Morphine-induced analgesic tolerance, locomotor sensitization and physical dependence do not require modification of mu opioid receptor, cdk5 and adenylate cyclase activity.
Acute morphine administration produces analgesia and reward, but prolonged use may lead to analgesic tolerance in patients chronically treated for pain and to compulsive intake in opioid addicts. Moreover, long-term exposure may induce physical dependence, manifested as somatic withdrawal symptoms in the absence of the drug. We set up three behavioral paradigms to model these adaptations in mice, using distinct regimens of repeated morphine injections to induce either analgesic tolerance, locomotor sensitization or physical dependence. Interestingly, mice tolerant to analgesia were not sensitized to hyperlocomotion, whereas sensitized mice displayed some analgesic tolerance. We then examined candidate molecular modifications that could underlie the development of each behavioral adaptation. First, analgesic tolerance was not accompanied by mu opioid receptor desensitization in the periaqueductal gray. Second, cdk5 and p35 protein levels were unchanged in caudate-putamen, nucleus accumbens and prefrontal cortex of mice displaying locomotor sensitization. Finally, naloxone-precipitated morphine withdrawal did not enhance basal or forskolin-stimulated adenylate cyclase activity in nucleus accumbens, prefrontal cortex, amygdala, bed nucleus of stria terminalis or periaqueductal gray. Therefore, the expression of behavioral adaptations to chronic morphine treatment was not associated with the regulation of micro opioid receptor, cdk5 or adenylate cyclase activity in relevant brain areas. Although we cannot exclude that these modifications were not detected under our experimental conditions, another hypothesis is that alternative molecular mechanisms, yet to be discovered, underlie analgesic tolerance, locomotor sensitization and physical dependence induced by chronic morphine administration.
Contet
Candice
C
Département de Neurobiologie, IGBMC (Institut de Génétique et de Biologie Moléculaire et Cellulaire), INSERM U596, CNRS UMR7104, Université Louis Pasteur, 1 rue Laurent Fries, F-67400 Illkirch, France.
Filliol
Dominique
D
Matifas
Audrey
A
Kieffer
Brigitte L
BL
D000262:Adenylyl Cyclases / Q000378:metabolism*; D000700:Analgesics; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001921:Brain / Q000033:anatomy & histology / Q000187:drug effects / Q000378:metabolism; D051360:Cyclin-Dependent Kinase 5 / Q000378:metabolism*; D004334:Drug Administration Schedule; D004361:Drug Tolerance / Q000502:physiology*; D005260:Female; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000494:pharmacology; D008124:Locomotion / Q000187:drug effects*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009020:Morphine / Q000008:administration & dosage*; D009021:Morphine Dependence / Q000209:etiology*; D009270:Naloxone / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology; D009294:Narcotics / Q000008:administration & dosage*; D011485:Protein Binding / Q000187:drug effects; D017450:Receptors, Opioid, mu / Q000378:metabolism*; D013997:Time Factors
D000700:Analgesics; D009292:Narcotic Antagonists; D009294:Narcotics; D017450:Receptors, Opioid, mu; D009270:Naloxone; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D009020:Morphine; D051360:Cyclin-Dependent Kinase 5; C495907:Cdk5 protein, rat; D000262:Adenylyl Cyclases