Amygdala-prefrontal pathways and the dopamine system affect nociceptive responses in the prefrontal cortex

Abstract

Background: We previously demonstrated nociceptive discharges to be evoked by mechanical noxious stimulation in the prefrontal cortex (PFC). The nociceptive responses recorded in the PFC are conceivably involved in the affective rather than the sensory-discriminative dimension of pain. The PFC receives dense projection from the limbic system. Monosynaptic projections from the basolateral nucleus of the amygdala (BLA) to the PFC are known to produce long-lasting synaptic plasticity. We examined effects of high frequency stimulation (HFS) delivered to the BLA on nociceptive responses in the rat PFC.

Results: HFS induced long lasting suppression (LLS) of the specific high threshold responses of nociceptive neurons in the PFC. Microinjection of N-methyl-D-aspartic acid (NMDA) receptor antagonists (2-amino-5-phosphonovaleric acid (APV), dizocilpine (MK-801)) and also metabotropic glutamate receptor (mGluR) group antagonists (α-methyl-4-carboxyphenylglycine (MCPG), and 2-[(1S,2S)-2-carboxycyclopropyl]-3-(9H-xanthen-9-yl)-D-alanine (LY341495)), prevented the induction of LLS of nociceptive responses. We also examined modulatory effects of dopamine (DA) on the LLS of nociceptive responses. With depletion of DA in response to 6-hydroxydopamine (6-OHDA) injection into the ipsilateral forebrain bundle, LLS of nociceptive responses was decreased, while nociceptive responses were normally evoked. Antagonists of DA receptor subtypes D2 (sulpiride) and D4 (3-{[4-(4-chlorophenyl) piperazin-1-yl] methyl}-1H-pyrrolo [2, 3-b] pyridine (L-745,870)), microinjected into the PFC, inhibited LLS of nociceptive responses.

Conclusions: Our results indicate that BLA-PFC pathways inhibited PFC nociceptive cell activities and that the DA system modifies the BLA-PFC regulatory function.

Figure 1

A typical example of nociceptive discharges evoked by peripheral mechanical stimulation. A. The top trace represents an ECoG. The second trace is multiple unit discharges evoked by mechanical stimulation. The third trace is an EEG recorded via stimulating electrodes in the BLA. Nociceptive stimulation also induced EEG changes. The bottom trace represents a pressure curve. B. Durations of responses and post-stimulus discharges (PSD) are shown as a histogram. One bin is 500 msec. Vertical lines represent the stimulus starting point and the horizontal broken line represents the mean level of spontaneous discharges.

Figure 2

HFS delivered to the BLA suppressed nociceptive responses recorded in the PFC. On the left, unit discharges: on the right, the histogram of single unit discharges calculated from the unit discharge. A. Unit discharges recorded in the PFC. Pre: Nociceptive responses evoked by 500 gf stimulation applied to the rat tail. At 50 min after HFS delivery to the BLA, the nociceptive responses were entirely blocked. At 90 min after HFS, nociceptive responses had recovered to the pre-HFS control level. B. Inhibitory effects of nociceptive responses were induced by HFS delivered to the BLA. The inhibitory effects of nociceptive responses appeared within 10 min and lasted longer than 60 min after HFS. The duration of the control nociceptive responses was assessed as 100% and changes in duration after HFS to the BLA were converted into percentages of the control value. n = 9. *p < 0.05, versus the pre-HFS control value, **p < 0.001, versus the pre-HFS control value. Error bars represent S.E. C. The mean discharge frequency of the control nociceptive responses was assessed as 100% and changes in mean discharge frequency after HFS to the BLA were converted into percentages of this control value. *p < 0.05, versus the pre-HFS control value, **p < 0.001, versus the pre-HFS control value. Error bars represent S.E. Mean discharge frequency of nociceptive responses also decreased after HFS in the same manner as the response duration. The statistical significance of differences between results obtained by the two methods was calculated using ANOVA. There were no significant differences between the mean discharge frequency of responses changes (n = 9) and response duration changes (n = 9).

Figure 3

A glutamate receptor blocker blunted the inhibitory effects of nociceptive responses induced by HFS. A. Pre: Smaller unit discharges in response to mechanical stimulation. The second trace represents single unit responses selected by cluster analysis from multiple units in the top line. At 30 min after HFS, microinjection of MK-801 completely inhibited LLS of nociceptive responses. B. NMDA antagonists, APV and MK-801, suppressed the effects of HFS on nociceptive responses. The duration of control nociceptive responses was assessed as 100% and changes in duration after HFS to the BLA were converted into percentages of the control value. There were no significant changes from the pre-HFS control value. In the ACSF group, nociceptive responses were completely blocked at 10 and 30 min after HFS but had recovered to the pre-HFS control value by 60 min. *p < 0.05, versus the pre-HFS control value. Error bars represent S.E. n = 15. C. After microinjection of MCPG (an mGluR group I and II antagonist) into the PFC, unit discharges were recorded in the PFC. Pre: prior to HFS delivery to the BLA. Multiple unit discharges responded to peripheral noxious stimulation. At 30 min after HFS, microinjection of MCPG blocked induction of LLS of nociceptive responses. D. Effects of mGluR antagonists on LLS of nociceptive response. MCPG partially blocked LLS of nociceptive responses induced by HFS to the BLA. Inhibitory effects were observed only at 30 min after HFS. An mGluR group II antagonist, LY341495, completely blocked LLS of nociceptive responses. *p < 0.05, versus the pre-HFS control value. Error bars represent S.E. n = 12.

Figure 4

DA depletion impaired the inhibitory effects of nociceptive responses induced by HFS. A. Nociceptive discharges were recorded in the PFC of the side ipsilateral to 6-OHDA injection. Pre: Nociceptive responses were normally evoked by mechanical stimulation delivered to the rat tail. At 60 min after HFS delivery to the BLA, there were no apparent effects on nociceptive responses. DA depletion completely blocked LLS of nociceptive responses induced by HFS. B. The duration of nociceptive responses tended to increase in this group, but the difference from the pre-HFS control value did not reach statistical significance. Error bars represent S.E. n = 8 The control figure is same as figure 2 B. *p < 0.05, **p < 0.001, versus the pre-HFS control value.

Figure 5

DA receptor subtypes modified LLS of nociceptive responses induced by HFS. A. Pre: A typical case with sulpiride injection is shown. Nociceptive responses were normally evoked by mechanical stimulation delivered to the rat tail after microinjection of sulpiride (upper trace). At 30 min after HFS, a D2 receptor antagonist completely blocked LLS of nociceptive responses induced by HFS to the BLA (lower trace). B. D2 and D4 receptor antagonists suppressed the induction of LLS of nociceptive responses by HFS. Error bars represent S.E. n = 19. The control figure is same as figure 3 B, C. *p < 0.05, **p < 0.001, versus the pre-HFS control value.

Figure 6

Areas of mPFC recording and BLA stimulation. A. Recording points of unit discharges. The solid squares represent actual recording points. All unit discharges are scattered throughout surface layers of the cingulate and prelimbic areas. The numbers above represent distance from the bregma. B. In the BLA, the solid squares represent stimulus points. The numbers represent distance from the bregma.