TY - JOUR
T1 - The role of orexin-1 receptor signaling in demand for the opioid fentanyl
AU - Fragale, Jennifer E.
AU - Pantazis, Caroline B.
AU - James, Morgan H.
AU - Aston-Jones, Gary
N1 - Funding Information:
This work was supported by NIH postdoctoral fellowship (K12 GM093854) to JEF, NIH graduate fellowship (F31DA042588) to CBP, National Health and Medical Research Council of Australia C.J. Martin Fellowship (No. 1072706) and National Institute on Drug Abuse (NIDA; K99DA045765) Fellowships to MHJ, and by a U.S. Public Health Service award from NIDA to GA-J (R01 DA006214). The authors declare that the research was conducted without any commercial or financial relationships that could be considered a potential conflict of interest.
Publisher Copyright:
© 2019, American College of Neuropsychopharmacology.
PY - 2019/9/1
Y1 - 2019/9/1
N2 - The orexin system is a potential treatment target for drug addiction. Orexin-1 receptor (OxR1) antagonism reduces demand for cocaine and remifentanil, indicating that orexin-based therapies may reduce demand for many classes of abused drugs. However, pharmacokinetics vary greatly among opioids and it is unclear if OxR1 antagonism would reduce demand for all opioids, particularly ones with high abuse liability. Here, we established a behavioral economics (BE) procedure to assess the effects of OxR1 antagonism on demand for the highly abused opioid fentanyl. We also investigated the utility of our procedure to predict OxR1 antagonism efficacy and relapse propensity. Demand parameters α (demand elasticity or price sensitivity of consumption, an inverse measure of drug motivation) and Qo (drug consumption at null cost) were assessed. The OxR1 antagonist SB-334867 (SB) decreased motivation (increased α) for fentanyl without affecting Qo. Baseline α values predicted SB efficacy, such that SB was most effective at reducing motivation (increasing α) in highly motivated rats. Baseline α values predicted the amount of cued reinstatement of fentanyl seeking; this reinstatement behavior was attenuated by SB administration. These results highlight the promise of the orexin system as a treatment target for opioid addiction and emphasize the usefulness of BE procedures in the study of opioid abuse.
AB - The orexin system is a potential treatment target for drug addiction. Orexin-1 receptor (OxR1) antagonism reduces demand for cocaine and remifentanil, indicating that orexin-based therapies may reduce demand for many classes of abused drugs. However, pharmacokinetics vary greatly among opioids and it is unclear if OxR1 antagonism would reduce demand for all opioids, particularly ones with high abuse liability. Here, we established a behavioral economics (BE) procedure to assess the effects of OxR1 antagonism on demand for the highly abused opioid fentanyl. We also investigated the utility of our procedure to predict OxR1 antagonism efficacy and relapse propensity. Demand parameters α (demand elasticity or price sensitivity of consumption, an inverse measure of drug motivation) and Qo (drug consumption at null cost) were assessed. The OxR1 antagonist SB-334867 (SB) decreased motivation (increased α) for fentanyl without affecting Qo. Baseline α values predicted SB efficacy, such that SB was most effective at reducing motivation (increasing α) in highly motivated rats. Baseline α values predicted the amount of cued reinstatement of fentanyl seeking; this reinstatement behavior was attenuated by SB administration. These results highlight the promise of the orexin system as a treatment target for opioid addiction and emphasize the usefulness of BE procedures in the study of opioid abuse.
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U2 - 10.1038/s41386-019-0420-x
DO - 10.1038/s41386-019-0420-x
M3 - Article
C2 - 31112988
AN - SCOPUS:85066780261
VL - 44
SP - 1690
EP - 1697
JO - Neuropsychopharmacology
JF - Neuropsychopharmacology
SN - 0893-133X
IS - 10
ER -