Skip to main page content
Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Randomized Controlled Trial
. 2008 May 21;28(21):5465-72.
doi: 10.1523/JNEUROSCI.5336-07.2008.

Blockade of Endogenous Opioid Neurotransmission Enhances Acquisition of Conditioned Fear in Humans

Affiliations
Free PMC article
Randomized Controlled Trial

Blockade of Endogenous Opioid Neurotransmission Enhances Acquisition of Conditioned Fear in Humans

Falk Eippert et al. J Neurosci. .
Free PMC article

Abstract

The endogenous opioid system is involved in fear learning in rodents, as opioid agonists attenuate and opioid antagonists facilitate the acquisition of conditioned fear. It has been suggested that an opioidergic signal, which is engaged through conditioning and acts inhibitory on unconditioned stimulus input, is the source of these effects. To clarify whether blockade of endogenous opioid neurotransmission enhances acquisition of conditioned fear in humans, and to elucidate the neural underpinnings of such an effect, we used functional magnetic resonance imaging in combination with behavioral recordings and a double-blind pharmacological intervention. All subjects underwent the same classical fear-conditioning paradigm, but subjects in the experimental group received the opioid antagonist naloxone before and during the experiment, in contrast to subjects in the control group, who received saline. Blocking endogenous opioid neurotransmission with naloxone led to more sustained responses to the unconditioned stimulus across trials, evident in both behavioral and blood oxygen level-dependent responses in pain responsive cortical regions. This effect was likely caused by naloxone blocking conditioned responses in a pain-inhibitory circuit involving opioid-rich areas such as the rostral anterior cingulate cortex, amygdala, and periaqueductal gray. Most importantly, naloxone enhanced the acquisition of fear on the behavioral level and changed the activation profile of the amygdala: whereas the control group showed rapidly decaying conditioned responses across trials, the naloxone group showed sustained conditioned responses in the amygdala. Together, these results demonstrate that in humans the endogenous opioid system has an inhibitory role in the acquisition of fear.

Figures

Figure 1.
Figure 1.
Experimental design. Subjects were assigned in a double-blind manner to two groups: the experimental group received the opioid antagonist naloxone before and during the experiment, whereas the control group received saline. Subjects underwent a classical fear-conditioning paradigm in which two simple geometric stimuli (blue triangle and green pentagon) served as the CS. Each CS was presented for 10 s. One stimulus (CS+) was paired with the US (heat pain delivered to left forearm at 8.5 s after CS onset) in 50% of its presentations. After each CS presentation, subjects rated the intensity of pain present on that trial on a VAS and a variable intertrial interval (ITI) followed. Subjects additionally performed an RT task at the onset of CS presentation in that they indicated whether the CS was presented in the left or right half of the screen. SCRs CRs to CS and US were recorded and BOLD responses were investigated with fMRI at three time points: early conditioned responses at CS onset, late conditioned responses 5 s after CS onset, and unconditioned responses at 8.5 s after CS onset on CS+ trials.
Figure 2.
Figure 2.
Habituation of responses to the US. a, Habituating responses to the US on the behavioral level (pain ratings and SCR). For each subject, we calculated a regression with time as predictor and then compared the ensuing average regression coefficients of both groups. The bars in this graph thus represent the average regression coefficient of each group. The control group showed stronger habituation effects in the pain ratings (as reflected by a more negative average regression coefficient) than the naloxone group. In addition to this trend-level significant effect, the control group showed significantly stronger habituation effects in SCR to the US. b, Habituating BOLD responses to the US. The dorsal anterior cingulate cortex showed significantly stronger habituating responses to the US in the control group than in the naloxone group. The bar graph on the right shows peak voxel parameter estimates that reflect the strength of habituation (i.e., the more negative, the stronger the habituation). The parameter estimates show that the BOLD responses in the control group habituate strongly, whereas the naloxone group shows sustained BOLD responses in dorsal anterior cingulate cortex. The image is thresholded at p < 0.005 (uncorrected) for visualization purposes. *p < 0.05. Error bars indicate SEM.
Figure 3.
Figure 3.
Conditioning induced responses in the antinociceptive system. The right (R) rostral anterior cingulate cortex shows a significant condition by group interaction late in the CS interval (i.e., 5 s after CS onset; visualization threshold: p < 0.005 uncorrected). As the parameter estimates in the bar graph show, this effect is mainly driven by a strong CS+ response in the control group that is almost completely blocked in the naloxone group; both groups show almost no response to the CS−. The parameter estimates indicate that the response to the CS+ in the control group is a deactivation, which we aimed to characterize further by examining the time course of this response. The rightmost panel thus shows the time course of the response on CS+ trials in the two groups (Ctrl, control group; Nlx, naloxone group). The time course of the control group was shifted slightly to the right to avoid overlapping of error bars; time courses were obtained from an analysis that used FIRs as basis functions and does not make any assumptions about the shape of the hemodynamic response. Dotted lines show the time courses on CS− trials. The CS+ time course of the control group shows a distinct deactivation, which starts at ∼5 s after CS onset and ceases at ∼15 s. Importantly, this deactivation is almost completely absent in the naloxone group. Error bars indicate SEM.
Figure 4.
Figure 4.
Conditioned amygdala responses at CS onset. The right (R) dorsomedial amygdala shows a significant time by condition by group interaction (visualization threshold: p < 0.005 uncorrected). The insert uses a more liberal threshold and three slices of the averaged anatomical image of all subjects for additional characterization of the spatial extent and localization of this response. The three-dimensional plots on the right show the group-averaged fitted response in the amygdala to the CS+ over the course of the experiment. The control group shows strongly decaying responses to the CS+ over time (i.e., decreasing responses along the axis labeled Scans). In contrast, the naloxone group shows sustained responses over time.

Similar articles

See all similar articles

Cited by 24 articles

See all "Cited by" articles

Publication types

LinkOut - more resources

Feedback