μ-Opioid receptors and limbic responses to aversive emotional stimuli

Abstract

Functional neuroimaging studies implicate limbic and paralimbic activity in emotional responses, but few studies have sought to understand neurochemical mechanisms which modulate these responses. We have used positron emission tomography to measure -opioid receptor binding, and cerebral blood flow in the same subjects, and demonstrated that the baseline binding potential and the regional cerebral blood flow in the left inferior temporal pole are functionally related. Higher baseline -opioid receptor binding potential was associated with lower regional cerebral blood flow in this region during presentation of emotionally salient stimuli. This is consistent with an inhibitory͞anxiolytic role of the endogenous opioid system in limbic regions of the temporal lobe and basal forebrain. N euroimaging studies have implicated temporal lobe and basal forebrain in the mediation of emotional responses. These large neuroanatomical regions contain central components of the limbic system, such as the amygdala and hippocampus, as well as associated limbic and paralimbic cortex (1). Functional neuroimaging studies, along with lesion data and animal research, have began to illuminate specific roles of limbic structures in various components of emotional processing, including the role of extended amygdala in salience (2, 3) and the role of orbitofrontal cortex in processing reward contingencies (4). A more precise understanding of the specific roles of limbic regions is essential for a better understanding of pathological conditions involving emotional dysregulation, e.g., psychiatric disorders. Functional studies of limbic structures in psychiatric disorders have just begun, but initial findings suggest that abnormal regional cerebral blood flow (rCBF) in these regions might be characteristic of specific diagnoses (5-7) or, alternatively, specific psychiatric symptoms, cutting across diagnostic boundaries (8, 9). Although such findings suggest hypo-or hyperactivity of limbic regions in a particular disorder, pathophysiologic processes giving rise to abnormal rCBF remain poorly understood. The study of neurotransmitter systems in vivo can provide an important link between cellular neurochemistry and functional neuroanatomy; although relatively few studies have attempted to make such links so far. The development of positron-emitting radiotracers designed for characterizing specific receptor sites, which can probe the neurochemistry of limbic systems in vivo, provides an attractive tool to combine with functional activation studies of limbic brain.Work in our laboratory has implicated the extended amygdala in the mediation of aversive emotional responses, such as fear or disgust (2, 10, 11), consistent with both the animal literature (12, 13) and with other imaging studies (14,15). Among the various neurotransmitter systems implicated in the regulation of limbic and paralimbic regions, the endogenous opioid system and -opioid receptors have been implicated in the modulation of fear (16), the suppression of affective defense behavio...

Antidepressant-like Effects of Buprenorphine are Mediated by Kappa Opioid Receptors

“…These findings can be seen as in line with neuroimaging studies in depressed patients, which have highlighted low KOR availability in Amy-anterior cingulate cortex-ventral striatal circuitry in the phenotypic expression of dysphoria (Pietrzak et al, 2014) and aberrant MOR signaling in the cortical-amygdalar circuitry in the response to aversive stimuli (Kennedy et al, 2006;Liberzon et al, 2002). They also agree in part with the results of opioid gene expression in post-mortem studies of suicide victims (Hurd et al, 1997).…”

Opioids Inhibit Lateral Amygdala Pyramidal Neurons by Enhancing a Dendritic Potassium Current

“…The opioid system in the amygdala has been implicated in the modulation of fear (Good and Westbrook, 1995), as well as consolidation of memories and the antinociceptive actions of conditioned stimuli (McGaugh, 1989). In agreement with these modulatory effects, functional imaging studies have shown that activation of receptors is associated with inhibition of amygdala function (Liberzon et al, 2002). However, the mechanisms underlying this inhibition are not understood.…”

“…Thus, the physiological actions of upregulation of this current are evident during brief depolarizations, such as during synaptic activation or after somatic puffer application of glutamate. Activation of this current may be the mechanism underlying the reduction in amygdala activity that has been observed during aversive emotional stimuli when receptors in the amygdala are occupied (Liberzon et al, 2002). The amygdala has long been implicated in "emotional" processing and particularly in mediating responses associated with fear and anxiety (LeDoux, 2000;Davis and Whalen, 2001).…”

Stress-evoked opioid release inhibits pain in major depressive disorder

“…Thus, stress-induced opioid release apparently suppressed anxiety both in MDD participants and non-depressed controls. Functional neuroimaging studies suggest that the endogenous opioid system has an anxiolytic role in regions of the temporal lobe that project to the amygdala [35], and suppresses affective states such as sadness [30,51].…”