Src Kinase Inhibition Attenuates Morphine Tolerance without Affecting Reinforcement or Psychomotor Stimulation

Fiona A. Bull, Daniel T. Baptista-Hon, Claire Sneddon, Lisa Wright, Wendy Walwyn, Tim G. Hales (Lead / Corresponding author)

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    5 Citations (Scopus)
    142 Downloads (Pure)

    Abstract

    Background: Prolonged opioid administration leads to tolerance characterised by reduced analgesic potency. Pain management is additionally compromised by the hedonic effects of opioids, the cause of their misuse. The multifunctional protein β-arrestin2 regulates the hedonic effects of morphine and participates in tolerance. These actions might reflect µ opioid receptor up-regulation through reduced endocytosis. β-Arrestin2 also recruits kinases to µ receptors. We explored the role of Src kinase in morphine analgesic tolerance, locomotor stimulation and reinforcement in C57BL/6 mice.

    Methods: Analgesic (tail withdrawal latency; % maximum possible effect (MPE), n = 8-16), locomotor (distance travelled, n = 7-8) and reinforcing (conditioned place preference, n = 7-8) effects of morphine were compared in wild type, µ+/-, µ-/- and β-arrestin2-/- mice. The influence of c-Src inhibitors, dasatinib (n = 8) and PP2 (n = 12), were examined.

    Results: Analgesia in morphine treated wild type mice exhibited tolerance, declining by day 10 to a median of 62% MPE (interquartile range (IQR): 29-92). Tolerance was absent from mice receiving dasatinib. Tolerance was enhanced in µ+/- mice (34% MPE; IQR: 5-52 on day 5); dasatinib attenuated tolerance (100% MPE; IQR: 68-100) as did PP2 (91% MPE; IQR: 78-100). By contrast, c-Src inhibition neither affected morphine-evoked locomotor stimulation nor reinforcement. Remarkably, dasatinib not only attenuated tolerance, but also reversed established tolerance in µ+/- mice.

    Conclusions: The ability of c-Src inhibitors to inhibit tolerance, thereby restoring analgesia, without altering the hedonic effect of morphine, make c-Src inhibitors promising candidates as adjuncts to opioid analgesics.
    Original languageEnglish
    Pages (from-to)878-889
    Number of pages12
    JournalANESTHESIOLOGY
    Volume127
    Issue number5
    DOIs
    Publication statusPublished - 1 Nov 2017

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