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

Long-Lasting Pain Killers Opioids are among the most widely used and extensively studied drugs in the world. A continuous application of relatively low opioid doses is thought to be necessary to maintain synaptic depression in pain pathways. Drdla-Schutting et al. (p. 235) found that a single opioid application could produce lasting reversal of synaptic long-term potentiation in pain pathways. Chronic pain is often associated with synaptic potentiation in nociceptive pathways. A brief, high-dose application of opioids depotentiated long-term potentiation in spinal pain pathways. The same dose also reversed hyperalgesia in behaving animals. Thus, opioids not only attenuate pain but also may eradicate a significant cause for chronic pain. Opioid administration turns down a pain amplifier by reversing synaptic long-term potentiation in spinal nociceptive pathways. 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.