Opioid-induced decreases in rat brain adenosine levels are reversed by inhibiting adenosine deaminase

Ariana M. Nelson, Alanna S. Battersby, Helen Baghdoyan, Ralph Lydic

Research output: Contribution to journalArticle

36 Citations (Scopus)

Abstract

BACKGROUND: Opioids disrupt sleep and adenosine promotes sleep, but no studies have characterized the effects of opioids on adenosine levels in brain regions known to regulate states of arousal. Delivering opioids to the pontine reticular formation (PRF) and substantia innominata (SI) region of the basal forebrain disrupts sleep. In contrast, administering adenosine agonists to the PRF or SI increases sleep. These findings encouraged the current study testing the hypothesis that microdialysis delivery of opioids to the PRF or SI decreases adenosine levels in the PRF or SI, respectively. METHODS: A microdialysis probe was placed in the PRF of isoflurane anesthetized rats and perfused with Ringer's solution (control) followed by Ringer's solution containing morphine (0, 10, 30, 100, or 300 μm), fentanyl (100 μm), morphine (100 μm) and the adenosine deaminase inhibitor EHNA (100 μm), or naloxone (10 μm) and morphine (100 μm). Additional experiments measured adenosine levels in the SI before and during microdialysis delivery of morphine, fentanyl, and morphine plus EHNA. RESULTS: Morphine caused a significant (P < 0.05) concentration-dependent decrease in PRF adenosine levels. The significant decrease (-20%) in adenosine caused by 100 μm morphine was blocked by coadministration of naloxone. Fentanyl also significantly decreased (-13.3%) PRF adenosine. SI adenosine levels were decreased by morphine (-26.8%) and fentanyl (-27.4%). In both PRF and SI, coadministration of morphine and EHNA prevented the significant decrease in adenosine levels caused by morphine alone. CONCLUSIONS: These data support the interpretation that decreased adenosine levels in sleep-regulating brain regions may be one of the mechanisms by which opioids disrupt sleep.

Original languageEnglish (US)
Pages (from-to)1327-1333
Number of pages7
JournalAnesthesiology
Volume111
Issue number6
DOIs
StatePublished - Jan 1 2009

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Adenosine Deaminase
Substantia Innominata
Adenosine
Opioid Analgesics
Morphine
Brain
Sleep
Fentanyl
Microdialysis
Naloxone
Adenosine Deaminase Inhibitors
Pontine Tegmentum
Isoflurane
Arousal

All Science Journal Classification (ASJC) codes

  • Anesthesiology and Pain Medicine

Cite this

Opioid-induced decreases in rat brain adenosine levels are reversed by inhibiting adenosine deaminase. / Nelson, Ariana M.; Battersby, Alanna S.; Baghdoyan, Helen; Lydic, Ralph.

In: Anesthesiology, Vol. 111, No. 6, 01.01.2009, p. 1327-1333.

Research output: Contribution to journalArticle

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abstract = "BACKGROUND: Opioids disrupt sleep and adenosine promotes sleep, but no studies have characterized the effects of opioids on adenosine levels in brain regions known to regulate states of arousal. Delivering opioids to the pontine reticular formation (PRF) and substantia innominata (SI) region of the basal forebrain disrupts sleep. In contrast, administering adenosine agonists to the PRF or SI increases sleep. These findings encouraged the current study testing the hypothesis that microdialysis delivery of opioids to the PRF or SI decreases adenosine levels in the PRF or SI, respectively. METHODS: A microdialysis probe was placed in the PRF of isoflurane anesthetized rats and perfused with Ringer's solution (control) followed by Ringer's solution containing morphine (0, 10, 30, 100, or 300 μm), fentanyl (100 μm), morphine (100 μm) and the adenosine deaminase inhibitor EHNA (100 μm), or naloxone (10 μm) and morphine (100 μm). Additional experiments measured adenosine levels in the SI before and during microdialysis delivery of morphine, fentanyl, and morphine plus EHNA. RESULTS: Morphine caused a significant (P < 0.05) concentration-dependent decrease in PRF adenosine levels. The significant decrease (-20{\%}) in adenosine caused by 100 μm morphine was blocked by coadministration of naloxone. Fentanyl also significantly decreased (-13.3{\%}) PRF adenosine. SI adenosine levels were decreased by morphine (-26.8{\%}) and fentanyl (-27.4{\%}). In both PRF and SI, coadministration of morphine and EHNA prevented the significant decrease in adenosine levels caused by morphine alone. CONCLUSIONS: These data support the interpretation that decreased adenosine levels in sleep-regulating brain regions may be one of the mechanisms by which opioids disrupt sleep.",
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N2 - BACKGROUND: Opioids disrupt sleep and adenosine promotes sleep, but no studies have characterized the effects of opioids on adenosine levels in brain regions known to regulate states of arousal. Delivering opioids to the pontine reticular formation (PRF) and substantia innominata (SI) region of the basal forebrain disrupts sleep. In contrast, administering adenosine agonists to the PRF or SI increases sleep. These findings encouraged the current study testing the hypothesis that microdialysis delivery of opioids to the PRF or SI decreases adenosine levels in the PRF or SI, respectively. METHODS: A microdialysis probe was placed in the PRF of isoflurane anesthetized rats and perfused with Ringer's solution (control) followed by Ringer's solution containing morphine (0, 10, 30, 100, or 300 μm), fentanyl (100 μm), morphine (100 μm) and the adenosine deaminase inhibitor EHNA (100 μm), or naloxone (10 μm) and morphine (100 μm). Additional experiments measured adenosine levels in the SI before and during microdialysis delivery of morphine, fentanyl, and morphine plus EHNA. RESULTS: Morphine caused a significant (P < 0.05) concentration-dependent decrease in PRF adenosine levels. The significant decrease (-20%) in adenosine caused by 100 μm morphine was blocked by coadministration of naloxone. Fentanyl also significantly decreased (-13.3%) PRF adenosine. SI adenosine levels were decreased by morphine (-26.8%) and fentanyl (-27.4%). In both PRF and SI, coadministration of morphine and EHNA prevented the significant decrease in adenosine levels caused by morphine alone. CONCLUSIONS: These data support the interpretation that decreased adenosine levels in sleep-regulating brain regions may be one of the mechanisms by which opioids disrupt sleep.

AB - BACKGROUND: Opioids disrupt sleep and adenosine promotes sleep, but no studies have characterized the effects of opioids on adenosine levels in brain regions known to regulate states of arousal. Delivering opioids to the pontine reticular formation (PRF) and substantia innominata (SI) region of the basal forebrain disrupts sleep. In contrast, administering adenosine agonists to the PRF or SI increases sleep. These findings encouraged the current study testing the hypothesis that microdialysis delivery of opioids to the PRF or SI decreases adenosine levels in the PRF or SI, respectively. METHODS: A microdialysis probe was placed in the PRF of isoflurane anesthetized rats and perfused with Ringer's solution (control) followed by Ringer's solution containing morphine (0, 10, 30, 100, or 300 μm), fentanyl (100 μm), morphine (100 μm) and the adenosine deaminase inhibitor EHNA (100 μm), or naloxone (10 μm) and morphine (100 μm). Additional experiments measured adenosine levels in the SI before and during microdialysis delivery of morphine, fentanyl, and morphine plus EHNA. RESULTS: Morphine caused a significant (P < 0.05) concentration-dependent decrease in PRF adenosine levels. The significant decrease (-20%) in adenosine caused by 100 μm morphine was blocked by coadministration of naloxone. Fentanyl also significantly decreased (-13.3%) PRF adenosine. SI adenosine levels were decreased by morphine (-26.8%) and fentanyl (-27.4%). In both PRF and SI, coadministration of morphine and EHNA prevented the significant decrease in adenosine levels caused by morphine alone. CONCLUSIONS: These data support the interpretation that decreased adenosine levels in sleep-regulating brain regions may be one of the mechanisms by which opioids disrupt sleep.

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