Morphine-induced mechanical hypersensitivity in mice requires δ receptors, β-arrestin2 and c-Src activity

    Research output: Contribution to conferencePosterpeer-review


    Background: Morphine diminishes acute pain, but long-term use is compromised by tolerance and hyperalgesia. Studies implicate  receptors, β-arrestin2 and Src kinase in tolerance. We examined whether these proteins are also involved in morphine-induced hypersensitivity (MIH). A common pathway for tolerance and hypersensitivity may provide a single target to guide improved analgesic approaches.
    Methods: We examined mechanical sensitivity using automated von Frey in wild type (WT) and transgenic male and female C57Bl/6 mice before and after hind paw inflammation by complete Freund’s adjuvant (CFA). We explored the expression of opioid genes in the spinal cord using quantitative RT-PCR.
    Results: CFA-evoked hypersensitivity ceased on day 7 in WT mice but persisted for the 15-day testing period in μ-/- mice. Recovery was delayed until day 13 in -/- mice. Restoration to basal sensitivity in WT mice occurred with increased δ expression. By contrast, κ expression was reduced, while μ remained unchanged. Daily morphine reduced hypersensitivity in WT mice on day 3 compared to controls, however hypersensitivity recurred on day 9 and beyond. By contrast, WT mice had no recurrence of hypersensitivity in the absence of daily morphine. We used β-arrestin2-/-, -/- and Src inhibition by dasatinib in WT mice to establish whether these approaches, which diminish tolerance, also attenuate MIH. While none of these approaches affected CFA-evoked inflammation or acute hypersensitivity, all caused sustained morphine anti-hypersensitivity, abolishing MIH.
    Conclusions: Like morphine tolerance, MIH in this model requires  receptors, β-arrestin2 and Src activity. Our findings suggest that MIH is caused by a tolerance-induced reduction in endogenous opioid signalling.
    Original languageEnglish
    Publication statusPublished - 22 Sept 2021
    EventInternational Association for the Study of Pain - Toronto, Canada
    Duration: 19 Sept 202223 Sept 2022
    Conference number: 19


    ConferenceInternational Association for the Study of Pain
    Abbreviated titleIASP
    Internet address


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