Sensitivity to μ-opioid receptor-mediated anti-nociception is determined by cross-regulation between μ- And δ-opioid receptors at supraspinal level

Abstract

Background and Purpose The perception of pain and its inhibition varies considerably between individuals, and this variability is still unexplained. The aim of the present study is to determine whether functional interactions between opioid receptors are involved in the inter-individual variability in the sensitivity to μ-opioid receptor agonists. Experimental Approach Anti-nociceptive tests, radioligand binding, stimulation of [ 35S]GTP-γ-S binding, inhibition of cAMP production and co-immunoprecipitation experiments were performed in two strains of rat (Sprague-Dawley bred at our university - SDU - and Wistar) that differ in their sensitivity to opioids. Key Results The increased anti-nociceptive potency of μ-opioid receptor agonists in SDU rats was reversed by the δ-opioid receptor antagonist, naltrindole. Inhibition of the binding of [ 3H] naltrindole by μ-opioid receptor agonists was different in brain membranes from SDU and Wistar rats. Differences were also evident in the effect of δ-opioid receptor ligands on the binding of [ 35S]GTP-γ-S stimulated by μ-opioid receptors agonists. No strain-related differences were detected in spinal cord membranes. The potency of morphine to inhibit cAMP production in brain membranes varied between the strains, in the presence of deltorphin II and naltrindole. Co-immunoprecipitation experiments demonstrated that δ-opioid receptors were associated with μ-opioid receptors to a higher extent in brain synaptosomal fractions from SDU than in those from Wistar rats. Conclusions and Implications There was increased supraspinal cross-talk between μ and δ-opioid receptors in SDU, as compared with Wistar rats. This was related to an enhanced sensitivity to anti-nociception induced by μ-opioid receptor agonists. © 2011 The British Pharmacological Society.