Evidence for endogenous opioid release in the amygdala during positive emotion

Abstract

Endogenous opioid release has been linked to relief from aversive emotional memories, thereby promoting a euphoric state and subsequent interactions towards social stimuli resulting in the formation of social preferences. However, this theory remains controversial. Using positron emission tomography and [¹¹C]diprenorphine (DPN) in healthy volunteers, we found significantly reduced DPN binding to opioid receptor in the hippocampus during positive mood induction compared to neutral mood. Furthermore, the magnitude of positive mood change correlated negatively with DPN binding in the amygdala bilaterally. Our finding of reduced DPN binding is consistent with increased release of endogenous opioids, providing direct evidence that localised release of endogenous opioids is involved in the regulation of positive emotion in humans.

Introduction

Opioid peptides act as mediators of use-dependent synaptic activity modulating the effect of fast-acting primary neurotransmitters, such as glutamate and dopamine (Snyder and Pasternak, 2003). In a number of species, the opioid system has been linked to the rewarding (pleasurable) effects of a variety of behaviours: affiliative behaviours (Panksepp et al., 1980a, Matthes et al., 1996, Moles et al., 2004), pain relief (Quirarte et al., 1998, Fields, 2007, Leknes and Tracey, 2008), palatable food intake (Berridge, 1996, Will et al., 2004, Pecina, 2008), social play (Panksepp et al., 1980b, Panksepp and Bishop, 1981), sex (Agmo and Berenfeld, 1990, Paredes and Martinez, 2001), brain stimulation reward (Belluzzi and Stein, 1977, Trujillo et al., 1989) and heroin self-administration (Koob et al., 1989, Wise, 1989). Panksepp and others (Panksepp et al., 1980a, Panksepp et al., 1980b, Panksepp et al., 1997) have provocatively argued that positive social stimuli elicit release of endogenous opioids, thereby promoting a euphoric state and subsequent interactions towards social stimuli resulting in the formation of social preferences.

In humans, studies that relate opioid neurotransmission to mood have so far been limited to pharmacological challenges (Preston and Bigelow, 1993) and post-mortem studies in suicide victims (Gabilondo et al., 1995). These studies reported increased numbers of opioid receptors or opioid radioligand binding and suggested an adaptive response of the postsynaptic receptors to altered levels of presynaptically released endogenous opioids. A recent PET study unexpectedly found increased binding of the μ-opioid receptor agonist ¹¹C-carfentanil during a sustained sadness state compared to a neutral state in healthy controls, which was interpreted as deactivation of neurotransmitter release (Zubieta et al., 2003). In contrast, decreased ¹¹C-carfentanil during sustained sadness was observed in the insular cortex, amygdala and thalamus of patients with major depressive disorders (Kennedy et al., 2006).

The binding of the radioligand [¹¹C]diprenorphine (DPN) to mu, kappa, and delta opioid receptors can be altered by pain stimulation (Jones et al., 1999) and seizure activity (Bartenstein et al., 1993, Koepp et al., 1998, Hammers et al., 2007a) and is thus considered to be sensitive to the release of endogenous opioids. Here we demonstrate, consistent with Panksepp's hypothesis, that experience of positive emotions is associated with decreased amygdala activity modulated through increased opioid-related inhibition.