title: Distinct mechanisms underlying pronociceptive effects of opioids.
abstract: In addition to analgesia, opioids may also produce paradoxical pain amplification [opioid-induced hyperalgesia (OIH)] either on abrupt withdrawal or during continuous long-term application. Here, we assessed antinociceptive and pronociceptive effects of three clinically used opioids at C-fiber synapses in the rat spinal dorsal horn in vivo. During 60 min of intravenous infusions of remifentanil (450 μg·kg⁻¹·h⁻¹), fentanyl (48 μg·kg⁻¹·h⁻¹), or morphine (14 mg·kg⁻¹·h⁻¹), C-fiber-evoked field potentials were depressed and paired-pulse ratios (PPR) were increased, indicating a presynaptic inhibition by all three opioids. After withdrawal, postsynaptic responses were enhanced substantially for the remaining of the recording periods of at least 3 h. Withdrawal from remifentanil led to long-term potentiation (LTP) of synaptic strength in C-fibers via activation of spinal μ-opioid receptors (MORs) and spinal NMDA receptors (NMDARs). Fentanyl and morphine caused an enhancement of synaptic transmission at C-fibers, which involved two distinct mechanisms: (1) an opioid withdrawal LTP that also required activation of spinal MORs and NMDARs and that was associated with a decrease in PPR suggestive of a presynaptic mechanism of its expression, and (2) an immediate-onset, descending facilitation of C-fiber-evoked field potentials during and after intravenous infusion of fentanyl and morphine. Immediate-onset, descending facilitation was mediated by the activation of extraspinal MORs, descending serotonergic pathways, and spinal 5-hydroxytryptamine-3 receptors (5-HT₃Rs). Our study identified fundamentally different pronociceptive effects of clinically used opioids and suggests that OIH can be prevented by the combined use of NMDAR and 5-HT₃R antagonists.
authors.affiliation: Department of Neurophysiology, Center for Brain Research, Medical University of Vienna, 1090 Vienna, Austria.
authors.forename: Céline
authors.initials: C
authors.lastname: Heinl
authors.forename: Ruth
authors.initials: R
authors.lastname: Drdla-Schutting
authors.forename: Dimitris N
authors.initials: DN
authors.lastname: Xanthos
authors.forename: Jürgen
authors.initials: J
authors.lastname: Sandkühler
mesh_terms: D015763:2-Amino-5-phosphonovalerate / Q000494:pharmacology; D000701:Analgesics, Opioid / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D017829:Granisetron / Q000494:pharmacology; D006930:Hyperalgesia / Q000139:chemically induced / Q000188:drug therapy; D017774:Long-Term Potentiation / Q000187:drug effects; D008297:Male; D009270:Naloxone / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology; D036421:Nerve Fibers, Unmyelinated / Q000187:drug effects / Q000502:physiology; D017294:Ondansetron / Q000494:pharmacology; D017288:Pain Threshold / Q000187:drug effects*; D020671:Posterior Horn Cells / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012702:Serotonin Antagonists / Q000494:pharmacology; D013004:Somatostatin / Q000031:analogs & derivatives / Q000494:pharmacology; D013116:Spinal Cord / Q000166:cytology; D013375:Substance Withdrawal Syndrome / Q000503:physiopathology; D009435:Synaptic Transmission / Q000187:drug effects
chemical_list: D015763:2-Amino-5-phosphonovalerate; D000701:Analgesics, Opioid; D018691:Excitatory Amino Acid Antagonists; D017829:Granisetron; D009270:Naloxone; D009292:Narcotic Antagonists; D017294:Ondansetron; D012702:Serotonin Antagonists; D013004:Somatostatin; C049352:phenylalanyl-cyclo(cysteinyltyrosyl-tryptophyl-ornithyl-threonyl-penicillamine)threoninamide
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