Plasticity in dorsal root ganglion (DRG) neurons that promotes pain requires activity-dependent mRNA translation. Protein synthesis inhibitors block the ability of many pain-promoting molecules to enhance excitability in DRG neurons and attenuate behavioral signs of pain plasticity. In line with this, we have recently shown that phosphorylation of the 5' cap-binding protein, eIF4E, plays a pivotal role in plasticity of DRG nociceptors in models of hyperalgesic priming. However, mRNA targets of eIF4E phosphorylation have not been elucidated in the DRG. Brain-derived neurotrophic factor (BDNF) signaling from nociceptors in the DRG to spinal dorsal horn neurons is an important mediator of hyperalgesic priming. Regulatory mechanisms that promote pain plasticity via controlling BDNF expression that is involved in promoting pain plasticity have not been identified. We show that phosphorylation of eIF4E is paramount for Bdnf mRNA translation in the DRG. Bdnf mRNA translation is reduced in mice lacking eIF4E phosphorylation (eIF4E(S209A)) and pro-nociceptive factors fail to increase BDNF protein levels in the DRGs of these mice despite robust upregulation of Bdnf-201 mRNA levels. Importantly, bypassing the DRG by giving intrathecal injection of BDNF in eIF4E(S209A) mice creates a strong hyperalgesic priming response that is normally absent or reduced in these mice. We conclude that eIF4E phosphorylation-mediated translational control of BDNF expression is a key mechanism for nociceptor plasticity leading to hyperalgesic priming.

The mechanisms that mediate the maintenance of chronic pain states are poorly understood, but elucidation of such could yield insight into how pain becomes chronic and how the process can potentially be reversed. This thesis investigated the role of ascending and descending spinal dorsal horn circuitry and interneurons in the plasticity that mediates a transition to pathological pain plasticity using hyperalgesic priming model. The results showed that, while dorsal horn neurokinin 1 receptor-positive neurons or descending serotonergic neurons mediated IL-6- and carrageenan-induced acute mechanical hypersensitivity, they were not required for PGE₂-induced mechanical hypersensitivity. In stark contrast, ablation of dopaminergic neurons did interrupt the IL-6- and carrageenan-induced mechanical hypersensitivity, but the subsequent PGE₂ injection failed to cause mechanical hypersensitivity - thereby reflecting that primed state plasticity is driven by differential mechanisms. In addition, the pharmacological antagonism of spinal dopamine D1/D5 receptors reversed priming and its agonism induced mechanical hypersensitivity exclusively in primed mice, which suggests dopaminergic control of pathological pain plasticity in a D1/D5-dependent manner. Moreover, in a primed state, changes to spinal dorsal horn GABA pharmacology were accompanied by upregulation of neuroligin 2 mRNA and protein expression. These findings 1) indicate a novel role for descending dopaminergic neurons in the maintenance of pathological pain plasticity, and 2) point to the inhibitory synaptic expression of neuroligin-2 as the spinal determinants of this type of pain plasticity.