Evaluation of dynorphin and kappa-opioid receptor level in the human blood lymphocytes and plasma: Possible role as a biomarker in severe opioid use disorder

Background: The dynorphin (DYN)/kappa opioid receptor (KOR) system plays an important role in the development of addiction, and dysregulation of this system could lead to abnormal activity in the reward pathway. It has been reported that the expression state of the neurotransmitters and their receptors in the brain is reflected in peripheral blood lymphocytes (PBLs). Methods: We have evaluated the PBLs and plasma samples of four groups: 1) subjects with severe opioid use disorder (SOD), 2) methadone-maintenance treated (MMT) individuals, 3) long-term abstinent subjects having former SOD, and 4) healthy control subjects (n = 20 in each group). The mRNA expression level of preprodynorphin (pPDYN) and KOR in PBLs has been evaluated by real-time PCR. Peptide expression of PDYN in PBLs has been studied by western blot, and DYN concentration in plasma has been measured by ELISA. Results: The relative expression level of the pPDYN mRNA and PDYN peptide in PBLs were significantly upregulated in SOD, MMT, and abstinent groups compared to control subjects. No significant difference was found in the plasma DYN concentration between study groups. The expression level of the KOR mRNA in PBLs was significantly decreased in all three study groups compared to the control subjects. Conclusion: the expression changes in the DYN/KOR system after chronic exposure to opioids, including methadone, seems to be stable and does not return to normal levels even after 12 months abstinence. These longtime and permanent changes in PBLs may serve as a biomarker and footprint of SOD development in the periphery.