Withdrawal from an opioid induces a transferable memory trace in the cerebrospinal fluid.

Opioids are the most powerful analgesics available to date. However, they may also induce adverse effects including paradoxical opioid-induced hyperalgesia (OIH). A mechanism that might underlie OIH is the amplification of synaptic strength at spinal C-fibre synapses after withdrawal from systemic opioids such as remifentanil ("opioid-withdrawal-LTP").Here, we show that both, the induction as well as the maintenance of opioid-withdrawal-LTP were abolished by pharmacological blockade of spinal glial cells. In contrast, the blockade of TLR4 had no effect on the induction of opioid-withdrawal-LTP. D-serine, which may be released upon glial cell activation, was necessary for withdrawal-LTP. D-serine is the dominant co-agonist for neuronal NMDA-receptors, which are required for the amplification of synaptic strength upon remifentanil withdrawal.Unexpectedly, opioid-withdrawal-LTP was transferable via the cerebrospinal fluid between animals. This suggests that glial cell-derived mediators accumulate in the extracellular space and reach the cerebrospinal fluid at biologically active concentrations, thereby creating a soluble memory trace that is transferable to another animal ("transfer-LTP"). When we enzymatically degraded D-serine in the superfusate, LTP could no longer be transferred. Transfer-LTP was insensitive to pharmacological blockade of glial cells in the recipient animal, thus representing a rare form of glial-cell independent LTP in the spinal cord.