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Delta opioid receptor antagonism/inverse agonism and its effect on mu opioid receptor signaling in SH‐SY5Y cells
Author(s) -
Griggs Nicholas,
Mosberg Henry,
Traynor John
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.664.9
Subject(s) - damgo , naltrindole , pharmacology , μ opioid receptor , chemistry , opioid , agonist , naltrexone , opioid receptor , δ opioid receptor , g protein , competitive antagonist , receptor , medicine , biochemistry
Opioid analgesics are prescribed with success to combat chronic and severe pain, yet there are many clinical and public health problems associated with the use of these medications that include constipation, respiratory depression and physical dependence. Academic scientists to pharmaceutical companies are developing opioid drugs, G‐protein biased agonists and allosteric modulators to name a few, in an effort to identify safer and more effective analgesics. Previous studies have reported that the co‐administration of naltrindole (a delta opioid receptor antagonist) with morphine (mu opioid receptor agonist) in vivo maintains analgesia yet reduces the development of morphine tolerance and dependence. Following this observation, in collaboration with the Mosberg lab we have discovered and characterized several mu agonist/delta antagonist “bifunctional compounds” that lack tolerance and dependence liabilities in vivo . The goal of my studies is to use these bifunctional compounds, as well as selective mu and delta opioid receptor ligands, in an attempt to explain this phenomenon on a molecular level. The SH‐SY5Y human neuroblastoma cell line is an ideal system in which to assess mu and delta receptor cross‐talk because it endogenously expresses both receptor types. My first objective was to demonstrate mu opioid receptor tolerance at the level of the G protein (a decrease in GTPγ 35 S binding) using the selective agonist DAMGO. Compared to untreated cells, DAMGO (1μM, 6 hours) treated cells showed a 50% reduction in DAMGO‐mediated GTPγ 35 S binding and a slight decrease in basal GTPγ 35 S binding. I then found that the addition of the delta inverse agonist ICI 174,864 (1μM, 6 hours) prevented DAMGO‐mediated tolerance. To further study this response I used another delta antagonist TIPPΨ and three bifunctional compounds. Overall the results suggest that delta opioid receptor inhibition is advantageous for sustained mu opioid receptor function in a cellular model of opioid tolerance. Experiments are ongoing to decipher how delta blockade alters mu‐opioid receptor signaling. Support or Funding Information DA‐03910 and NIGMS‐GM007767