Morphine-induced mechanical hypersensitivity in mice requires delta receptors, beta-arrestin2 and c-Src activity

Abstract

BackgroundMorphine 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. MethodsWe 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 Freunds adjuvant (CFA). We explored the expression of opioid genes in the spinal cord using quantitative RT-PCR. ResultsCFA-evoked hypersensitivity ceased on day 7 in WT mice but persisted in -/- 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 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. ConclusionsLike 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.