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

Sirohi, Smita; Kumar, Priyank; Yoburn, Byron C.

doi:10.1124/jpet.107.127019

Cited by 25 publications

(28 citation statements)

References 38 publications

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“…In the case of naltrexone, after opioid detoxification or if a scheduled dose is missed, patients have reduced tolerance to opioids and are vulnerable to overdose. Although opioid antagonists up‐regulated μ‐receptors and induced supersensitivity to morphine in a mouse model,91 healthy humans show no evidence of μ‐receptor up‐regulation in the respiratory control system, the most likely site of opioid overdose lethality 92. Overall, the risk of overdose is significantly lower in patients who are actively involved in medication‐assisted treatment whether it is with methadone, buprenorphine, or naltrexone 93.…”

Section: Current Approach To Treatment Of Opioid Use Disorder: Choosimentioning

confidence: 95%

Antagonists in the medical management of opioid use disorders: Historical and existing treatment strategies

et al. 2018

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Background and ObjectivesOpioid use disorder (OUD) is a chronic condition with potentially severe health and social consequences. Many who develop moderate to severe OUD will repeatedly seek treatment or interact with medical care via emergency department visits or hospitalizations. Thus, there is an urgent need to develop feasible and effective approaches to help persons with OUD achieve and maintain abstinence from opioids. Treatment that includes one of the three FDA‐approved medications is an evidence‐based strategy to manage OUD. The purpose of this review is to address practices for managing persons with moderate to severe OUD with a focus on opioid withdrawal and naltrexone‐based relapse‐prevention treatment.MethodsLiterature available on PubMed was used to review the evolution of treatment strategies from the 1960s onward to manage opioid withdrawal and initiate treatment with naltrexone.ResultsEmerging practices for extended‐release naltrexone induction include the use of agonist tapers and adjuvant medications. Clinical challenges frequently encountered when initiating this therapy include managing withdrawal and ongoing opioid use during treatment. Clinical factors may inform decisions regarding patient selection and length of naltrexone treatment, such as recent opioid use and patient preferences.Conclusions and Scientific SignificanceTreatment strategies to manage opioid withdrawal have evolved, but many patients with OUD do not receive medication for the prevention of relapse. Clinical strategies for induction onto extended‐release naltrexone are now available and can be safely and effectively implemented in specialty and select primary care settings. (© 2018 The Authors. The American Journal on Addictions Published by Wiley Periodicals, Inc. on behalf of The American Academy of Addiction Psychiatry (AAAP);27:177–187)

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Section: Current Approach To Treatment Of Opioid Use Disorder: Choosimentioning

confidence: 95%

Antagonists in the medical management of opioid use disorders: Historical and existing treatment strategies

et al. 2018

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“…Studies strongly suggest that the commonly used opioid antagonists naloxone and naltrexone display negative efficacy and are therefore classified as inverse agonists (Costa and Herz, 1989;Wang et al, 2001;Marczak et al, 2007). Although all opioid antagonists are capable of reversing or blocking the effects of opioid agonists, only inverse agonists inhibit signaling of constitutively active opioid receptors (Wang et al, 2004;Sadée et al, 2005;Sirohi et al, 2007). However, in the absence of constitutive receptor activity, inverse agonists are generally indistinguishable from neutral antagonists.…”

Section: Discussionmentioning

confidence: 99%

“…The ED 50 value to block fentanyl subcutaneously induced analgesia (100 g/kg) was estimated for subcutaneous naltrexone, naloxone, and 6␤-naltrexol. The peak effect for all antagonists was determined previously (Sirohi et al, 2007;(naltrexone and naloxone, 40 min;6␤-naltrexol, 70 min). Next, the dose-response function and LD 50 value for fentanyl were determined.…”

Section: Methodsmentioning

confidence: 99%

“…In behavioral studies in opioid-dependent mice, inverse opioid agonists (e.g., naltrexone and naloxone) precipitate withdrawal jumping, whereas neutral antagonists (e.g., 6␤-naltrexol and D-Phe-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH 2 ) are dramatically less potent (Wang et al, 2001;Raehal et al, 2005;Walker and Sterious, 2005;Sirohi et al, 2007). In biochemical studies, inverse opioid agonists increase cyclic AMP levels and inhibit guanosine 5Ј-O-(3-thio)triphosphate binding in cells previously exposed to opioid agonists (Liu and Prather, 2001;Wang et al, 2001;Raehal et al, 2005).…”

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confidence: 99%

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The Relative Potency of Inverse Opioid Agonists and a Neutral Opioid Antagonist in Precipitated Withdrawal and Antagonism of Analgesia and Toxicity

Sirohi

Dighe²,

Madia³

et al. 2009

J Pharmacol Exp Ther

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Opioid antagonists can be classified as inverse agonists and neutral antagonists. In the opioid-dependent state, neutral antagonists are significantly less potent in precipitating withdrawal than inverse agonists. Consequently, neutral opioid antagonists may offer advantages over inverse agonists in the management of opioid overdose. In this study, the relative potency of three opioid antagonists to block opioid analgesia and toxicity and precipitate withdrawal was examined. First, the potency of two opioid inverse agonists (naltrexone and naloxone) and a neutral antagonist (6␤-naltrexol) to antagonize fentanyl-induced analgesia and lethality was determined. The order of potency to block analgesia was naltrexone Ͼ naloxone Ͼ 6␤-naltrexol (17, 4, 1), which was similar to that to block lethality (13, 2, 1). Next, the antagonists were compared using withdrawal jumping in fentanyl-dependent mice. The order of potency to precipitate withdrawal jumping was naltrexone Ͼ naloxone 6␤-naltrexol (1107, 415, 1). The relative potencies to precipitate withdrawal for the inverse agonists compared with the neutral antagonist were dramatically different from that for antagonism of analgesia and lethality. Finally, the effect of 6␤-naltrexol pretreatment on naloxone-precipitated jumping was determined in morphine and fentanyl-dependent mice. 6␤-Naltrexol pretreatment decreased naloxone precipitated withdrawal, indicating that 6␤-naltrexol is a neutral antagonist. These data demonstrate that inverse agonists and neutral antagonists have generally comparable potencies to block opioid analgesia and lethality, whereas the neutral opioid antagonist is substantially less potent in precipitating opioid withdrawal. These results support suggestions that neutral antagonists may have advantages over inverse agonists in the management of opioid overdose.

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“…Previous studies have shown that continuous administration of nonselective opioid antagonists, such as naloxone and naltrexone, will up-regulate the number of receptors and increase the potency of -and -opioid agonists (Morris et al, 1988;Paronis and Holtzman, 1991;Sirohi et al, 2007). Similar increases in potency of a -agonist might be expected during chronic treatment with buprenorphine on the basis of its -antagonist actions; the present results provide no evidence of sensitization to the behavioral effects of U50,488 during daily treatment with 0.32 mg/kg buprenorphine.…”

Section: Discussionmentioning

confidence: 99%

Buprenorphine and Opioid Antagonism, Tolerance, and Naltrexone-Precipitated Withdrawal

Paronis¹,

Bergman²

2010

J Pharmacol Exp Ther

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The dual antagonist effects of the mixed-action -opioid partial agonist/-opioid antagonist buprenorphine have not been previously compared in behavioral studies, and it is unknown whether they are comparably modified by chronic exposure. To address this question, the dose-related effects of levorphanol, trans-(Ϫ) -3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl] benzeneacetamide (U50,488), heroin, and naltrexone on food-maintained behavior in rhesus monkeys were studied after acute and chronic treatment with buprenorphine (0.3 mg/kg/day). In acute studies, the effects of levorphanol and U50,488 were determined at differing times after buprenorphine (0.003-10.0 mg/kg i.m.). Results show that buprenorphine produced similar, dose-dependent rightward shifts of the levorphanol and U50,488 dose-response curves that persisted for Ն24 h after doses larger than 0.1 mg/kg buprenorphine. During chronic treatment with buprenorphine, the effects of levorphanol, U50,488, heroin, and naltrexone were similarly determined at differing times (10 min to 48 h) after intramuscular injection. Overall, results show that buprenorphine produced comparable 3-to 10-fold rightward shifts in the U50,488 dose-response curve under both acute and chronic conditions, but that chronic buprenorphine produced larger (10-to Ն30-fold) rightward shifts in the heroin dose-effect function than observed acutely. Naltrexone decreased operant responding in buprenorphine-treated monkeys, and the position of the naltrexone dose-effect curve shifted increasingly to the left as the time after daily buprenorphine treatment increased from 10 min to 48 h. These results suggest that the -antagonist, but not the -antagonist, effects of buprenorphine are augmented during chronic treatment. In addition, the leftward shift of the naltrexone dose-effect function suggests that daily administration of 0.3 mg/kg buprenorphine is adequate to produce opioid dependence.

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

Cited by 25 publications

References 38 publications

Antagonists in the medical management of opioid use disorders: Historical and existing treatment strategies

Antagonists in the medical management of opioid use disorders: Historical and existing treatment strategies

The Relative Potency of Inverse Opioid Agonists and a Neutral Opioid Antagonist in Precipitated Withdrawal and Antagonism of Analgesia and Toxicity

Buprenorphine and Opioid Antagonism, Tolerance, and Naltrexone-Precipitated Withdrawal

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