title: Molecular mechanisms underlying the enhanced analgesic effect of oxycodone compared to morphine in chemotherapy-induced neuropathic pain.
abstract: Oxycodone is a μ-opioid receptor agonist, used for the treatment of a large variety of painful disorders. Several studies have reported that oxycodone is a more potent pain reliever than morphine, and that it improves the quality of life of patients. However, the neurobiological mechanisms underlying the therapeutic action of these two opioids are only partially understood. The aim of this study was to define the molecular changes underlying the long-lasting analgesic effects of oxycodone and morphine in an animal model of peripheral neuropathy induced by a chemotherapic agent, vincristine. Using a behavioural approach, we show that oxycodone maintains an optimal analgesic effect after chronic treatment, whereas the effect of morphine dies down. In addition, using DNA microarray technology on dorsal root ganglia, we provide evidence that the long-term analgesic effect of oxycodone is due to an up-regulation in GABAB receptor expression in sensory neurons. These receptors are transported to their central terminals within the dorsal horn, and subsequently reinforce a presynaptic inhibition, since only the long-lasting (and not acute) anti-hyperalgesic effect of oxycodone was abolished by intrathecal administration of a GABAB receptor antagonist; in contrast, the morphine effect was unaffected. Our study demonstrates that the GABAB receptor is functionally required for the alleviating effect of oxycodone in neuropathic pain condition, thus providing new insight into the molecular mechanisms underlying the sustained analgesic action of oxycodone.
authors.affiliation: Brain Plasticity Unit, ESPCI-ParisTech, Paris, France; Centre National de la Recherche Scientifique, UMR 8249, Paris, France; Neurorestoration Group, The Wolfson Centre for Age-Related Diseases, King's College London, London, United Kingdom.
authors.forename: Karine
authors.initials: K
authors.lastname: Thibault
authors.affiliation: Brain Plasticity Unit, ESPCI-ParisTech, Paris, France; Centre National de la Recherche Scientifique, UMR 8249, Paris, France.
authors.forename: Bernard
authors.initials: B
authors.lastname: Calvino
authors.affiliation: Equipe de Statistique Appliquée, ESPCI-ParisTech, Paris, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Rivals
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, Unité 1107, NEURO-DOL, Clermont-Ferrand, France; Clermont Université, Université d'Auvergne, Pharmacologie Fondamentale et Clinique de la Douleur, Clermont-Ferrand, France.
authors.forename: Fabien
authors.initials: F
authors.lastname: Marchand
authors.affiliation: Brain Plasticity Unit, ESPCI-ParisTech, Paris, France; Centre National de la Recherche Scientifique, UMR 8249, Paris, France.
authors.forename: Sophie
authors.initials: S
authors.lastname: Dubacq
authors.affiliation: Neurorestoration Group, The Wolfson Centre for Age-Related Diseases, King's College London, London, United Kingdom.
authors.forename: Stephen B
authors.initials: SB
authors.lastname: McMahon
authors.affiliation: Brain Plasticity Unit, ESPCI-ParisTech, Paris, France; Centre National de la Recherche Scientifique, UMR 8249, Paris, France.
authors.forename: Sophie
authors.initials: S
authors.lastname: Pezet
mesh_terms: D000701:Analgesics, Opioid / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects; D001522:Behavior, Animal / Q000187:drug effects; D004195:Disease Models, Animal; D005727:Ganglia, Spinal / Q000187:drug effects / Q000378:metabolism; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects; D008297:Male; D009020:Morphine / Q000008:administration & dosage / Q000494:pharmacology*; D009437:Neuralgia / Q000139:chemically induced / Q000188:drug therapy* / Q000209:etiology*; D010098:Oxycodone / Q000008:administration & dosage / Q000494:pharmacology*; D021381:Protein Transport; D018080:Receptors, GABA-B / Q000235:genetics / Q000378:metabolism; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism
chemical_list: D000701:Analgesics, Opioid; D000970:Antineoplastic Agents; D018080:Receptors, GABA-B; D009020:Morphine; D010098:Oxycodone