RT Journal Article
SR Electronic
T1 Morphine-induced mechanical hypersensitivity in mice requires δ receptors, β-arrestin2 and c-Src activity
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2022.12.16.520707
DO 10.1101/2022.12.16.520707
A1 Singleton, Samuel
A1 Hales, Tim G.
YR 2022
UL http://biorxiv.org/content/early/2022/12/19/2022.12.16.520707.abstract
AB Background Morphine diminishes acute pain, but long-term use is compromised by tolerance and hyperalgesia. Studies implicate δ 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 in μ-/- mice. Recovery was delayed until day 13 in δ-/- 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-/-, δ-/- 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 δ receptors, β-arrestin2 and Src activity. Our findings suggest that MIH is caused by a tolerance-induced reduction in endogenous opioid signalling.Competing Interest StatementThe authors have declared no competing interest.