Cholecystokinin in the rostral ventromedial medulla mediates opioid-induced hyperalgesia and antinociceptive tolerance

Jennifer Y. Xie, David S. Herman, Carl Olav Stiller, Luis R. Gardell, Michael H. Ossipov, Josephine Lai, Frank Porreca, Todd W Vanderah

Research output: Contribution to journalArticle

145 Citations (Scopus)

Abstract

Opioid-induced hyperalgesia is characterized by hypersensitivity to innocuous or noxious stimuli during sustained opiate administration. Microinjection of lidocaine into the rostral ventromedial medulla (RVM), or dorsolateral funiculus (DLF) lesion, abolishes opioid-induced hyperalgesia, suggesting the importance of descending pain facilitation mechanisms. Here, we investigate the possibility that cholecystokinin (CCK), a pronociceptive peptide, may drive such descending facilitation from the RVM during continuous opioid administration. In opioid-naive rats, CCK in the RVM produced acute tactile and thermal hypersensitivity that was antagonized by the CCK2 receptor antagonist L365,260 or by DLF lesion. CCK in the RVM also acutely displaced the spinal morphine antinociceptive dose-response curve to the right. Continuous systemic morphine elicited sustained tactile and thermal hypersensitivity within 3 d. Such hypersensitivity was reversed in a time-dependent manner by L365,260 in the RVM, and blockade of CCK2 receptors in the RVM also blocked the rightward displacement of the spinal morphine antinociceptive dose-response curve. Microdialysis studies in rats receiving continuous morphine showed an approximately fivefold increase in the basal levels of CCK in the RVM when compared with controls. These data suggest that activation of CCK2 receptors in the RVM promotes mechanical and thermal hypersensitivity and antinociceptive tolerance to morphine. Enhanced, endogenous CCK activity in the RVM during sustained morphine exposure may diminish spinal morphine antinociceptive potency by activating descending pain facilitatory mechanisms to exacerbate spinal nociceptive sensitivity. Prevention of opioid-dose escalation in chronic pain states by CCK receptor antagonism represents a potentially important strategy to limit unintended enhanced clinical pain and analgesic tolerance.

Original languageEnglish (US)
Pages (from-to)409-416
Number of pages8
JournalJournal of Neuroscience
Volume25
Issue number2
DOIs
StatePublished - Jan 12 2005

Fingerprint

Cholecystokinin
Hyperalgesia
Morphine
Opioid Analgesics
Cholecystokinin B Receptor
Hypersensitivity
Hot Temperature
Touch
Pain
Opiate Alkaloids
Cholecystokinin Receptors
Microdialysis
Microinjections
Lidocaine
Chronic Pain
Analgesics
Peptides

Keywords

  • Antinociceptive tolerance
  • CCK
  • Cholecystokinin
  • L365,260
  • Microdialysis
  • Morphine
  • Opioid hyperalgesia
  • Receptor
  • Rostral ventromedial medulla

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Cholecystokinin in the rostral ventromedial medulla mediates opioid-induced hyperalgesia and antinociceptive tolerance. / Xie, Jennifer Y.; Herman, David S.; Stiller, Carl Olav; Gardell, Luis R.; Ossipov, Michael H.; Lai, Josephine; Porreca, Frank; Vanderah, Todd W.

In: Journal of Neuroscience, Vol. 25, No. 2, 12.01.2005, p. 409-416.

Research output: Contribution to journalArticle

Xie, Jennifer Y. ; Herman, David S. ; Stiller, Carl Olav ; Gardell, Luis R. ; Ossipov, Michael H. ; Lai, Josephine ; Porreca, Frank ; Vanderah, Todd W. / Cholecystokinin in the rostral ventromedial medulla mediates opioid-induced hyperalgesia and antinociceptive tolerance. In: Journal of Neuroscience. 2005 ; Vol. 25, No. 2. pp. 409-416.
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abstract = "Opioid-induced hyperalgesia is characterized by hypersensitivity to innocuous or noxious stimuli during sustained opiate administration. Microinjection of lidocaine into the rostral ventromedial medulla (RVM), or dorsolateral funiculus (DLF) lesion, abolishes opioid-induced hyperalgesia, suggesting the importance of descending pain facilitation mechanisms. Here, we investigate the possibility that cholecystokinin (CCK), a pronociceptive peptide, may drive such descending facilitation from the RVM during continuous opioid administration. In opioid-naive rats, CCK in the RVM produced acute tactile and thermal hypersensitivity that was antagonized by the CCK2 receptor antagonist L365,260 or by DLF lesion. CCK in the RVM also acutely displaced the spinal morphine antinociceptive dose-response curve to the right. Continuous systemic morphine elicited sustained tactile and thermal hypersensitivity within 3 d. Such hypersensitivity was reversed in a time-dependent manner by L365,260 in the RVM, and blockade of CCK2 receptors in the RVM also blocked the rightward displacement of the spinal morphine antinociceptive dose-response curve. Microdialysis studies in rats receiving continuous morphine showed an approximately fivefold increase in the basal levels of CCK in the RVM when compared with controls. These data suggest that activation of CCK2 receptors in the RVM promotes mechanical and thermal hypersensitivity and antinociceptive tolerance to morphine. Enhanced, endogenous CCK activity in the RVM during sustained morphine exposure may diminish spinal morphine antinociceptive potency by activating descending pain facilitatory mechanisms to exacerbate spinal nociceptive sensitivity. Prevention of opioid-dose escalation in chronic pain states by CCK receptor antagonism represents a potentially important strategy to limit unintended enhanced clinical pain and analgesic tolerance.",
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AU - Gardell, Luis R.

AU - Ossipov, Michael H.

AU - Lai, Josephine

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AU - Vanderah, Todd W

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