Methadone Reverses Analgesic Tolerance Induced by Morphine Pretreatment.
BACKGROUND
Opiates such as morphine are the most powerful analgesics, but their protracted use is restrained by the development of tolerance to analgesic effects. Recent works suggest that tolerance to morphine might be due to its inability to promote mu opioid receptor endocytosis, and the co-injection of morphine with a mu opioid receptor internalizing agonist like [D-Ala(2),N-Me-Phe(4),Gly-ol(5)]enkephalin 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 mu opioid receptor internalizing agonist used in therapy) to reverse morphine tolerance and the associated cellular mechanisms in the periaqueductal gray matter, a region involved in pain control.


METHODS
We measured analgesic response following a challenge dose of morphine in the hot plate test and investigated regulation of mu opioid receptor (coupling and endocytosis) and some cellular mechanisms involved in tolerance such as adenylate cyclase superactivation and changes in N-methyl-d-aspartate receptor subunits expression and phosphorylation state.


RESULTS
A chronic treatment with morphine promoted tolerance to its analgesic effects and was associated with a lack of mu opioid receptor endocytosis, adenylate cyclase overshoot, NR2A and NR2B downregulation, and phosphorylation of NR1. We reported that a methadone treatment in morphine-treated mice reversed morphine tolerance to analgesia by promoting mu opioid receptor endocytosis and blocking cellular mechanisms of tolerance.


CONCLUSIONS
Our data might lead to rational strategies to tackle opiate tolerance in the frame of opiate rotation.
['Posa|Luca|L|', 'Accarie|Alison|A|', 'Noble|Florence|F|', 'Marie|Nicolas|N|']
D000262:Adenylyl Cyclases D000701:Analgesics, Opioid D000818:Animals D004305:Dose-Response Relationship, Drug D015536:Down-Regulation D004361:Drug Tolerance D004705:Endocytosis D008297:Male D008691:Methadone D051379:Mice D009020:Morphine D010147:Pain Measurement D010766:Phosphorylation D016194:Receptors, N-Methyl-D-Aspartate D017450:Receptors, Opioid, mu
methadone morphine mu opioid receptor endocytosis adenylate cyclase analgesia NMDA receptor