title: Chronic opioid antagonist treatment dose-dependently regulates mu-opioid receptors and trafficking proteins in vivo.
abstract: Chronic opioid antagonist treatment increases the density of mu-opioid receptors (muOR) in many model systems. In previous studies, naltrexone treatment produced an increase in muOR density accompanied by decreases in GRK-2 and DYN-2 protein abundance. To examine the relationship between changes in receptor density and proteins involved in receptor trafficking, the dose-dependent effect of chronic naloxone infusion was determined. Dose-dependent antagonism of morphine analgesia was also examined. Mice were infused with naloxone (0.1, 1.0, 5.0 mg/kg/day sc) for 7 days via osmotic pump. Controls were treated with placebo pellets. On the 7th day, morphine dose-response studies were determined using the tail flick. Other mice were sacrificed at the end of the treatment and spinal cords were collected for determination of muOR density and GRK-2 and DYN-2 protein abundance. Naloxone infusion dose-dependently increased spinal muOR density with no change in affinity. The increases in mu-receptor density were proportional to dose-dependent decreases in GRK-2 and DYN-2 protein levels. Furthermore, naloxone dose-dependently antagonized morphine. These data suggest that opioid antagonist-induced muOR up-regulation in mouse spinal cord is associated with regulation of proteins involved in receptor trafficking and support suggestions that opioid antagonist-induced receptor up-regulation is due to reduced constitutive internalization of opioid receptors.
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy and Allied Health Professions, St. John's University, Queens, NY 11439 USA.
authors.forename: Vikram
authors.initials: V
authors.lastname: Rajashekara
authors.forename: Chintan N
authors.initials: CN
authors.lastname: Patel
authors.forename: Kaushal
authors.initials: K
authors.lastname: Patel
authors.forename: Vishal
authors.initials: V
authors.lastname: Purohit
authors.forename: Byron C
authors.initials: BC
authors.lastname: Yoburn
mesh_terms: D000818:Animals; D004305:Dose-Response Relationship, Drug; D008297:Male; D051379:Mice; D009270:Naloxone / Q000008:administration & dosage*; D009292:Narcotic Antagonists / Q000008:administration & dosage*; D011485:Protein Binding / Q000187:drug effects / Q000502:physiology; D021381:Protein Transport / Q000187:drug effects / Q000502:physiology; D017450:Receptors, Opioid, mu / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology
chemical_list: D009292:Narcotic Antagonists; D017450:Receptors, Opioid, mu; D009270:Naloxone