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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 D_2/3 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 (p_FWE < 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 (p_FWE < 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.

SUBMITTER: Shokri-Kojori E

PROVIDER: S-EPMC8410787 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:The development of opioid dependence involves classical neuronal opioid receptor activation and is due in part to engagement of glia causing a proinflammatory response. Such opioid-induced glial activation occurs, at least in part, through a non-classical opioid mechanism involving Toll-like-receptor 4 (TLR4). Among the immune factors released following the opioid-glia-TLR4 interaction, interleukin-1? (IL-1?) plays a prominent role. Previous animal behavioral studies have demonstrated significant heterogeneity of chronic morphine-induced tolerance and dependence between different mouse strains. The aim of this study was to investigate whether the heterogeneity of chronic opioid-induced IL-1? expression contributes to differences in opioid tolerance and withdrawal behaviors. Chronic morphine-induced tolerance and dependence were assessed in 3 inbred wild-type mouse strains (Balb/c, CBA, and C57BL/6) and 2 knockout strains (TLR4 and MyD88). Analysis of brain nuclei (medial prefrontal cortex, cortex, brain stem, hippocampus, and midbrain and diencephalon regions combined) revealed that, of inbred wild-type mice, there are significant main effects of morphine treatment on IL-1? expression in the brain regions analyzed (p<0.02 for all regions analyzed). A significant increase in hippocampal IL-1? expression was found in C57BL/6 mice after morphine treatment, whilst, a significant decrease was found in the mPFC region of wild-type Balb/c mice. Furthermore, the results of wild-type inbred strains demonstrated that the elevated hippocampal IL-1? expression is associated with withdrawal jumping behavior. Interestingly, knockout of TLR4, but not MyD88 protected against the development of analgesic tolerance. Gene sequence differences of IL - 1? and TLR4 genes alone did not explain the heterogeneity of dependence behavior between mouse strains. Together, these data further support the involvement of opioid-induced CNS immune signaling in dependence development. Moreover, this study demonstrated the advantages of utilizing multiple mouse strains and indicates that appropriate choice of mouse strains could enhance future research outcomes.

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

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