Erasure of a Spinal Memory Trace of Pain by a Brief, High-Dose Opioid Administration

• Published in: Science (American Association for the Advancement of Science) 2012-01, Vol.335 (6065), p.235-238
• Main Authors: Drdla-Schutting, Ruth, Benrath, Justus, Wunderbaldinger, Gabriele, Sandkühler, Jürgen
• Format: Article
• Language: English
• Subjects: Analgesics; Analgesics, Opioid - administration & dosage; Animals; Biological and medical sciences; Calcium; Calcium Signaling; Drug dosages; Evoked Potentials; Hyperalgesia; Hyperalgesia - chemically induced; Hyperalgesia - drug therapy; Long term depression; Long term potentiation; Long-Term Potentiation - drug effects; Male; Medical sciences; Memory trace; Naloxone - administration & dosage; Narcotics; Nerve Fibers, Unmyelinated - drug effects; Nerve Fibers, Unmyelinated - physiology; Neurons; Neuropharmacology; Neuroscience; Nociceptive Pain - drug therapy; Nociceptive Pain - physiopathology; Opioid analgesics; Pain; Pain management; Pharmacology; Pharmacology. Drug treatments; Phosphorylation; Piperidines - administration & dosage; Protein Kinase C - antagonists & inhibitors; Protein Kinase C - metabolism; Protein Phosphatase 1 - antagonists & inhibitors; Protein Phosphatase 1 - metabolism; Rats; Rats, Sprague-Dawley; Receptors; Receptors, AMPA - metabolism; Receptors, Opioid, mu - agonists; Receptors, Opioid, mu - metabolism; Sciatic Nerve - drug effects; Sciatic Nerve - physiology; Somatostatin - administration & dosage; Somatostatin - analogs & derivatives; Spinal cord; Spinal Cord - physiology; Synapses; Synapses - drug effects; Synapses - physiology
• ISSN: 0036-8075; 1095-9203
• DOI: 10.1126/science.1211726

Painful stimuli activate nociceptive C fibers and induce synaptic long-term potentiation (LTP) at their spinal terminals. LTP at C-fiber synapses represents a cellular model for pain amplification (hyperalgesia) and for a memory trace of pain. μ-Opioid receptor agonists exert a powerful but reversible depression at C-fiber synapses that renders the continuous application of low opioid doses the gold standard in pain therapy. We discovered that brief application of a high opioid dose reversed various forms of activity-dependent LTP at C-fiber synapses. Depotentiation involved Ca²⁺ -dependent signaling and normalization of the phosphorylation state of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors. This also reversed hyperalgesia in behaving animals. Opioids thus not only temporarily dampen pain but may also erase a spinal memory trace of pain.