Our study examined whether the mesocortical DA system directly affects nociceptive responses in the PFC. HFS delivered to the VTA inhibited nociceptive responses recorded in the PFC. Basically, the DA concentration in the PFC, which receives direct inputs from the VTA [20, 21], is tonically maintained by activities of dopaminergic neurons in the VTA. HFS delivered to the VTA  and activation of VTA neurons by N-methyl-D-aspartate (NMDA)  increase the extracellular DA concentration, thereby producing inhibitory effects on PFC neurons . Higher DA concentrations induced by HFS may produce inhibition of nociceptive responses in the PFC. The inhibition, which was induced by a HFS of a moderate intensity, persisted for 60 min. In PFC slice studies, bath application of DA strongly modulated long-term depression of glutamatergic synapses . Our previous in vivo study  indicated that DA modulated LLS induced by glutamate receptor activation. Burst stimulation of VTA increased DA release in PFC, which induced plasticity of PFC neurons . DA release by HFS delivered to VTA may induce plastic changes in glutamatergic synapses to receive nociceptive inputs from peripheral tissue.
In contrast, DA depletion induced by 6-OHDA  or a decrease in the DA concentration induced by κ-opiate application  had no effect on nociceptive responses in the PFC. DA depletion by 6-OHDA increased the low amplitude and high frequency components in background ECoG, as reported previously . Decreased tonic DA release suppressed D2-mediated activities followed by augmentation of PFC neuron activities . These reports indicate that a low level of DA affects spontaneous activities of PFC neurons, but effects on evoked responses remain unclear. Our results and those of a previous report  demonstrated a low DA concentration in the PFC to impair plastic changes but not normal nociceptive responses.
In the rodent PFC, local application of DA reportedly induced spike activities, while a D2R antagonist impaired suppression of spontaneous discharges [28, 33, 34]. Our results from HFS to the VTA and local injection of a D2R agonist indicate D2R activation to be responsible for the LLS of nociceptive responses induced by HFS of the VTA. A D1R antagonist, however, had minimal effects on nociceptive responses, as reported by Godbout . DA D1R and D2R are found on both pre- and post-synaptic pyramidal neurons in the PFC [35–37]. D1R activating adenylate cyclase through interactions with G-proteins (Gs)  enhanced the NMDA current , which induced long-term potentiation (LTP) in the PFC . A question is why HFS did not evoke excitatory effects via D1Rs activities. More D1Rs are expressed on gamma-aminobutyric acid (GABA) neurons than on pyramidal cells in the PFC , suggesting that D1R activities evoked by HFS did not consistently induce excitatory responses. Another possibility is that DA D1R produces an inverted-U shaped response, indicating a higher dose to be associated with somewhat lower performance [42, 43]. The DA concentrations induced by HFS of the VTA may evoke DA D2- but not DA D1-mediated activities in PFC neurons.
The PFC receives numerous projections from several areas involved in complex higher brain functions. The medial pain pathways extend from the periphery to the PFC [5, 22] and direct projections from the VTA terminate in the PFC. Both inputs converged in the same areas (Additional file 1) where unit discharges were recorded in this study. Projections from the amygdala and hippocampus also terminate in the PFC and thereby change pain responses [8, 44]. These areas are related to emotion and memory, suggesting that the PFC unifies affectional information and pain. According to human brain imaging analyses, the strength of conscious pain, which is related to psychological condition, reflects activities of the PFC . DA modified synaptic plasticity [8, 46] and prolonged DA-mediated modulation biases the long-term processing dynamics of PFC networks .