Distinct Mechanisms Underlying Pronociceptive Effects of Opioids

• Published in: The Journal of neuroscience Vol. 31; no. 46; pp. 16748 - 16756
• Main Authors: Heinl, Céline, Drdla-Schutting, Ruth, Xanthos, Dimitris N., Sandkühler, Jürgen
• Format: Journal Article
• Language: English
• Published: United States Society for Neuroscience 16.11.2011
• Subjects: 2-Amino-5-phosphonovalerate - pharmacology; Analgesics, Opioid - administration & dosage; Analgesics, Opioid - pharmacology; Animals; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Interactions; Excitatory Amino Acid Antagonists - pharmacology; Granisetron - pharmacology; Hyperalgesia - chemically induced; Hyperalgesia - drug therapy; Long-Term Potentiation - drug effects; Male; Naloxone - pharmacology; Narcotic Antagonists - pharmacology; Nerve Fibers, Unmyelinated - drug effects; Nerve Fibers, Unmyelinated - physiology; Ondansetron - pharmacology; Pain Threshold - drug effects; Posterior Horn Cells - drug effects; Rats; Rats, Sprague-Dawley; Serotonin Antagonists - pharmacology; Somatostatin - analogs & derivatives; Somatostatin - pharmacology; Spinal Cord - cytology; Substance Withdrawal Syndrome - physiopathology; Synaptic Transmission - drug effects
• ISSN: 0270-6474; 1529-2401; 1529-2401
• DOI: 10.1523/JNEUROSCI.3491-11.2011

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-HT 3 Rs). 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-HT 3 R antagonists.