We previously recorded nociceptive responses in layer II and also found Fos expression to be induced by mechanical noxious stimulation in surface layers of the PFC [6
]. Monosynaptic projections from the BLA also terminated in layer II of the PFC [11
]. Assuming that nociceptive information from peripheral nociceptors and inputs from the BLA integrate at the same pyramidal cells in layer II of the PFC, HFS delivered to BLA-PFC may induce heterosynaptic plasticity. Heterosynaptic-LTD, which has been demonstrated in perforant path synapses of the hippocampus [20
], is reportedly blocked by NMDA receptor blockers [22
]. In our experiments, APV and MK-801 impaired LLS of nociceptive responses. NMDA receptor activities were required for the induction of LLS of nociceptive responses, suggesting heterosynaptic-LTD like mechanisms to underlie these responses. Brief application of Group I and II mGluR agonists [23
] or co-activation of mGluR II and NMDA receptors reportedly induces LTD in pyramidal neurons [24
]. Depolarization of postsynaptic cells is indispensable for mGluR mediated heterosynaptic-LTD [25
]. In our experiments, glutamate release via ascending pathways relying sensory information and NMDA activation by HFS delivered to the BLA produced LLS of nociceptive responses in the PFC characterizing the responses as LTD.
The DA system has been assumed to modulate PFC plasticity [26
]. Co-application of DA and the mGluR agonist without tetanic stimulation induced LTD in PFC pyramidal neurons [27
]. DA does not directly mediate synaptic transmission but affects it by altering the synaptic properties of target neurons [15
]. A behavioral study of pain demonstrated that DA depletion induces significant changes in thresholds for mechanical noxious stimuli [28
]. Partial DA depletion in our experiments had no effects on nociceptive responses themselves but blocked plastic changes in nociceptive responses. DA application produces only a small membrane depolarization (2-3 mV) in pyramidal cells [29
] but affects spike afterpotentials [30
] which consist of after-hyperpolarization or depolarization. Partial depletion of DA may inhibit slow after-depolarization followed by LLS induction, while having little effect on the initiation of action potentials [31
]. Emotional influences of inputs from the BLA on PFC nociceptive responses might be modulated by DA.
A D2 receptor antagonist, sulpiride, blocked LLS of nociceptive responses in the PFC. Postsynaptic D2 receptor activities reduce membrane depolarization evoked by a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid agonist application [15
]. Moreover, D2 receptor knockout mice showed impaired LTD induction in response to tetanic stimulation delivered to cortico-striatal pathways [32
]. In addition to postsynaptic D2 receptor inhibitory effects, presynaptic D2 receptors showed impaired glutamate release in the ventral tegmental area [33
]. D2 antagonists may affect both pre- and post-synaptic receptors and thereby block the induction of LLS of nociceptive responses. D4 receptors, which are highly expressed in PFC pyramidal cells [34
], inhibit adenylate cyclase through Gi/o-proteins by functioning as D2-like receptors [35
]. Electrophysiological experiments using current and voltage clamp methods demonstrated spontaneous hyper-excitability of pyramidal neurons in a D4 receptor knockout mouse model [36
]. Hence, D4 receptors normally exert an inhibitory influence on the activities of pyramidal neurons. D4 receptor activities may facilitate induction of LLS of nociceptive responses by HFS delivered to the BLA.
According to human brain image analysis, the strength of conscious pain reflects activities of the ACC [2
]. BLA-PFC projections may transmit aversive information from the limbic area to the PFC, which is involved in psychological states of dependent pain sensation like fear conditioning analgesia. BLA-PFC pathways are reportedly involved in fear expression and extinction [39
]. NMDA activation in the BLA and PFC are required for relearning of inhibitory fear responses in extinction [40
]. Our LLS results suggest that impulses from the BLA depressed nociceptive responses, as a consequence, pain recognition in the PFC was inhibited in fear responses.
The mesocortical DA system from the ventral tegmental area to the PFC plays roles in psychological conditions such as attention and motivation. Our results indicate that amygdala inputs to the PFC influence pain sensations via emotional stimulation and that the DA system exerts modulatory effects on conscious pain processing.