Abstract
Highly correlated presynaptic and postsynaptic activity evokes spike timing-dependent long-term potentiation (t-LTP) at primary afferent synapses onto spinal projection neurons. While prior evidence indicates that t-LTP depends upon an elevation in intracellular Ca2+ within projection neurons, the downstream signaling pathways that trigger the observed increase in glutamate release from sensory neurons remain poorly understood. Using in vitro patch-clamp recordings from female mouse lamina I spino-parabrachial neurons, the present study demonstrates a critical role for prostaglandin synthesis in the generation of t-LTP. Bath application of the selective phospholipase A2 (PLA2) inhibitor arachidonyl trifluoromethyl ketone (AACOCF3) or the cyclooxygenase 2 (Cox-2) inhibitor nimesulide prevented t-LTP at sensory synapses onto spino-parabrachial neurons. Similar results were observed following the block of the EP2 subtype of prostaglandin E2 (PGE2) receptor with PF 04418948. Meanwhile, perfusion with PGE2 or the EP2 agonist butaprost potentiated the amplitude of monosynaptic primary afferent-evoked EPSCs while decreasing the paired-pulse ratio, suggesting a presynaptic site of action. Cox-2 was constitutively expressed in both spinal microglia and lamina I projection neurons within the superficial dorsal horn (SDH). Suppression of microglial activation with minocycline had no effect on the production of t-LTP, suggesting the possibility that prostaglandins produced within projection neurons could contribute to an enhanced probability of glutamate release at primary afferent synapses. Collectively, the results suggest that the amplification of ascending nociceptive transmission by the spinal SDH network is governed by PLA2-Cox-2-PGE2 signaling.SIGNIFICANCE STATEMENT Long-term potentiation (LTP) of primary afferent synapses contributes to the sensitization of spinal nociceptive circuits and has been linked to greater pain sensation in humans. Prior work has implicated elevated glutamate release in the generation of spike timing-dependent LTP (t-LTP) at sensory synapses onto ascending spinal projection neurons, but the underlying mechanisms remain unknown. Here we provide evidence that the activation of EP2 prostaglandin receptors by prostaglandin E2, occurring downstream of phospholipase A2 and cyclooxygenase 2 activation, mediates t-LTP at these synapses via changes in presynaptic function. This suggests that prostaglandins can increase the flow of nociceptive information from the spinal cord to the brain independently of their known ability to suppress synaptic inhibition within the dorsal horn.