate that DA signaling
dictates the timing rules governing the plasticity of sensory synapses onto spinal PNs. The outcome of these
investigations will be the identification of new spinal mechanisms that augment nociceptive transmission to the
brain, and the demonstration that aberrant neuromodulation contributes to the persistent sensitization of spinal
nociceptive circuits after early tissue damage. Thus the proposed research is significant because it will provide
knowledge needed to design novel interventional strategies to disrupt spinal LTP as a means to alleviate
chronic pain and to minimize the long-term consequences of neonatal tissue injury for the developing CNS.

Grant Number: 5R37NS122141-04
NIH Institute/Center: NIH
Principal Investigator: Mark Baccei