Abstract
Dopamine (DA) neurotransmission is critical in the neurobiology of reward and aversion, but its contribution to the aversive state of opioid withdrawal remains unknown in humans. To address this, we used updated voxelwise methods and retrospectively analyzed a [11C]raclopride-PET dataset to measure D2/3 receptor availability and relative cerebral blood flow (R1) in male opioid use disorder (OUD) participants (n = 10) during placebo and acute opioid withdrawal conditions. We found that acute withdrawal precipitated by the opioid antagonist naloxone significantly increased dorsal striatal DA release in OUD participants (pFWE < 0.05). Net changes in striatal DA were significantly correlated with a subjective index of withdrawal aversion such that greater DA increases were associated with more aversive responses (r(8) = 0.82, p < 0.005). Withdrawal also affected brain function, as indexed by increases in relative cerebral blood flow in the insula and putamen (pFWE < 0.05). Our findings are different from preclinical studies that have primarily reported decreases in ventral striatal DA during naloxone precipitated withdrawal, whereas this effect was not significant in OUD participants (p = 0.79). In sum, we provide evidence for the contribution of increases in dorsal striatal DA to the aversive state of naloxone precipitated withdrawal in humans.
Highlights
The opioid epidemic is a leading health crisis in the US
Stimulation of mu-opioid receptor (MOR) suppresses the inhibitory effect of GABA interneurons on DA neurons in the ventral tegmental area (VTA). This indirect inhibition results in increased DA release in the ventral striatum that has been associated with the rewarding effects of opioid drugs [8]
We explored the functional effects of NAL precipitated withdrawal (NPW) on the pituitary [15, 19] and habenula [20]
Summary
The opioid epidemic is a leading health crisis in the US. Acute opioid withdrawal is an important contributor to drug-seeking behavior and relapse, and its underlying neurobiology is critical for the treatment development of opioid use disorder (OUD). Stimulation of mu-opioid receptor (MOR) suppresses the inhibitory effect of GABA interneurons on DA neurons in the VTA. This indirect inhibition results in increased DA release in the ventral striatum that has been associated with the rewarding effects of opioid drugs [8]. Kappa opioid receptors (KORs) regulate DA release through their direct effect on DA neurons and are implicated in aversion including opioid withdrawal [9, 10]. Different effects of opioid antagonists and agonists on the opioid receptors in the SNc and VTA could differentially affect DA release in the dorsal and ventral striatum [11]
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