m-Trifluoromethyl-diphenyl diselenide (m-CF3-PhSe)2 modulates the hippocampal neurotoxic adaptations and abolishes a depressive-like phenotype in a short-term morphine withdrawal in mice

Prog Neuropsychopharmacol Biol Psychiatry. 2020 Mar 2:98:109803. doi: 10.1016/j.pnpbp.2019.109803. Epub 2019 Nov 2.

Abstract

The opioid withdrawal syndrome is defined as a complex phenomenon involving multiple cellular adaptations, which leads to the emergence of aversive physical and affective signs. The m-trifluoromethyl-diphenyl diselenide (m-CF3-PhSe)2 elicits an antidepressant-like effect by modulating the opioid system in different animal models of mood disorders. Notably, repeated exposure to (m-CF3-PhSe)2 developed neither tolerance nor withdrawal signs in mice. The aim of the present study was to investigate whether (m-CF3-PhSe)2 attenuates the physical signs and the depressive-like phenotype during morphine withdrawal through its neuroprotective effects on oxidative stress, the NMDA receptor and the proBDNF/mBDNF signaling in the hippocampus of mice. Adult Swiss mice received saline solution or escalating doses (20-100 mg/kg, sc) of morphine for six days. For the next three days, the animals were treated with canola oil, (m-CF3-PhSe)2 (5 and 10 mg/kg, ig) or methadone (5 mg/kg, sc) whereas morphine injections were discontinued. On day 9, physical withdrawal signs and depressive-like behavior were assessed 30 min after the last administration of (m-CF3-PhSe)2. Although short-term treatment with (m-CF3-PhSe)2 at both doses suppressed the aversive physical and affective signs in morphine withdrawn-mice, the highest dose of (m-CF3-PhSe)2 per se increased the teeth chattering manifestation. The intrinsic antioxidant property of (m-CF3-PhSe)2 modulated oxidative stress, it also restored the NMDA receptor levels in the hippocampus of morphine withdrawn-mice. Besides, (m-CF3-PhSe)2 downregulated the proBDNF/p-75NTR/JNK pro-apoptotic pathway without affecting the mBDNF/TrkB/ERK/CREB pro-survival signaling in the hippocampus of morphine withdrawn-mice. The results show that (m-CF3-PhSe)2 treatment modulated the hippocampal neurotoxic adaptations and abolished the depressive-like phenotype following morphine withdrawal in mice.

Keywords: Depressive-like; Neuroprotection; Opioid withdrawal syndrome; Organoselenium; Oxidative stress.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptation, Physiological
  • Animals
  • Antidepressive Agents / pharmacology*
  • Behavior, Animal
  • Depression / drug therapy
  • Hippocampus / drug effects*
  • Hippocampus / physiopathology*
  • Mice
  • Morphine*
  • Narcotics*
  • Neuroprotective Agents / pharmacology*
  • Neurotoxicity Syndromes / physiopathology*
  • Organosilicon Compounds / pharmacology*
  • Oxidative Stress / drug effects
  • Phenotype
  • Signal Transduction / drug effects
  • Substance Withdrawal Syndrome / drug therapy*
  • Substance Withdrawal Syndrome / physiopathology
  • Substance Withdrawal Syndrome / psychology*

Substances

  • Antidepressive Agents
  • Narcotics
  • Neuroprotective Agents
  • Organosilicon Compounds
  • m-trifluoromethyl-diphenyl diselenide
  • Morphine