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

• Published in: Pain (Amsterdam) Vol. 160; no. 12; pp. 2819 - 2828
• Main Authors: Drdla-Schutting, Ruth, Heinl, Céline, Hadschieff, Viktoria, Sandkühler, Jürgen
• Format: Journal Article
• Language: English
• Published: United States Wolters Kluwer 01.12.2019
• Subjects: Analgesics, Opioid - adverse effects; Analgesics, Opioid - pharmacology; Animals; Long-Term Potentiation - drug effects; Male; Memory - drug effects; Microglia - drug effects; Minocycline - pharmacology; Rats; Rats, Sprague-Dawley; Remifentanil - adverse effects; Substance Withdrawal Syndrome - cerebrospinal fluid
• ISSN: 0304-3959; 1872-6623; 1872-6623
• DOI: 10.1097/j.pain.0000000000001688

Opioids are the most powerful analgesics available to date. However, they may also induce adverse effects including paradoxical opioid-induced hyperalgesia. A mechanism that might underlie opioid-induced hyperalgesia is the amplification of synaptic strength at spinal C-fibre synapses after withdrawal from systemic opioids such as remifentanil (“opioid-withdrawal long-term potentiation [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. By 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 coagonist for neuronal NMDA receptors, which are required for the amplification of synaptic strength on remifentanil withdrawal. Unexpectedly, opioid-withdrawal LTP was transferable through 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.