How opioids inhibit GABA-mediated neurotransmission.
The midbrain region periaqueductal grey (PAG) is rich in opioid receptors and endogenous opioids and is a major target of analgesic action in the central nervous system. It has been proposed that the analgesic effect of opioids on the PAG works by suppressing the inhibitory influence of the neurotransmitter GABA (gamma-aminobutyric acid) on neurons that form part of a descending antinociceptive pathway. Opioids inhibit GABA-mediated (GABAergic) synaptic transmission in the PAG and other brain regions by reducing the probability of presynaptic neurotransmitter release, but the mechanisms involved remain uncertain. Here we report that opioid inhibition of GABAergic synaptic currents in the PAG is controlled by a presynaptic voltage-dependent potassium conductance. Opioid receptors of the mu type in GABAergic presynaptic terminals are specifically coupled to this potassium conductance by a pathway involving phospholipase A2, arachidonic acid and 12-lipoxygenase. Furthermore, opioid inhibition of GABAergic synaptic transmission is potentiated by inhibitors of the enzymes cyclooxygenase and 5-lipoxygenase, presumably because more arachidonic acid is available for conversion to 12-lipoxygenase products. These mechanisms account for the analgesic action of cyclooxygenase inhibitors in the PAG and their synergism with opioids.
Vaughan
C W
CW
Department of Pharmacology, The University of Sydney, New South Wales, Australia. chrisv@pharmacol.usyd.edu.au
Ingram
S L
SL
Connor
M A
MA
Christie
M J
MJ
D000818:Animals; D001092:Arachidonate 12-Lipoxygenase / Q000378:metabolism; D016718:Arachidonic Acid / Q000378:metabolism; D001241:Aspirin / Q000494:pharmacology; D001418:Baclofen / Q000494:pharmacology; D004744:Enkephalin, Methionine / Q000494:pharmacology; D018755:GABA Agonists / Q000494:pharmacology; D018756:GABA Antagonists / Q000494:pharmacology*; D066298:In Vitro Techniques; D009294:Narcotics / Q000494:pharmacology*; D010487:Periaqueductal Gray / Q000187:drug effects* / Q000378:metabolism; D010741:Phospholipases A / Q000037:antagonists & inhibitors / Q000378:metabolism; D054467:Phospholipases A2; D011188:Potassium / Q000378:metabolism; D026902:Potassium Channel Blockers; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D018079:Receptors, GABA / Q000187:drug effects / Q000378:metabolism; D017450:Receptors, Opioid, mu / Q000187:drug effects / Q000378:metabolism; D015290:Second Messenger Systems; D013569:Synapses; D009435:Synaptic Transmission / Q000187:drug effects*; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
D018755:GABA Agonists; D018756:GABA Antagonists; D009294:Narcotics; D026902:Potassium Channel Blockers; D018079:Receptors, GABA; D017450:Receptors, Opioid, mu; D016718:Arachidonic Acid; D005680:gamma-Aminobutyric Acid; D004744:Enkephalin, Methionine; D001092:Arachidonate 12-Lipoxygenase; D011451:Prostaglandin-Endoperoxide Synthases; D010741:Phospholipases A; D054467:Phospholipases A2; D001418:Baclofen; D001241:Aspirin; D011188:Potassium