Scientific Understanding of Consciousness
Memory Trace Erasure of Pain by High-Dose Opioid
Science 13 January 2012: Vol. 335 no. 6065 pp. 235-238
Erasure of a Spinal Memory Trace of Pain by a Brief, High-Dose Opioid Administration
Ruth Drdla-Schutting, Justus Benrath, Gabriele Wunderbaldinger, Jürgen Sandkühler
Department of Neurophysiology, Center for Brain Research, Medical University of Vienna, A-1090 Vienna, Austria.
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.
μ-Opioid receptors (MORs) are expressed on spinal terminals of nociceptive C-fiber afferents and mediate the acute and quickly reversible presynaptic depression by opioids, mainly via inhibition of N- and P/Q-type voltage-gated calcium channels. In addition, brief activation of postsynaptic MORs triggers a rise in postsynaptic Ca2+ levels by increasing Ca2+ influx through N-methyl-d-aspartate (NMDA)–receptor channels and by releasing Ca2+ from ryanodine-sensitive intracellular Ca2+ stores.
The acute synaptic depression and the prevention of synaptic plasticity by opioids have been studied extensively. In contrast, surprisingly little is known about the potential induction of Ca2+-dependent synaptic plasticity by opioids.
Synaptic long-term potentiation (LTP) is a cellular model for learning and memory formation. The reversal of LTP, that is, synaptic depotentiation, is a potential mechanism of memory erasure. Depotentiation involves Ca2+-dependent signaling and may reverse LTP-associated changes in the phosphorylation state of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs). We tested the hypothesis that brief application of a MOR agonist reverses LTP at C-fiber synapses in superficial lumbar dorsal horn by Ca2+-dependent signaling pathways, which normalize the phosphorylation state of AMPAR subunits.
Taken together, the present and our previous data demonstrate that activation of spinal MORs triggers distinct, bidirectional, and state-dependent synaptic plasticity in naïve versus potentiated C-fiber synapses. Remifentanil activates Ca2+-dependent signaling pathways, leading to activation of PP1 and PKC. At potentiated synapses, this normalizes the phosphorylation state of GluR1 at Ser831 and that of GluR2 at Ser880 and thereby depotentiates synaptic strength in C fibers. The presently identified reversal of synaptic LTP in nociceptive pathways provides a rationale for novel therapeutic strategies to cure rather than to temporarily dampen some forms of pain with opioids.
[end of paraphrase]