Induction of synaptic long-term potentiation after opioid withdrawal.
mu-Opioid receptor (MOR) agonists represent the gold standard for the treatment of severe pain but may paradoxically also enhance pain sensitivity, that is, lead to opioid-induced hyperalgesia (OIH). We show that abrupt withdrawal from MOR agonists induces long-term potentiation (LTP) at the first synapse in pain pathways. Induction of opioid withdrawal LTP requires postsynaptic activation of heterotrimeric guanine nucleotide-binding proteins and N-methyl-d-aspartate receptors and a rise of postsynaptic calcium concentrations. In contrast, the acute depression by opioids is induced presynaptically at these synapses. Withdrawal LTP can be prevented by tapered withdrawal and shares pharmacology and signal transduction pathways with OIH. These findings provide a previously unrecognized target to selectively combat pro-nociceptive effects of opioids without compromising opioid analgesia.
Drdla
Ruth
R
Department of Neurophysiology, Center for Brain Research, Medical University of Vienna, Spitalgasse 4, 1090 Vienna, Austria.
Gassner
Matthias
M
Gingl
Ewald
E
Sandkühler
Jürgen
J
D000701:Analgesics, Opioid / Q000008:administration & dosage / Q000009:adverse effects* / Q000494:pharmacology; D000818:Animals; D002118:Calcium / Q000378:metabolism; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)- / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology; D005071:Evoked Potentials; D019204:GTP-Binding Proteins / Q000378:metabolism; D006930:Hyperalgesia / Q000139:chemically induced; D017774:Long-Term Potentiation / Q000187:drug effects; D008297:Male; D036421:Nerve Fibers, Unmyelinated / Q000502:physiology; D018408:Patch-Clamp Techniques; D010880:Piperidines / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology; D020671:Posterior Horn Cells / Q000187:drug effects / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D017450:Receptors, Opioid, mu / Q000819:agonists*; D000077208:Remifentanil; D015398:Signal Transduction; D013375:Substance Withdrawal Syndrome / Q000503:physiopathology*; D013569:Synapses / Q000187:drug effects / Q000502:physiology*
D000701:Analgesics, Opioid; D010880:Piperidines; D016194:Receptors, N-Methyl-D-Aspartate; D017450:Receptors, Opioid, mu; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D019204:GTP-Binding Proteins; D000077208:Remifentanil; D002118:Calcium