Scientific Understanding of Consciousness
Consciousness as an Emergent Property of Thalamocortical Activity

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.

[paraphrase]

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.

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