Neuropharmacology

Biography

Biography: Nicolas Marie

Abstract

Opiates such as morphine, are the most powerful analgesics however their protracted use is restricted by the development of tolerance to analgesic effects. Previous data suggest that the morphine inability to promote mu opioid receptor (MOPr) endocytosis could be at the origin of the tolerance and the co-injection of morphine with a MOPr internalizing reduces tolerance to morphine. So far, no studies have been conducted to evaluate the ability of methadone to reduce morphine tolerance in morphine-pretreated animals, a treatment sequence that could be encountered in opiate rotation protocol. We investigated the ability of methadone (a MOPr internalizing agonist used in therapeutic) to reverse morphine tolerance and the associated cellular mechanisms in the periaqueductal gray matter, a key region in pain control. Analgesic response was measured following a challenge dose of morphine in the hot plate test and regulation of MOPr (coupling and endocytosis) and some cellular mechanisms involved in tolerance such as adenylate cyclase superactivation and changes in N-methyl-d-aspartate (NMDA) receptor subunits expression and phosphorylation state were investigated. A chronic treatment with morphine promoted tolerance to its analgesic effects and was associated with a absence of MOPr endocytosis, adenylate cyclase overshoot, NR2A and NR2B down-regulation and NR1 phosphorylation. We found that a methadone treatment in morphine-treated mice reversed morphine tolerance to analgesia by promoting MOPr endocytosis and blocking cellular mechanisms of tolerance. Our data might lead to rational strategies to tackle opiate tolerance in the frame of opiate rotation.