The molecular neurobiology and neuropathology of opioid use disorder

Abstract

The number of people diagnosed with opioid use disorder has skyrocketed as a consequence of the opioid epidemic and the increased prescribing of opioid drugs for chronic pain relief. Opioid use disorder is characterized by loss of control of drug taking, continued drug use in the presence of adverse consequences, and repeated relapses to drug taking even after long periods of abstinence. Patients who suffer from opioid use disorder often present with cognitive deficits that are potentially secondary to structural brain abnormalities that vary according to the chemical composition of the abused opioid. This review details the neurobiological effects of oxycodone, morphine, heroin, methadone, and fentanyl on brain neurocircuitries by presenting the acute and chronic effects of these drugs on the human brain. In addition, we review results of neuroimaging in opioid use disorder patients and/or histological studies from brains of patients who had expired after acute intoxication following long-term use of these drugs. Moreover, we include relevant discussions of the neurobiological mechanisms involved in promoting abnormalities in the brains of opioid-exposed patients. Finally, we discuss how novel strategies could be used to provide pharmacological treatment against opioid use disorder.

Keywords: Fentanyl; Heroin; Methadone; Neuroimaging; Oxycodone; Postmortem.

Graphical abstract

Fig. 1

A model of the brain reward system. Sagittal illustration of a human brain depicting the dopaminergic pathways (blue) including the ventral tegmental area to the nucleus accumbens, striatum or frontal cortex; and the substantia nigra to the striatum. Glutamatergic pathways (green) are shown from the anterior cingulate cortex to the amygdala and striatum; hippocampus to the striatum; and the cortico-thalamo-cortical interactions. (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)

Fig. 2

Brain deficits in human opioid use disorders. Cartoon illustration of human brain showing areas affected by acute or chronic intoxication of heroin, morphine, oxycodone, methadone and fentanyl. Abbreviations: Bs, Brain stem; Cb, Cerebellum; Crb, Cerebrum; Cctx, Cingulate cortex; Cc, Corpus Callosum; GP, Globus Pallidus; Hippo, Hippocampus; HTH, Hypothalamus; Ip, Insula and putamen; NAc, Nucleus Accumbens; PFC, Prefrontal Cortex.

Fig. 3

Potential neurobiological mechanisms associated with craving in heroin addicts. Decision-making is part of the progression to chronic relapse and is associated with the prefrontal cortex. In postmortem brain heroin causes the (1) altered DNA methylation status in glutamatergic neurons. (2) Increased levels of G-protein subunits: Gαi_1/2, Gαo, Gαs, and Gαβ. (3) Another possible mechanism involves the upregulation of GRK 2 and GRK 6, which can lead to the phosphorylation of Mu opioid receptors. Moreover, GRKs and receptor phosphorylation leads to the recruitment of β-arrestin 2 causing desensitization of mu opioid receptors through internalization and degradation. Abbreviations: Mu, mu opioid receptor; G-proteins, guanine nucleotide-binding proteins; red and green arrows, increase and levels, respectively; GRK, G protein-coupled receptor kinase. (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)