Up to 10% of patients who are prescribed opioids for chronic pain develop an opioid use disorder. The molecular mechanisms underlying individual differences in susceptibility to opioid use disorder have been unclear.
Researchers used a heterogeneous rat population to mimic behavioral and genetic diversity among humans. The rats were allowed to press a lever to self-administer intravenous infusions of oxycodone up to 12 hours each day for 3 weeks and were divided into high-addicted and low-addicted groups.
Compared with rats never exposed to oxycodone, high-addicted rats showed lower levels of the endogenous opioid-like peptide nociceptin in the brain’s central nucleus of the amygdala (CeA).
Compared with low-addicted rats, high-addicted rats also showed higher spontaneous activity of CeA neurons that release the inhibitory brain chemical γ-aminobutyric acid (GABA).
Nociceptin administration decreased the activity of these neurons to a greater extent in CeA slices from high-addicted rats compared with low-addicted rats. Moreover, nociceptin injections into the CeA reduced oxycodone self-administration in high-addicted rats, but not in low-addicted rats.
According to the authors, the findings suggest that opioids may lead to addiction in susceptible individuals by decreasing nociceptin levels in the CeA and subsequently increasing GABA release. In addition, the results suggest that small molecules targeting the nociceptin system may help treat opioid use disorder
Molecular mechanism of drug addiction
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