Decreased opioid receptor availability and impaired neurometabolic coupling as signatures of morphine tolerance in male rats: A positron emission tomography study

Translational neuroimaging techniques are needed to address the impact of opioid tolerance on brain function and quantitatively monitor the impaired neuropharmacological response to opioids at the CNS level. A multiparametric PET study was conducted in rats. Rats received morphine daily to induce tolerance (15 mg/kg/day for 5 days), followed by 2-day withdrawal. Then, opioid effects were precipitated using a buprenorphine challenge (0.1 mg/kg, s.c, BUP-challenge), which safely enables full occupancy of available mu-opioid receptors (MOR). The impact of the BUP-challenge on the pain threshold was estimated using the hot-plate test. The corresponding availability of MOR was estimated using [¹¹C]buprenorphine PET imaging (n = 4). The brain glucose metabolism was investigated using [¹⁸F]2-fluoro-D-deoxy-glucose ([¹⁸F]FDG) PET imaging after the BUP-challenge or saline (n = 5-6). Opioid tolerance was confirmed by the attenuated antinociceptive response to the BUP-challenge in morphine-treated rats compared to saline controls (p < 0.001). In tolerant rats, [¹¹C]buprenorphine binding was decreased in MOR-rich regions (p < 0.01), and the baseline uptake of [¹⁸F]FDG was decreased (p < 0.05). The BUP-challenge decreased [¹⁸F]FDG uptake to a lower extent in tolerant rats compared with opioid-naive animals (p < 0.05), suggesting impaired neurometabolic coupling. Moreover, the impact of the BUP-challenge on the neurometabolic connectivity across brain regions was disrupted by opioid tolerance. PET imaging enables the study of the decreased availability of MOR and impaired neurometabolic coupling as molecular signatures of opioid tolerance in rats. Combining molecular neuroimaging with a suitable pharmacological challenge may provide a translational and quantitative paradigm to explore opioid tolerance at the CNS level in parallel to pharmacodynamics.