Opioid Agonists Differentially Regulate μ-Opioid Receptors and Trafficking Proteins in Vivo

Patel, Minesh; Patel, Chintan; Rajashekara, Vikram; Yoburn, Byron C.

doi:10.1124/mol.62.6.1464

Cited by 59 publications

(54 citation statements)

References 35 publications

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“…It is widely speculated that differences in short-term MOR regulatory events underlie the profound agonist-selective differences observed in the development of tolerance in vivo (Whistler et al, 1999;Stafford et al, 2001;Walker and Young, 2001;Patel et al, 2002;Grecksch et al, 2006;Pawar et al, 2007). There is no consensus, however, on which elements of MOR regulation-signaling efficacy, desensitization, internalization, or resensitization-are most directly correlated with tolerance (Whistler et al, 1999;Bohn et al, 2000;Williams et al, 2001;Connor et al, 2004;von Zastrow, 2004;Bailey and Connor, 2005;Koch et al, 2005).…”

Section: Enkephalin (Me) [D-alamentioning

confidence: 99%

Agonist-Specific Regulation of μ-Opioid Receptor Desensitization and Recovery from Desensitization

Virk

Williams

2008

Mol Pharmacol

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Agonist-selective actions of opioids on the desensitization of -opioid receptors (MORs) have been well characterized, but few if any studies have examined agonist-dependent recovery from desensitization. The outward potassium current induced by several opioids was studied using whole-cell voltage-clamp recordings in locus ceruleus neurons. A brief application of the irreversible opioid antagonist ␤-chlornaltrexamine (␤-CNA) was applied immediately after treatment of slices with saturating concentrations of opioid agonists. This approach permitted the measurement of desensitization and recovery from desensitization using multiple opioid agonists, including [Met] 5 enkephalin (ME), [D-Ala 2 ,N-Me-Phe 4 ,Gly 5 -ol]-enkephalin (DAMGO), etorphine, fentanyl, methadone, morphine, morphine-6-glucuronide, oxycodone, and oxymorphone. The results indicate that desensitization protects receptors from irreversible antagonism with ␤-CNA. The amount of desensitization was measured as the decrease in current during a 10-min application of a saturating agonist concentration and was a good predictor of the extent of receptor protection from irreversible inactivation with ␤-CNA. After desensitization with ME or DAMGO and treatment with ␤-CNA, there was an initial profound inhibition of MOR-induced current that recovered significantly after 45 min. There was, however, no recovery of MOR-mediated current with time after treatment with agonists that did not cause desensitization, such as oxycodone. These results demonstrate that desensitization prevents irreversible inactivation of receptors by ␤-CNA.

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Section: Enkephalin (Me) [D-alamentioning

confidence: 99%

Agonist-Specific Regulation of μ-Opioid Receptor Desensitization and Recovery from Desensitization

Virk

Williams

2008

Mol Pharmacol

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“…It seemed likely that antagonist efficacy might determine up-regulation and supersensitivity given that previous studies indicate that agonist efficacy plays a role in -opioid receptor down-regulation and tolerance (e.g., Pawar et al, 2007). Although data indicate that antagonistinduced up-regulation and agonist-induced down-regulation are mechanistically distinct (e.g., Yoburn et al, 2004;Pawar et al, 2007), the evidence linking agonist efficacy, tolerance, and receptor regulation is compelling (Patel et al, 2002;Pawar et al, 2007), and some studies have suggested that antagonist efficacy may be important in up-regulation and supersensitivity (Morris and Millan, 1991;Milligan and Bond, 1997). Therefore, it seemed plausible that antagonist efficacy might have an impact on -opioid receptor up-regulation and functional supersensitivity.…”

mentioning

confidence: 96%

“…Receptor density regulation is a well documented phenomenon in the opioid system (e.g., Yoburn et al, 1986;Keith et al, 1996Keith et al, , 1998Patel et al, 2002). 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).…”

mentioning

confidence: 99%

“…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). For example, chronic treatment with high-efficacy agonists (e.g., etorphine, DAMGO) can induce internalization and down-regulation of -opioid receptors in vitro and in vivo Keith et al, 1998;Whistler and von Zastrow, 1998).…”

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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“…The regulation and trafficking of -opioid receptors has been shown to be agonist-dependent (Sternini et al, 1996;Whistler and von Zastrow, 1998;Alvarez et al, 2002;Patel et al, 2002;Borgland et al, 2003). Most agonists, when applied at saturating concentrations, cause receptor desensitization and internalization.…”

Section: Desensitization and Receptor Reservementioning

confidence: 99%

Chronic Morphine Treatment Reduces Recovery from Opioid Desensitization

Dang¹,

Williams²

2004

J. Neurosci.

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Tolerance and dependence result from long-term exposure to opioids, and there is growing evidence linking acute receptor desensitization to these more long-term processes. Receptor desensitization encompasses a series of events leading to the loss of receptor function and internalization. This study examines the onset and recovery from desensitization in locus ceruleus neurons recorded in brain slices taken from animals that have been chronically treated with morphine. After chronic morphine treatment, desensitization was altered as follows. First, the rate of desensitization was increased. Second, recovery from desensitization was always incomplete, even after a brief (1-2 min) exposure to agonist. This contrasts with experiments in controls in which recovery from desensitization, after a brief exposure to agonist, was complete within 25 min. Finally, morphine-6-␤-D-glucuronide, a metabolite of morphine that was ineffective at causing desensitization in controls, induced significant desensitization in slices from morphine-treated animals. When brain slices from controls were treated with inhibitors of PKC or monensin, agents known to compromise G-protein-coupled receptor resensitization, desensitization was increased, and recovery was significantly reduced. These results indicate that receptor resensitization maintains signaling during periods of intense and sustained stimulation. After chronic morphine treatment, desensitization is potentiated, and receptor resensitization is compromised.

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Opioid Agonists Differentially Regulate μ-Opioid Receptors and Trafficking Proteins in Vivo

Cited by 59 publications

References 35 publications

Agonist-Specific Regulation of μ-Opioid Receptor Desensitization and Recovery from Desensitization

Agonist-Specific Regulation of μ-Opioid Receptor Desensitization and Recovery from Desensitization

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

Chronic Morphine Treatment Reduces Recovery from Opioid Desensitization

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