Abstract
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 Statement
The authors have declared no competing interest.
Footnotes
Data Availability: The data that support the findings of this study are available from the corresponding author, upon reasonable request.
Funding/support This study was supported by a NIAA (BJA/RCoA) grants WKR0-2017-0066 and WKR0-2019-0067 awarded to TGH.
Conflict of Interest The authors state that there were no conflicts of interest.