How to design an opioid drug that causes reduced tolerance and dependence

Amy Chang Berger, Jennifer Whistler

Research output: Contribution to journalReview article

39 Citations (Scopus)

Abstract

Mu opioid receptor (MOR) agonists such as morphine are extremely effective treatments for acute pain. In the setting of chronic pain, however, their long-term utility is limited by the development of tolerance and physical dependence. Drug companies have tried to overcome these problems by simply "dialing up" signal transduction at the receptor, designing more potent and efficacious agonists and more long-lasting formulations. Neither of these strategies has proven to be successful, however, because the net amount of signal transduction, particularly over extended periods of drug use, is a product of much more than the pharmacokinetic properties of potency, efficacy, half-life, and bioavailability, the mainstays of traditional pharmaceutical screening. Both the quantity and quality of signal transduction are influenced by many regulated processes, including receptor desensitization, trafficking, and oligomerization. Importantly, the efficiency with which an agonist first stimulates signal transduction is not necessarily related to the efficiency with which it stimulates these other processes. Here we describe recent findings that suggest MOR agonists with diminished propensity to cause tolerance and dependence can be identified by screening drugs for the ability to induce MOR desensitization, endocytosis, and recycling. We also discuss preliminary evidence that heteromers of the delta opioid receptor and the MOR are pronociceptive, and that drugs that spare such heteromers may also induce reduced tolerance.

Original languageEnglish (US)
Pages (from-to)559-569
Number of pages11
JournalAnnals of Neurology
Volume67
Issue number5
DOIs
StatePublished - May 1 2010
Externally publishedYes

Fingerprint

mu Opioid Receptor
Drug Design
Opioid Analgesics
Signal Transduction
Pharmaceutical Preparations
Preclinical Drug Evaluations
delta Opioid Receptor
Acute Pain
Recycling
Endocytosis
Chronic Pain
Morphine
Biological Availability
Half-Life
Pharmacokinetics
Therapeutics

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology

Cite this

How to design an opioid drug that causes reduced tolerance and dependence. / Berger, Amy Chang; Whistler, Jennifer.

In: Annals of Neurology, Vol. 67, No. 5, 01.05.2010, p. 559-569.

Research output: Contribution to journalReview article

@article{278e4fbc560146a5a6638200cb722807,
title = "How to design an opioid drug that causes reduced tolerance and dependence",
abstract = "Mu opioid receptor (MOR) agonists such as morphine are extremely effective treatments for acute pain. In the setting of chronic pain, however, their long-term utility is limited by the development of tolerance and physical dependence. Drug companies have tried to overcome these problems by simply {"}dialing up{"} signal transduction at the receptor, designing more potent and efficacious agonists and more long-lasting formulations. Neither of these strategies has proven to be successful, however, because the net amount of signal transduction, particularly over extended periods of drug use, is a product of much more than the pharmacokinetic properties of potency, efficacy, half-life, and bioavailability, the mainstays of traditional pharmaceutical screening. Both the quantity and quality of signal transduction are influenced by many regulated processes, including receptor desensitization, trafficking, and oligomerization. Importantly, the efficiency with which an agonist first stimulates signal transduction is not necessarily related to the efficiency with which it stimulates these other processes. Here we describe recent findings that suggest MOR agonists with diminished propensity to cause tolerance and dependence can be identified by screening drugs for the ability to induce MOR desensitization, endocytosis, and recycling. We also discuss preliminary evidence that heteromers of the delta opioid receptor and the MOR are pronociceptive, and that drugs that spare such heteromers may also induce reduced tolerance.",
author = "Berger, {Amy Chang} and Jennifer Whistler",
year = "2010",
month = "5",
day = "1",
doi = "10.1002/ana.22002",
language = "English (US)",
volume = "67",
pages = "559--569",
journal = "Annals of Neurology",
issn = "0364-5134",
publisher = "John Wiley and Sons Inc.",
number = "5",

}

TY - JOUR

T1 - How to design an opioid drug that causes reduced tolerance and dependence

AU - Berger, Amy Chang

AU - Whistler, Jennifer

PY - 2010/5/1

Y1 - 2010/5/1

N2 - Mu opioid receptor (MOR) agonists such as morphine are extremely effective treatments for acute pain. In the setting of chronic pain, however, their long-term utility is limited by the development of tolerance and physical dependence. Drug companies have tried to overcome these problems by simply "dialing up" signal transduction at the receptor, designing more potent and efficacious agonists and more long-lasting formulations. Neither of these strategies has proven to be successful, however, because the net amount of signal transduction, particularly over extended periods of drug use, is a product of much more than the pharmacokinetic properties of potency, efficacy, half-life, and bioavailability, the mainstays of traditional pharmaceutical screening. Both the quantity and quality of signal transduction are influenced by many regulated processes, including receptor desensitization, trafficking, and oligomerization. Importantly, the efficiency with which an agonist first stimulates signal transduction is not necessarily related to the efficiency with which it stimulates these other processes. Here we describe recent findings that suggest MOR agonists with diminished propensity to cause tolerance and dependence can be identified by screening drugs for the ability to induce MOR desensitization, endocytosis, and recycling. We also discuss preliminary evidence that heteromers of the delta opioid receptor and the MOR are pronociceptive, and that drugs that spare such heteromers may also induce reduced tolerance.

AB - Mu opioid receptor (MOR) agonists such as morphine are extremely effective treatments for acute pain. In the setting of chronic pain, however, their long-term utility is limited by the development of tolerance and physical dependence. Drug companies have tried to overcome these problems by simply "dialing up" signal transduction at the receptor, designing more potent and efficacious agonists and more long-lasting formulations. Neither of these strategies has proven to be successful, however, because the net amount of signal transduction, particularly over extended periods of drug use, is a product of much more than the pharmacokinetic properties of potency, efficacy, half-life, and bioavailability, the mainstays of traditional pharmaceutical screening. Both the quantity and quality of signal transduction are influenced by many regulated processes, including receptor desensitization, trafficking, and oligomerization. Importantly, the efficiency with which an agonist first stimulates signal transduction is not necessarily related to the efficiency with which it stimulates these other processes. Here we describe recent findings that suggest MOR agonists with diminished propensity to cause tolerance and dependence can be identified by screening drugs for the ability to induce MOR desensitization, endocytosis, and recycling. We also discuss preliminary evidence that heteromers of the delta opioid receptor and the MOR are pronociceptive, and that drugs that spare such heteromers may also induce reduced tolerance.

UR - http://www.scopus.com/inward/record.url?scp=77951704231&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=77951704231&partnerID=8YFLogxK

U2 - 10.1002/ana.22002

DO - 10.1002/ana.22002

M3 - Review article

VL - 67

SP - 559

EP - 569

JO - Annals of Neurology

JF - Annals of Neurology

SN - 0364-5134

IS - 5

ER -