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Opioid–galanin receptor heteromers mediate the dopaminergic effects of opioids


Ning-Sheng Cai et al., The Journal of Clinical Investigation, 2019


Identifying nonaddictive opioid medications is a high priority in medical science, but μ-opioid receptors (MORs) mediate both the analgesic and addictive effects of opioids. And as possibly everyone knows, the opioid epidemic shows a severe public health crisis worldwide.
Maintenance treatment with the (MOR) agonist methadone is the most highly researched and evidence-based treatment for opioid use disorder. Yet public perception concerning the substitution of illicit drugs (such as heroin) with medication (such as methadone) has led to stigmatized views of maintenance treatment, stalling the advancement of addiction treatment policy and access to medication-based treatments. MOR agonism also offers the most effective treatment for severe pain, making the search for a nonaddictive opioid drug the holy grail of pain research.
The neuropeptide galanin acts as a modulator of neurotransmission in the CNS and the PNS, and It is coexpressed with different neurotransmitters and coreleased by the major ascending noradrenergic, serotoninergic, histaminergic, and cholinergic systems. The authors recently reported the existence of functionally significant heteromers of the MOR and galanin 1 receptor (Gal1R) in the ventral tegmental area that could explain these galanin-opioid antagonistic interactions.
The present study sought to answer 2 main questions that arose from our study of MOR-Gal1R heteromers: (a) What are the mechanisms involved in the interactions between galanin and opioid ligands within the MOR-Gal1R heteromer? and (b) Do these interactions also involve morphine and synthetic opioids, such as methadone or fentanyl, differentially?

Results from nanoScan PET/CT

For the animal experiments, the authors have used a nanoScan PET/CT, which provided high resolution and sensitivity to follow the [18F]FDG uptake in the selected brain regions, and find significant differences after using the below mentioned drugs in rats.
The timeline of the experiment was slightly different from the usual PET/CT scans, as it involved two acquisitions: for the baseline scan, saline was injected i.p. (1 ml/kg) into the rats, and after 30 mins, [18F]FDG tracer was applied (i.p. as well). After 30 mins post-injection time, conventional 20 mins long PET/CT acquisitions was performed. After 2 days, the second part was coming, but instead of saline, morphine (1 mg/kg) or methadone (1 mg/kg) was injected i.p. After accessing [18F]FDG, the second PET/CT was conducted as before. For the reconstruction, Teratomo 3D engine was used with attenuation and scatter corrections, with a 0.4 mm resolution.

Figure 4. shows the main results from the PET/CT acquisitions: A. The timeline of the experiment (explained above). B. [18F]FDG uptake after administration of saline (baseline, n = 14), morphine (1 mg/kg, n = 7), or methadone (1 mg/kg, n = 7). Coronal and sagittal images (1.5 mm anterior to bregma and 1.4 mm lateral from the midline, respectively) show the average SUVR calculated using the whole brain as a reference region. C. Voxel-based parametric mapping analyses revealed significantly decreased metabolic activity from baseline values in a basal forebrain region that included the nucleus accumbens and its projecting areas after morphine, but not methadone, treatment. Statistical parametric maps of significant decreases of [18F]FDG uptake (P < 0.05, paired t test). D. and E. VOI analyses of the frontal cortex (FCx), dorsal striatum (DS), and basal forebrain (BF) region, showing a significant differential pattern of [18F]FDG uptake after administration of morphine (D) or methadone (E).

  • The authors found significant pharmacodynamic difference between morphine and methadone that is determined entirely by heteromerization of MORs with Gal1Rs, rendering a profound decrease in the potency of methadone. This finding was explained by the weaker proficiency of methadone in activating the dopaminergic system as compared with morphine and predicted a dissociation of the therapeutic and euphoric effects of methadone, which was corroborated by a significantly lower incidence of self-reports of feeling “high” in methadone-medicated patients.
  • These results suggest that μ-opioid–Gal1R heteromers mediate the dopaminergic effects of opioids. The results further suggest a lower addictive liability of some opioids, such as methadone, due to their selective low potency for the μ-opioid–Gal1R heteromer.

Full article on jci.org

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