Withdrawal from an opioid induces a transferable memory trace in the cerebrospinal fluid. Issue 12 (December 2019)

• Record Type: Journal Article
• Authors: Drdla-Schutting, Ruth; Heinl, Céline; Hadschieff, Viktoria; Sandkühler, Jürgen
• Is Part Of: Pain. Volume 160:Issue 12(2019)
• Publication Date: 2019-12
• Subjects: Opioids -- Withdrawal -- Spinal cord -- LTP -- Glial cells; Pain -- Periodicals; Douleur -- Périodiques; Anesthésie -- Périodiques; Pain; Electronic journals; Periodicals; Electronic journals; 616.0472
• DOI: 10.1097/j.pain.0000000000001688
• Languages: English
• ISSNs: 0304-3959

Abstract

Abstract : Abstract: 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. Abstract : Withdrawal from an opioid induces synaptic plasticity in pain pathways, which is transferable through the cerebrospinal fluid between animals.