Chronic opioid antagonist treatment dose-dependently regulates μ-opioid receptors and trafficking proteins in vivo

Rajashekara, Vikram; Patel, Chintan; Patel, Kaushal; Purohit, Vishal B.; Yoburn, Byron C.

doi:10.1016/s0091-3057(03)00166-7

Cited by 30 publications

(23 citation statements)

References 21 publications

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“…3D.). These data with naloxone and naltrexone are consistent with earlier studies (e.g., Patel et al, 2003;Rajashekara et al, 2003), whereas up-regulation following 6␤-naltrexol is a novel finding. Naloxone and 6␤-naltrexol were equipotent in producing Ϸ2-fold increase in morphine potency (Fig.…”

Section: Discussionsupporting

confidence: 91%

“…4, left). Increases in the functional potency of opioid agonists following antagonist treatment have been reported often (e.g., Patel et al, 2003;Rajashekara et al, 2003). Overall, these findings demonstrate that inverse agonists and a neutral antagonist are equieffective in up-regulating -opioid receptors and producing functional supersensitivity.…”

Section: Discussionsupporting

confidence: 52%

“…These results contrast with the effects of chronic antagonist treatment. In the intact mouse, chronic antagonist treatment induces no change in -opioid receptor mRNA and decreases in Dynamin-2 and GRK-2 (Duttaroy et al, 1999;Rajashekara et al, 2003). Interestingly, antagonist-induced up-regulation of -opioid receptors is detected by radioligand binding studies, but not by Western blotting, a finding that suggests that up-regulation may involve recruitment of immature receptors (Yoburn et al, 2004).…”

Section: Discussionmentioning

confidence: 93%

“…Both opioid agonists and antagonists have been shown to regulate -opioid receptor density (Chakrabarti et al, 1997;Zaki et al, 2000;Rajashekara et al, 2003), and these changes can have an impact on the potency of opioid agonists (e.g., Stafford et al, 2001;Patel et al, 2003). The efficacy of an opioid agonist has been proposed to play an important role in -opioid receptor regulation (Patel et al, 2002;Pawar et al, 2007).…”

mentioning

confidence: 99%

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μ-Opioid Receptor Up-Regulation and Functional Supersensitivity Are Independent of Antagonist Efficacy

Sirohi

Kumar²,

Yoburn³

2007

J Pharmacol Exp Ther

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Chronic opioid antagonist treatment up-regulates opioid receptors and produces functional supersensitivity. Although opioid antagonists vary from neutral to inverse, the role of antagonist efficacy in mediating the chronic effects of opioid antagonists is not known. In this study, the effects of two putative inverse agonists (naltrexone, naloxone) and a putative neutral antagonist (6␤-naltrexol) were examined. Initially, peak effect (40 min, naltrexone and naloxone; 70 min, 6␤-naltrexol) and relative potency to antagonize morphine analgesia were determined (relative potencies ϭ 1, 2, and 16, 6␤-naltrexol, naloxone, and naltrexone, respectively). Next, mice were infused for 7 days with naloxone (0.1-10 mg/kg/day), naltrexone (10 or 15 mg s.c. pellet), or 6␤-naltrexol (0.2-20 mg/kg/day), and spinal -opioid receptor density was examined, or morphine analgesia doseresponse studies were conducted. All antagonists up-regulated -opioid receptors (60 -122%) and induced supersensitivity (1.8 -2.0-fold increase in morphine potency). There were no differences in antagonist potency to produce up-regulation or supersensitivity. These data suggest that opioid antagonist-induced -opioid receptor up-regulation and supersensitivity require occupancy of the receptor and that antagonist efficacy is not critical. Finally, the ED 50 to precipitate withdrawal jumping was examined in morphine-dependent mice. Naltrexone, naloxone, and 6␤-naltrexol produced withdrawal jumping, although potencies relative to 6␤-naltrexol were 211, 96, and 1, respectively. Thus, antagonist potency to precipitate opioid withdrawal was related to inverse agonist efficacy. Overall, the estimated relative potency of the opioid antagonists was a function of the outcome measured, and inverse agonist activity was not required for -opioid receptor up-regulation and supersensitivity.

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Section: Discussionsupporting

confidence: 91%

Section: Discussionsupporting

confidence: 52%

Section: Discussionmentioning

confidence: 93%

mentioning

confidence: 99%

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μ-Opioid Receptor Up-Regulation and Functional Supersensitivity Are Independent of Antagonist Efficacy

Sirohi

Kumar²,

Yoburn³

2007

J Pharmacol Exp Ther

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“…Chronic antagonist-induced decreases in lysosomal enzyme (␤-glucuronidase and ␤-hexoseaminidase) activities and in trafficking proteins (G protein-coupled receptor kinase 2 and dynamin2) were reported to be important in facilitating receptor expression (Belcheva et al, 1992;Rajashekara et al, 2003). However, our results do not support this explanation because naloxone treatment did not affect the turnover rate of the mature receptor ( Fig.…”

Section: Down-regulation and Chaperone Effects Seem To Have Similar Tcontrasting

confidence: 70%

Ligands Regulate Cell Surface Level of the Human κ Opioid Receptor by Activation-Induced Down-Regulation and Pharmacological Chaperone-Mediated Enhancement: Differential Effects of Nonpeptide and Peptide Agonists

Chen¹,

Chen²,

Wang³

et al. 2006

J Pharmacol Exp Ther

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Two peptide agonists, eight nonpeptide agonists, and five nonpeptide antagonists were evaluated for their capacity to regulate FLAG (DYKDDDDK)-tagged human opioid receptors (hKORs) stably expressed in Chinese hamster ovary cells after incubation for 4 h with a ligand at a concentration ϳ1000-fold of its EC 50 (agonist) or K i (antagonist) value. Dynorphins A and B decreased the fully glycosylated mature form (55-kDa) of FLAG-hKOR by 70%, whereas nonpeptide full agonists [2-(3,4-dichlorophenyl 17-cyclopropylmethyl-3,14-dihydroxy-4,5-epoxy-6-[N-methyl-trans-3-(3-furyl) acrylamido] morphinan hydrochloride (TRK-820), ethylketocyclazocine, bremazocine, asimadoline, and (RS)- [3-[1-[[(3,4-dichlorophenyl)acetyl]-methylamino]-2-(1-pyrrolidinyl)ethyl]phenoxy] acetic acid hydrochloride (ICI 204,448) caused 10 -30% decreases. In contrast, pentazocine (partial agonist) and etorphine (full agonist) up-regulated by ϳ15 and 25%, respectively. The antagonists naloxone and norbinaltorphimine also significantly increased the 55-kDa receptor, whereas selective , ␦, and D 1 receptor antagonists had no effect. Naloxone up-regulated the receptor concentration-and time-dependently and enhanced the receptor maturation extent, without affecting its turnover. Treatment with brefeldin A (BFA), which disrupts Golgi, resulted in generation of a 51-kDa form that resided intracellularly. Naloxone up-regulated the new species, indicating that its action site is in the endoplasmic reticulum as a pharmacological chaperone. After treatment with BFA, all nonpeptide agonists up-regulated the 51-kDa form, whereas dynorphins A and B did not, indicating that nonpeptide agonists act as pharmacological chaperones, but peptide agonists do not. BFA treatment enhanced down-regulation of the cell surface receptor induced by nonpeptide agonists, but not that by peptide agonists, and unmasked etorphine-and pentazocine-mediated receptor downregulation. These results demonstrate that ligands have dual effects on receptor levels: enhancement by chaperone-like effects and agonist-promoted down-regulation, and the net effect reflects the algebraic sum of the two.The opioid receptor (KOR) is one of the three major types (, ␦, and ) of opioid receptors that mediate physiological and pharmacological effects of opioids in vivo. Stimulation of the KOR generates many effects, such as antinociception (especially for visceral chemical pain), dysphoria, water diuresis, hypothermia, modulation of immune responses, and alleviation of craving for cocaine in addicts (reviewed in LiuChen, 2004). The cDNA clones of KORs have been isolated and characterized from several species including human, mouse, rat, guinea pig, zebra fish, frog, and Caenorhabditis elegans.

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Low‐dose naltrexone for the treatment of fibromyalgia: Findings of a small, randomized, double‐blind, placebo‐controlled, counterbalanced, crossover trial assessing daily pain levels

Younger¹,

Noor²,

McCue³

et al. 2013

Arthritis & Rheumatism

168

131

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Objective. To determine whether low dosages (4.5 mg/day) of naltrexone reduce fibromyalgia severity as compared with the nonspecific effects of placebo. In this replication and extension study of a previous clinical trial, we tested the impact of low-dose naltrexone on daily self-reported pain. Secondary outcomes included general satisfaction with life, positive mood, sleep quality, and fatigue.Methods. Thirty-one women with fibromyalgia participated in the randomized, double-blind, placebocontrolled, counterbalanced, crossover study. During the active drug phase, participants received 4.5 mg of oral naltrexone daily. An intensive longitudinal design was used to measure daily levels of pain.Results. When contrasting the condition end points, we observed a significantly greater reduction of baseline pain in those taking low-dose naltrexone than in those taking placebo (28.8% reduction versus 18.0% reduction; P ‫؍‬ 0.016). Low-dose naltrexone was also associated with improved general satisfaction with life (P ‫؍‬ 0.045) and with improved mood (P ‫؍‬ 0.039), but not improved fatigue or sleep. Thirty-two percent of participants met the criteria for response (defined as a significant reduction in pain plus a significant reduction in either fatigue or sleep problems) during low-dose naltrexone therapy, as contrasted with an 11% response rate during placebo therapy (P ‫؍‬ 0.05). Low-dose naltrexone was rated equally tolerable as placebo, and no serious side effects were reported.Conclusion. The preliminary evidence continues to show that low-dose naltrexone has a specific and clinically beneficial impact on fibromyalgia pain. The medication is widely available, inexpensive, safe, and well-tolerated. Parallel-group randomized controlled trials are needed to fully determine the efficacy of the medication.

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Chronic opioid antagonist treatment dose-dependently regulates μ-opioid receptors and trafficking proteins in vivo

Cited by 30 publications

References 21 publications

μ-Opioid Receptor Up-Regulation and Functional Supersensitivity Are Independent of Antagonist Efficacy

μ-Opioid Receptor Up-Regulation and Functional Supersensitivity Are Independent of Antagonist Efficacy

Ligands Regulate Cell Surface Level of the Human κ Opioid Receptor by Activation-Induced Down-Regulation and Pharmacological Chaperone-Mediated Enhancement: Differential Effects of Nonpeptide and Peptide Agonists

Low‐dose naltrexone for the treatment of fibromyalgia: Findings of a small, randomized, double‐blind, placebo‐controlled, counterbalanced, crossover trial assessing daily pain levels

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