Kappa-opioid receptors, dynorphin, and cocaine addiction: a positron emission tomography study

Abstract

Animal studies indicate that the kappa-opioid receptor/dynorphin system plays an important role in cocaine binges and stressinduced relapse. Our goal was to investigate changes in kappa-opioid receptor (KOR) availability in the human brain using positron emission tomography (PET), before and after a cocaine binge. We also investigated the correlation between KOR and stress-induced cocaine self-administration. PET imaging was performed with the KOR selective agonist [ 11 C]GR103545. Subjects with cocaine-use disorder (CUD) underwent PET scans and performed two types of cocaine self-administration sessions in the laboratory as follows: (1) choice sessions following a cold pressor test, to induce stress, and (2) binge dosing of cocaine. This allowed us investigate the following: (1) the association between KOR binding and a laboratory model of stress-induced relapse and (2) the change in KOR binding following a 3-day cocaine binge, which is thought to represent a change in endogenous dynorphin. A group of matched healthy controls was included to investigate between group differences in KOR availability. A significant association between [ 11 C] GR103545 binding and cocaine self-administration was seen: greater KOR availability was associated with more choices for cocaine. In addition, the 3-day cocaine binge significantly reduced [ 11 C]GR103545 binding by 18% in the striatum and 14% across brain regions. No difference in [ 11 C]GR103545 binding was found between the CUD subjects and matched controls. In the context of previous studies, these findings add to the growing evidence that pharmacotherapies targeting the KOR have the potential to significantly impact treatment development for cocaine-use disorder.

Early Life Stress and Risks for Opioid Misuse: Review of Data Supporting Neurobiological Underpinnings

“…Although not specific to OUD, the findings from human positron-emission tomography (PET) imaging studies have found associations between endogenous opioid function, and subjective and behavioral responses to both drugs of abuse and pain. For example, k-opioid receptor availability is associated with stress-induced cocaine self-administration in subjects with cocaine-use disorder [ 279 ], altered vs. binding potential for the µ-receptor agonist [ 11 C]carfentanil is associated with alcohol craving and relapse risk in abstinent alcoholics [ 280 , 281 , 282 ], the µ-receptor binding potential correlates with nicotine dependence and reward in smokers [ 283 ], and alterations in endogenous opioids and µ-receptors in patients with chronic nonspecific back pain are associated with both sensory and affective elements of the pain experience [ 284 ]. To date, we are not aware of any neuroimaging studies that have evaluated the effects of ELS on opioid neurotransmission in humans or any controlled human laboratory studies that have examined ELS contribution to human opioid sensitivity.…”

A Survey of Molecular Imaging of Opioid Receptors

“…Just for example, κORs have an established role in the reinstatement of stress induced drug use in experimental animals, i.e. nicotine use [229], and very recent results indicate a relationship between κORs and stress-induced binge cocaine use [197].…”

“…Binge cocaine users showed a significant association between [ 11 C]GR103545 ( 25 ) binding to κORs with the amount of drug consumed. Furthermore, a three-day cocaine binge reduced binding by about 15% [197]. The cerebral binding (V T ) of the ORL1 ligand [ 11 C]NOP-1A ( 36 ) was globally elevated 10% in detoxified cocaine users [198].…”

The Role of the Kappa Opioid System in Comorbid Pain and Psychiatric Disorders: Function and Implications

“…The Dyn/KOR system is distributed throughout different brain regions, with KORs expressed in various types of mood-related neurons including serotonergic neurons ( Land et al, 2009 ), corticotropin-releasing factor (CRF) neurons ( Marchant et al, 2007 ), and DA neurons ( Liu et al, 2019 ; Figure 1 ). It is widely accepted that KOR activation produces negative affect, both in human beings and in rodents ( Martinez et al, 2019 ). Moreover, ablation of KORs from DA neurons or basolateral amygdala (BLA) glutamatergic terminals in the medial prefrontal cortex produces an anxiolytic phenotype ( Margolis et al, 2006 ; Lowery-Gionta et al, 2018 ), suggesting that the KOR system is critical for the expression of negative affect.…”