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Supra‐additive effects of morphine and the α2/3 preferring GABA A receptor ligand MP‐III‐024 on mechanical hyperalgesia and thermal nociception
Author(s) -
Fischer Bradford,
Rahman Mohammad,
Keck Thomas,
Poe Michael,
Sharmin Dishary,
Cook James
Publication year - 2021
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.2021.35.s1.03252
Subject(s) - morphine , nociception , pharmacology , opioid , hyperalgesia , chemistry , agonist , gabaa receptor , receptor , allosteric modulator , analgesic , medicine , biochemistry
Opioid and GABA A receptors are both located in central nociceptive pathways and compounds that activate these receptors have pain‐relieving properties. To date, the interactive effects of concurrent administration of these compounds in preclinical models of pain‐like behaviors have not been assessed. The purpose of this study was to examine the interactive effects of the µ‐opioid agonist morphine and the α2GABA A and α3GABA A receptor positive allosteric modulator methyl 8‐ethynyl‐6‐(pyridin‐2‐yl)‐4H‐benzo[f]imidazo[1,5‐a][1,4]diazepine‐3‐carboxylate (MP‐III‐024) in preclinical models of mechanical hyperalgesia and thermal nociception. Initially, the antihyperalgesic and antinociceptive effects of morphine and MP‐III‐024 administered alone were assessed, followed by fixed‐ratio mixtures of MP‐III‐024/morphine combinations. Drug interaction data were analyzed using isobolographic and dose‐addition analyses. In the assay of mechanical hyperalgesia, each compound produced dose‐dependent antihyperalgesic effects, whereas only morphine was effective on thermal nociception. Fixed‐ratio mixtures of MP‐III‐024/morphine were also dose‐dependently effective in both procedures. These drug combination studies revealed that morphine and MP‐III‐024 produced supra‐additive (synergistic) effects in both assays, depending on their relative proportions. These results demonstrate an interaction between α2GABA A and α3GABA A receptor‐ and µ‐opioid receptor‐mediated signals, and suggest that combination therapy may be useful for the treatment of pain‐related disorders.