Descending facilitatory pathways from the rostroventromedial medulla mediate naloxone-precipitated withdrawal in morphine-dependent rats

Louis P. Vera-Portocarrero, Michael H. Ossipov, Josephine Lai, Tamara King, Frank Porreca

Research output: Contribution to journalArticle

11 Citations (Scopus)

Abstract

Opioids produce analgesic effects, and extended use can produce physical dependence in both humans and animals. Dependence to opiates can be demonstrated by either termination of drug administration or through precipitation of the withdrawal syndrome by opiate antagonists. Key features of the opiate withdrawal syndrome include hyperalgesia, anxiety, and autonomic signs such as diarrhea. The rostral ventromedial medulla (RVM) plays an important role in the modulation of pain and for this reason, may influence withdrawal-induced hyperalgesia. The mechanisms that drive opiate withdrawal-induced hyperalgesia have not been elucidated. Here, rats made dependent upon morphine received naloxone to precipitate withdrawal. RVM microinjection of lidocaine, kynurenic acid (excitatory amino acid antagonist) or YM022 (CCK2 receptor antagonist) blocked withdrawal-induced hyperalgesia. Additionally, these treatments reduced both somatic and autonomic signs of naloxone-induced withdrawal. Spinal application of ondansetron, a 5HT3 receptor antagonist thought to ultimately be engaged by descending pain facilitatory drive, also blocked hyperalgesia and somatic and autonomic features of the withdrawal syndrome. These results indicate that the RVM plays a critical role in mediating components of opioid withdrawal that may contribute to opioid dependence. Perspective: Manipulations targeting these descending pathways from the RVM may diminish the consequences of prolonged opioid administration-induced dependence and be useful adjunct strategies in reducing the risk of opioid addiction.

Original languageEnglish (US)
Pages (from-to)667-676
Number of pages10
JournalJournal of Pain
Volume12
Issue number6
DOIs
StatePublished - Jun 2011

Fingerprint

Hyperalgesia
Opiate Alkaloids
Naloxone
Morphine
Opioid Analgesics
Cholecystokinin B Receptor
Kynurenic Acid
Opioid-Related Disorders
Pain
Ondansetron
Excitatory Amino Acid Antagonists
Microinjections
Lidocaine
Diarrhea
Anxiety
Pharmaceutical Preparations
Drive

Keywords

  • descending facilitation
  • hyperalgesia
  • morphine dependence
  • Naloxone-induced withdrawal
  • RVM

ASJC Scopus subject areas

  • Anesthesiology and Pain Medicine
  • Neurology
  • Clinical Neurology

Cite this

Descending facilitatory pathways from the rostroventromedial medulla mediate naloxone-precipitated withdrawal in morphine-dependent rats. / Vera-Portocarrero, Louis P.; Ossipov, Michael H.; Lai, Josephine; King, Tamara; Porreca, Frank.

In: Journal of Pain, Vol. 12, No. 6, 06.2011, p. 667-676.

Research output: Contribution to journalArticle

Vera-Portocarrero, Louis P. ; Ossipov, Michael H. ; Lai, Josephine ; King, Tamara ; Porreca, Frank. / Descending facilitatory pathways from the rostroventromedial medulla mediate naloxone-precipitated withdrawal in morphine-dependent rats. In: Journal of Pain. 2011 ; Vol. 12, No. 6. pp. 667-676.
@article{32562044a05f44de91eab65238c4212c,
title = "Descending facilitatory pathways from the rostroventromedial medulla mediate naloxone-precipitated withdrawal in morphine-dependent rats",
abstract = "Opioids produce analgesic effects, and extended use can produce physical dependence in both humans and animals. Dependence to opiates can be demonstrated by either termination of drug administration or through precipitation of the withdrawal syndrome by opiate antagonists. Key features of the opiate withdrawal syndrome include hyperalgesia, anxiety, and autonomic signs such as diarrhea. The rostral ventromedial medulla (RVM) plays an important role in the modulation of pain and for this reason, may influence withdrawal-induced hyperalgesia. The mechanisms that drive opiate withdrawal-induced hyperalgesia have not been elucidated. Here, rats made dependent upon morphine received naloxone to precipitate withdrawal. RVM microinjection of lidocaine, kynurenic acid (excitatory amino acid antagonist) or YM022 (CCK2 receptor antagonist) blocked withdrawal-induced hyperalgesia. Additionally, these treatments reduced both somatic and autonomic signs of naloxone-induced withdrawal. Spinal application of ondansetron, a 5HT3 receptor antagonist thought to ultimately be engaged by descending pain facilitatory drive, also blocked hyperalgesia and somatic and autonomic features of the withdrawal syndrome. These results indicate that the RVM plays a critical role in mediating components of opioid withdrawal that may contribute to opioid dependence. Perspective: Manipulations targeting these descending pathways from the RVM may diminish the consequences of prolonged opioid administration-induced dependence and be useful adjunct strategies in reducing the risk of opioid addiction.",
keywords = "descending facilitation, hyperalgesia, morphine dependence, Naloxone-induced withdrawal, RVM",
author = "Vera-Portocarrero, {Louis P.} and Ossipov, {Michael H.} and Josephine Lai and Tamara King and Frank Porreca",
year = "2011",
month = "6",
doi = "10.1016/j.jpain.2010.12.007",
language = "English (US)",
volume = "12",
pages = "667--676",
journal = "Journal of Pain",
issn = "1526-5900",
publisher = "Churchill Livingstone",
number = "6",

}

TY - JOUR

T1 - Descending facilitatory pathways from the rostroventromedial medulla mediate naloxone-precipitated withdrawal in morphine-dependent rats

AU - Vera-Portocarrero, Louis P.

AU - Ossipov, Michael H.

AU - Lai, Josephine

AU - King, Tamara

AU - Porreca, Frank

PY - 2011/6

Y1 - 2011/6

N2 - Opioids produce analgesic effects, and extended use can produce physical dependence in both humans and animals. Dependence to opiates can be demonstrated by either termination of drug administration or through precipitation of the withdrawal syndrome by opiate antagonists. Key features of the opiate withdrawal syndrome include hyperalgesia, anxiety, and autonomic signs such as diarrhea. The rostral ventromedial medulla (RVM) plays an important role in the modulation of pain and for this reason, may influence withdrawal-induced hyperalgesia. The mechanisms that drive opiate withdrawal-induced hyperalgesia have not been elucidated. Here, rats made dependent upon morphine received naloxone to precipitate withdrawal. RVM microinjection of lidocaine, kynurenic acid (excitatory amino acid antagonist) or YM022 (CCK2 receptor antagonist) blocked withdrawal-induced hyperalgesia. Additionally, these treatments reduced both somatic and autonomic signs of naloxone-induced withdrawal. Spinal application of ondansetron, a 5HT3 receptor antagonist thought to ultimately be engaged by descending pain facilitatory drive, also blocked hyperalgesia and somatic and autonomic features of the withdrawal syndrome. These results indicate that the RVM plays a critical role in mediating components of opioid withdrawal that may contribute to opioid dependence. Perspective: Manipulations targeting these descending pathways from the RVM may diminish the consequences of prolonged opioid administration-induced dependence and be useful adjunct strategies in reducing the risk of opioid addiction.

AB - Opioids produce analgesic effects, and extended use can produce physical dependence in both humans and animals. Dependence to opiates can be demonstrated by either termination of drug administration or through precipitation of the withdrawal syndrome by opiate antagonists. Key features of the opiate withdrawal syndrome include hyperalgesia, anxiety, and autonomic signs such as diarrhea. The rostral ventromedial medulla (RVM) plays an important role in the modulation of pain and for this reason, may influence withdrawal-induced hyperalgesia. The mechanisms that drive opiate withdrawal-induced hyperalgesia have not been elucidated. Here, rats made dependent upon morphine received naloxone to precipitate withdrawal. RVM microinjection of lidocaine, kynurenic acid (excitatory amino acid antagonist) or YM022 (CCK2 receptor antagonist) blocked withdrawal-induced hyperalgesia. Additionally, these treatments reduced both somatic and autonomic signs of naloxone-induced withdrawal. Spinal application of ondansetron, a 5HT3 receptor antagonist thought to ultimately be engaged by descending pain facilitatory drive, also blocked hyperalgesia and somatic and autonomic features of the withdrawal syndrome. These results indicate that the RVM plays a critical role in mediating components of opioid withdrawal that may contribute to opioid dependence. Perspective: Manipulations targeting these descending pathways from the RVM may diminish the consequences of prolonged opioid administration-induced dependence and be useful adjunct strategies in reducing the risk of opioid addiction.

KW - descending facilitation

KW - hyperalgesia

KW - morphine dependence

KW - Naloxone-induced withdrawal

KW - RVM

UR - http://www.scopus.com/inward/record.url?scp=79958108723&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=79958108723&partnerID=8YFLogxK

U2 - 10.1016/j.jpain.2010.12.007

DO - 10.1016/j.jpain.2010.12.007

M3 - Article

C2 - 21354865

AN - SCOPUS:79958108723

VL - 12

SP - 667

EP - 676

JO - Journal of Pain

JF - Journal of Pain

SN - 1526-5900

IS - 6

ER -