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

Abstract

Background: Morphine diminishes acute pain, but long-term use is compromised by tolerance and hyperalgesia. Studies implicate delta receptors, beta-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 mu -/- mice. Recovery was delayed until day 13 in delta-/- mice. Restoration to basal sensitivity in WT mice occurred with increased delta expression. By contrast, kappa expression was reduced, while mu 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 beta-arrestin2-/-, delta-/- 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 delta receptors, beta-arrestin2 and Src activity. Our findings suggest that MIH is caused by a tolerance-induced reduction in endogenous opioid signalling.