Naloxone precipitated withdrawal increases dopamine release in the dorsal striatum of opioid dependent men

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.

Brain opioid segments and striatal patterns of dopamine release induced by naloxone and morphine

“…Habenula was defined based on previously reported MNI coordinates (Lawson, Drevets, & Roiser, 2013). The pituitary region of interest (ROI) was defined as described previously (Shokri-Kojori et al, 2021). Additional subcortical regions were defined using the Harvard-Oxford atlas (probability threshold >50%; Desikan et al, 2006) and ascending autonomic network atlas (Edlow et al, 2012).…”

“…Considering the higher MOR expression in VTA, MRP could have more effectively removed the GABAergic inhibition in the VTA than SNc, leading to ventral striatal DA release. In contrast, MOR blockade by NAL in SNc could have had less inhibitory effects, leading to relative increases in DA release in the dorsal striatum during precipitated withdrawal (Shokri-Kojori et al, 2021). Chronic opioid exposure could upregulate KOR (X.-Y.…”

“…In humans, opioid withdrawal precipitated by nonselective opioid antagonist naloxone (NAL, see Section 2) (G.-J. Wang et al, 1997) resulted in DA increases in the dorsal striatum of participants with OUD (Shokri-Kojori, Wang, & Volkow, 2021). In contrast, the nonselective opioid agonist morphine (MRP, see Section 2) resulted in DA release primarily in the ventral striatum of healthy controls (Spagnolo et al, 2019).…”

“…We also compared drug-induced patterns of DA release to the distribution of MOR, KOR, and DOR across striatal sub-partitions. For this purpose, we used [ 11 C]raclopride-PET datasets where we had assessed DA release induced by NAL precipitated withdrawal in OUD men (Shokri-Kojori et al, 2021;G.-J. Wang et al, 1997), by MRP in healthy men (Spagnolo et al, 2019), and by MPH in healthy controls (Volkow et al, 2014), which we used here as a nonopioid control pharmacological condition.…”

Does stimulant drug–induced sensitization occur in primates?

“… 10 , 11 , 14 Dopamine release in humans is increased by all relapse triggers tested to date, including drug-related cues, 15 – 19 small quantities of the drug, 20 , 21 stress, 22 , 23 and, in people with long histories of opioid use, drug withdrawal. 24 , 25 As sagely noted by David Epstein, 26 no one feature is likely to account for all clinically relevant aspects of addiction. Claims that sensitization is not one of the critical elements are likely misguided.…”