Research PaperFundamental sex differences in morphine withdrawal-induced neuronal plasticityHadschieff, Viktoria; Drdla-Schutting, Ruth; Springer, David Niklas; Siegert, Anna Siobhán Maria; Schroeder, Hanna; Sandkühler, Jürgen*Author Information Department of Neurophysiology, Center for Brain Research, Medical University of Vienna, Vienna, Austria *Corresponding author. Address: Department of Neurophysiology, Center for Brain Research, Medical University of Vienna, 1090 Vienna, Austria. Tel.: +43 1 40160 34101; fax: +43 1 40160 934103. E-mail address: email@example.com (J. Sandkühler). Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article. V. Hadschieff and R. Drdla-Schutting contributed equally to this work. This is an open access article distributed under the terms of the Creative Commons Attribution-Non Commercial License 4.0 (CCBY-NC), where it is permissible to download, share, remix, transform, and buildup the work provided it is properly cited. The work cannot be used commercially without permission from the journal. PAIN: September 2020 - Volume 161 - Issue 9 - p 2022-2034 doi: 10.1097/j.pain.0000000000001901 Buy Metrics AbstractIn Brief Withdrawal from systemic opioids can induce long-term potentiation (LTP) at spinal C-fibre synapses (“opioid-withdrawal-LTP”). This is considered to be a cellular mechanism underlying opioid withdrawal-induced hyperalgesia, which is a major symptom of the opioid withdrawal syndrome. Opioids can activate glial cells leading to the release of proinflammatory mediators. These may influence synaptic plasticity and could thus contribute to opioid-withdrawal-LTP. Here, we report a sexual dimorphism in the mechanisms of morphine-withdrawal-LTP in adult rats. We recorded C-fibre-evoked field potentials in the spinal cord dorsal horn from deeply anaesthetised male and female rats. In both sexes, we induced a robust LTP through withdrawal from systemic morphine infusion (8 mg·kg−1 bolus, followed by a 1-hour infusion at a rate of 14 mg·kg−1·h−1). This paradigm also induced mechanical hypersensitivity of similar magnitude in both sexes. In male rats, systemic but not spinal application of (−)naloxone blocked the induction of morphine-withdrawal-LTP, suggesting the involvement of descending pronociceptive pathways. Furthermore, we showed that in male rats, the induction of morphine-withdrawal-LTP required the activation of spinal astrocytes and the release of the proinflammatory cytokines tumour necrosis factor and interleukin-1. In striking contrast, in female rats, the induction of morphine-withdrawal-LTP was independent of spinal glial cells. Instead, blocking µ-opioid receptors in the spinal cord was sufficient to prevent a facilitation of synaptic strength. Our study revealed fundamental sex differences in the mechanisms underlying morphine-withdrawal-LTP at C-fibre synapses: supraspinal and gliogenic mechanisms in males and a spinal, glial cell-independent mechanism in females. In males, morphine-withdrawal-long-term potentiation at spinal C-fibre synapses is triggered by descending pathways that activate spinal astrocytes, whereas females use spinal neuronal mechanisms. Copyright © 2020 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the International Association for the Study of Pain.