Methadone Antinociception Is Dependent on Peripheral Opioid Receptors

Li He, Joseph Kim, Chrissi Ou, Whitney McFadden, Richard M. van Rijn, Jennifer Whistler

Research output: Contribution to journalArticle

29 Citations (Scopus)

Abstract

Morphine and methadone are both high-affinity, potent μ-opioid peptide (MOP) receptor analgesics. In this report, we compared the antinociceptive potencies of these 2 drugs when administered subcutaneously (s.c.), intrathecally (i.t.), or intracerebroventricularly (i.c.v.) in both rat and mouse, using the tail-flick assay. We found that both morphine and methadone were potently antinociceptive when the drugs were administered s.c., showing comparable AD50 values in both species. However, the antinociception produced by methadone, when it was administered centrally, was much weaker than that produced by centrally administered morphine. Specifically, the AD50 value for methadone antinociception was more than 30-fold higher at both the i.t. and i.c.v. sites in mouse and not measurable in rat. Naloxone methiodide (NLX-M), a peripherally restricted antagonist, was used to further examine the relative contribution of central versus peripheral sites to morphine and methadone antinociception. NLX-M, when administered s.c., blocked the antinociceptive effect of either systemically or centrally administered methadone but had little effect on the antinociception produced by centrally administered morphine. Furthermore, centrally administered NLX-M significantly blocked antinociception produced by centrally administered morphine but not that produced by centrally administered methadone. Together, these results suggest that methadone antinociception is significantly dependent on an action of the drug at peripheral sites and could provide novel insight into the neural mechanisms that distinguish morphine versus methadone antinociception. Perspective: Methadone is often used as an alternative for pain management. The present study shows that a peripheral action plays a crucial role in methadone antinociception. This finding could have significant clinical relevance for the use of methadone versus morphine for the treatment of certain types of pain.

Original languageEnglish (US)
Pages (from-to)369-379
Number of pages11
JournalJournal of Pain
Volume10
Issue number4
DOIs
StatePublished - Apr 1 2009
Externally publishedYes

Fingerprint

Methadone
Opioid Receptors
Morphine
Pharmaceutical Preparations
Peptide Receptors
Opioid Peptides
Pain Management
Analgesics
Tail

Keywords

  • Antinociception
  • methadone
  • morphine
  • opioid receptor
  • periphery

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology
  • Anesthesiology and Pain Medicine

Cite this

Methadone Antinociception Is Dependent on Peripheral Opioid Receptors. / He, Li; Kim, Joseph; Ou, Chrissi; McFadden, Whitney; van Rijn, Richard M.; Whistler, Jennifer.

In: Journal of Pain, Vol. 10, No. 4, 01.04.2009, p. 369-379.

Research output: Contribution to journalArticle

He, Li ; Kim, Joseph ; Ou, Chrissi ; McFadden, Whitney ; van Rijn, Richard M. ; Whistler, Jennifer. / Methadone Antinociception Is Dependent on Peripheral Opioid Receptors. In: Journal of Pain. 2009 ; Vol. 10, No. 4. pp. 369-379.
@article{8d647a60b5504cd29d96c0bcad6deb84,
title = "Methadone Antinociception Is Dependent on Peripheral Opioid Receptors",
abstract = "Morphine and methadone are both high-affinity, potent μ-opioid peptide (MOP) receptor analgesics. In this report, we compared the antinociceptive potencies of these 2 drugs when administered subcutaneously (s.c.), intrathecally (i.t.), or intracerebroventricularly (i.c.v.) in both rat and mouse, using the tail-flick assay. We found that both morphine and methadone were potently antinociceptive when the drugs were administered s.c., showing comparable AD50 values in both species. However, the antinociception produced by methadone, when it was administered centrally, was much weaker than that produced by centrally administered morphine. Specifically, the AD50 value for methadone antinociception was more than 30-fold higher at both the i.t. and i.c.v. sites in mouse and not measurable in rat. Naloxone methiodide (NLX-M), a peripherally restricted antagonist, was used to further examine the relative contribution of central versus peripheral sites to morphine and methadone antinociception. NLX-M, when administered s.c., blocked the antinociceptive effect of either systemically or centrally administered methadone but had little effect on the antinociception produced by centrally administered morphine. Furthermore, centrally administered NLX-M significantly blocked antinociception produced by centrally administered morphine but not that produced by centrally administered methadone. Together, these results suggest that methadone antinociception is significantly dependent on an action of the drug at peripheral sites and could provide novel insight into the neural mechanisms that distinguish morphine versus methadone antinociception. Perspective: Methadone is often used as an alternative for pain management. The present study shows that a peripheral action plays a crucial role in methadone antinociception. This finding could have significant clinical relevance for the use of methadone versus morphine for the treatment of certain types of pain.",
keywords = "Antinociception, methadone, morphine, opioid receptor, periphery",
author = "Li He and Joseph Kim and Chrissi Ou and Whitney McFadden and {van Rijn}, {Richard M.} and Jennifer Whistler",
year = "2009",
month = "4",
day = "1",
doi = "10.1016/j.jpain.2008.09.011",
language = "English (US)",
volume = "10",
pages = "369--379",
journal = "Journal of Pain",
issn = "1526-5900",
publisher = "Churchill Livingstone",
number = "4",

}

TY - JOUR

T1 - Methadone Antinociception Is Dependent on Peripheral Opioid Receptors

AU - He, Li

AU - Kim, Joseph

AU - Ou, Chrissi

AU - McFadden, Whitney

AU - van Rijn, Richard M.

AU - Whistler, Jennifer

PY - 2009/4/1

Y1 - 2009/4/1

N2 - Morphine and methadone are both high-affinity, potent μ-opioid peptide (MOP) receptor analgesics. In this report, we compared the antinociceptive potencies of these 2 drugs when administered subcutaneously (s.c.), intrathecally (i.t.), or intracerebroventricularly (i.c.v.) in both rat and mouse, using the tail-flick assay. We found that both morphine and methadone were potently antinociceptive when the drugs were administered s.c., showing comparable AD50 values in both species. However, the antinociception produced by methadone, when it was administered centrally, was much weaker than that produced by centrally administered morphine. Specifically, the AD50 value for methadone antinociception was more than 30-fold higher at both the i.t. and i.c.v. sites in mouse and not measurable in rat. Naloxone methiodide (NLX-M), a peripherally restricted antagonist, was used to further examine the relative contribution of central versus peripheral sites to morphine and methadone antinociception. NLX-M, when administered s.c., blocked the antinociceptive effect of either systemically or centrally administered methadone but had little effect on the antinociception produced by centrally administered morphine. Furthermore, centrally administered NLX-M significantly blocked antinociception produced by centrally administered morphine but not that produced by centrally administered methadone. Together, these results suggest that methadone antinociception is significantly dependent on an action of the drug at peripheral sites and could provide novel insight into the neural mechanisms that distinguish morphine versus methadone antinociception. Perspective: Methadone is often used as an alternative for pain management. The present study shows that a peripheral action plays a crucial role in methadone antinociception. This finding could have significant clinical relevance for the use of methadone versus morphine for the treatment of certain types of pain.

AB - Morphine and methadone are both high-affinity, potent μ-opioid peptide (MOP) receptor analgesics. In this report, we compared the antinociceptive potencies of these 2 drugs when administered subcutaneously (s.c.), intrathecally (i.t.), or intracerebroventricularly (i.c.v.) in both rat and mouse, using the tail-flick assay. We found that both morphine and methadone were potently antinociceptive when the drugs were administered s.c., showing comparable AD50 values in both species. However, the antinociception produced by methadone, when it was administered centrally, was much weaker than that produced by centrally administered morphine. Specifically, the AD50 value for methadone antinociception was more than 30-fold higher at both the i.t. and i.c.v. sites in mouse and not measurable in rat. Naloxone methiodide (NLX-M), a peripherally restricted antagonist, was used to further examine the relative contribution of central versus peripheral sites to morphine and methadone antinociception. NLX-M, when administered s.c., blocked the antinociceptive effect of either systemically or centrally administered methadone but had little effect on the antinociception produced by centrally administered morphine. Furthermore, centrally administered NLX-M significantly blocked antinociception produced by centrally administered morphine but not that produced by centrally administered methadone. Together, these results suggest that methadone antinociception is significantly dependent on an action of the drug at peripheral sites and could provide novel insight into the neural mechanisms that distinguish morphine versus methadone antinociception. Perspective: Methadone is often used as an alternative for pain management. The present study shows that a peripheral action plays a crucial role in methadone antinociception. This finding could have significant clinical relevance for the use of methadone versus morphine for the treatment of certain types of pain.

KW - Antinociception

KW - methadone

KW - morphine

KW - opioid receptor

KW - periphery

UR - http://www.scopus.com/inward/record.url?scp=62649167899&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=62649167899&partnerID=8YFLogxK

U2 - 10.1016/j.jpain.2008.09.011

DO - 10.1016/j.jpain.2008.09.011

M3 - Article

C2 - 19327642

AN - SCOPUS:62649167899

VL - 10

SP - 369

EP - 379

JO - Journal of Pain

JF - Journal of Pain

SN - 1526-5900

IS - 4

ER -