Original Article

Neuropsychopharmacology (2015) 40, 2865–2872; doi:10.1038/npp.2015.159; published online 1 July 2015

Immediate and Persistent Effects of Salvinorin A on the Kappa Opioid Receptor in Rodents, Monitored In Vivo with PET

Michael S Placzek1,2, Genevieve C Van de Bittner1, Hsiao-Ying Wey1, Scott E Lukas2 and Jacob M Hooker1

  1. 1Department of Radiology, Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, USA
  2. 2Department of Psychiatry, McLean Imaging Center, McLean Hospital, Harvard Medical School, Belmont, MA, USA

Correspondence: Dr JM Hooker, Department of Radiology, Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Harvard Medical School, 149 13th Street, Charlestown, MA 02129, USA, Tel: +1 617 726 6596, Fax: +1 617 726 7422, E-mail: hooker@nmr.mgh.harvard.edu

Received 16 April 2015; Revised 18 May 2015; Accepted 2 June 2015
Accepted article preview online 10 June 2015; Advance online publication 1 July 2015

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Abstract

Monitoring changes in opioid receptor binding with positron emission tomography (PET) could lead to a better understanding of tolerance and addiction because altered opioid receptor dynamics following agonist exposure has been linked to tolerance mechanisms. We have studied changes in kappa opioid receptor (KOR) binding availability in vivo with PET following kappa opioid agonist administration. Male Sprague–Dawley rats (n=31) were anesthetized and treated with the (KOR) agonist salvinorin A (0.01–1.8mg/kg, i.v.) before administration of the KOR selective radiotracer [11C]GR103545. When salvinorin A was administered 1min prior to injection of the radiotracer, [11C]GR103545 binding potential (BPND) was decreased in a dose-dependent manner, indicating receptor binding competition. In addition, the unique pharmacokinetics of salvinorin A (half-life ~8min in non-human primates) allowed us to study the residual impact on KOR after the drug had eliminated from the brain. Salvinorin A was administered up to 5h prior to [11C]GR103545, and the changes in BPND were compared with baseline, 2.5h, 1h, and 1min pretreatment times. At lower doses (0.18mg/kg and 0.32mg/kg) we observed no prolonged effect on KOR binding but at 0.60mg/kg salvinorin A induced a sustained decrease in KOR binding (BPND decreased by 40–49%) which persisted up to 2.5h post administration, long after salvinorin A had been eliminated from the brain. These data point towards an agonist-induced adaptive response by KOR, the dynamics of which have not been previously studied in vivo with PET.

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