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TRV130 partial agonism and capacity to induce anti‐nociceptive tolerance revealed through reducing available μ‐opioid receptor number
Author(s) -
Singleton Samuel,
BaptistaHon Daniel T.,
Edelsten Emily,
McCaughey Kirsty S.,
Camplisson Ewan,
Hales Tim G.
Publication year - 2021
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/bph.15409
Subject(s) - partial agonist , nociception , receptor , damgo , pharmacology , agonist , morphine , opioid , intrinsic activity , receptor antagonist , antagonist , μ opioid receptor , opioid receptor , chemistry , medicine , biology
Background and Purpose β‐Arrestin2 recruitment to μ‐receptors may contribute to the development of opioid side effects. This possibility led to the development of TRV130 and PZM21, opioids reportedly biased against β‐arrestin2 recruitment in favour of G‐protein signalling. However, low efficacy β‐arrestin2 recruitment by TRV130 and PZM21 may simply reflect partial agonism overlooked due to overexpression of μ‐receptors. Experimental Approach Efficacies and apparent potencies of DAMGO, morphine, PZM21 and TRV130 as stimulators of β‐arrestin2 recruitment and inhibitors of cAMP accumulation were assessed in CHO cells stably expressing μ‐receptors. Receptor availability was depleted through prior exposure of cells to the irreversible antagonist, β‐FNA. We also examined whether μ‐receptor availability influences TRV130 anti‐nociception and/or tolerance using the tail withdrawal assay in wild‐type C57BL/6 and μ+/− mice. Key Results Morphine, PZM21 and TRV130 were partial agonists in the β‐arrestin2 recruitment assay. Only TRV130 exhibited partial agonism in the cAMP assay. Exposure to β‐FNA to reduce μ‐receptor availability further limited the efficacy of TRV130 and revealed morphine and PZM21 to be partial agonists. Despite having partial efficacy in vitro, TRV130 caused potent anti‐nociception (ED 50 : 0.33 mg·kg −1 ) in wild‐type mice, without tolerance after daily administration for 10 days. TRV130 caused similar anti‐nociception in μ+/− mice, with marked tolerance on day 4 of injections. Conclusion and Implications Our findings emphasise the importance of receptor reserve when characterising μ‐receptor agonists. Reduced receptor availability reveals that TRV130 is a partial agonist capable of tolerance, despite having limited efficacy for β‐arrestin2 recruitment to the μ‐receptor.