Cellular actions of opioids and other analgesics

Implications for synergism in pain relief

MacDonald J. Christie, Mark Connor, Christopher W. Vaughan, Susan Ingram, Elena E. Bagley

Research output: Contribution to journalArticle

75 Citations (Scopus)

Abstract

1. μ-Opioid receptor agonists mediate their central analgesic effects by actions on neurons within brain regions such as the mid-brain periaqueductal grey (PAG). Within the PAG, μ-opioid receptor-mediated analgesia results from inhibition of GABAergic influences on output projection neurons. We have established that μ-opioid receptor activation in the PAG causes a presynaptic inhibition of GABA release that is mediated by activation of a voltage-dependent K+ channel via 12-lipoxygenase (LOX) metabolites of arachidonic acid. 2. At a cellular level, μ-opioid agonists have also been shown to open inwardly rectifying K+ channels, close voltage- gated Ca2+ channels and presynaptically inhibit glutamatergic synaptic transmission in the PAG. 3. The μ-opioid receptor-mediated presynaptic inhibition of GABAergic transmission was abolished by phospholipase A2 inhibitors and non-specific LOX and specific 12-LOX inhibitors. Cyclo- oxygenase (COX) and specific 5-LOX inhibitors did not reduce the inhibitory effects of μ-opioid agonists. 4. The opioid actions on GABAergic transmission were mimicked by arachidonic acid and 12-LOX metabolites, but not 5-LOX metabolites. The efficacy of μ-opioids was enhanced synergistically by treatment of PAG neurons with inhibitors of the other major enzymes responsible for arachidonic acid metabolism, COX and 5-LOX. 5. These results explain a previously described analgesic action of COX inhibitors in the central nervous system that was both independent of prostanoid release and inhibited by opioid receptor antagonists and they also explain the synergistic interaction of opioids with COX inhibitors. These findings also suggest new avenues for the development of centrally active analgesic agents involving combinations of lowered doses of opioids and specific 5-LOX inhibitors.

Original languageEnglish (US)
Pages (from-to)520-523
Number of pages4
JournalClinical and Experimental Pharmacology and Physiology
Volume27
Issue number7
DOIs
StatePublished - 2000

Fingerprint

Periaqueductal Gray
Opioid Analgesics
Opioid Receptors
Pain
Lipoxygenase Inhibitors
Arachidonate 12-Lipoxygenase
Analgesics
Arachidonate 5-Lipoxygenase
Cyclooxygenase Inhibitors
Prostaglandin-Endoperoxide Synthases
Neurons
Phospholipase A2 Inhibitors
Inwardly Rectifying Potassium Channel
Lipoxygenase
Narcotic Antagonists
Brain
Arachidonic Acid
Synaptic Transmission
Analgesia
gamma-Aminobutyric Acid

Keywords

  • 5-lipoxygenase
  • Arachidonic acid
  • Non-steroidal anti-inflammatory drug
  • Opioid
  • Pain

ASJC Scopus subject areas

  • Physiology
  • Pharmacology (medical)
  • Pharmacology, Toxicology and Pharmaceutics(all)

Cite this

Cellular actions of opioids and other analgesics : Implications for synergism in pain relief. / Christie, MacDonald J.; Connor, Mark; Vaughan, Christopher W.; Ingram, Susan; Bagley, Elena E.

In: Clinical and Experimental Pharmacology and Physiology, Vol. 27, No. 7, 2000, p. 520-523.

Research output: Contribution to journalArticle

Christie, MacDonald J. ; Connor, Mark ; Vaughan, Christopher W. ; Ingram, Susan ; Bagley, Elena E. / Cellular actions of opioids and other analgesics : Implications for synergism in pain relief. In: Clinical and Experimental Pharmacology and Physiology. 2000 ; Vol. 27, No. 7. pp. 520-523.
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AB - 1. μ-Opioid receptor agonists mediate their central analgesic effects by actions on neurons within brain regions such as the mid-brain periaqueductal grey (PAG). Within the PAG, μ-opioid receptor-mediated analgesia results from inhibition of GABAergic influences on output projection neurons. We have established that μ-opioid receptor activation in the PAG causes a presynaptic inhibition of GABA release that is mediated by activation of a voltage-dependent K+ channel via 12-lipoxygenase (LOX) metabolites of arachidonic acid. 2. At a cellular level, μ-opioid agonists have also been shown to open inwardly rectifying K+ channels, close voltage- gated Ca2+ channels and presynaptically inhibit glutamatergic synaptic transmission in the PAG. 3. The μ-opioid receptor-mediated presynaptic inhibition of GABAergic transmission was abolished by phospholipase A2 inhibitors and non-specific LOX and specific 12-LOX inhibitors. Cyclo- oxygenase (COX) and specific 5-LOX inhibitors did not reduce the inhibitory effects of μ-opioid agonists. 4. The opioid actions on GABAergic transmission were mimicked by arachidonic acid and 12-LOX metabolites, but not 5-LOX metabolites. The efficacy of μ-opioids was enhanced synergistically by treatment of PAG neurons with inhibitors of the other major enzymes responsible for arachidonic acid metabolism, COX and 5-LOX. 5. These results explain a previously described analgesic action of COX inhibitors in the central nervous system that was both independent of prostanoid release and inhibited by opioid receptor antagonists and they also explain the synergistic interaction of opioids with COX inhibitors. These findings also suggest new avenues for the development of centrally active analgesic agents involving combinations of lowered doses of opioids and specific 5-LOX inhibitors.

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