The Journal of Physiological Sciences

, Volume 69, Issue 2, pp 281–293 | Cite as

Decrease of inhibitory synaptic currents of locus coeruleus neurons via orexin type 1 receptors in the context of naloxone-induced morphine withdrawal

  • Mahnaz DavoudiEmail author
  • Hossein AziziEmail author
  • Javad Mirnajafi-Zadeh
  • Saeed SemnanianEmail author
Original Paper


Acute opioid withdrawal syndrome is a series of neurological symptoms caused by the abrupt cessation of the chronic administration of opioids such as morphine. The locus coeruleus (LC) in the brain stem receives a dense projection of orexinergic fibers from the hypothalamus and is a candidate site for the expression of the somatic aspects of morphine withdrawal. Previous studies have shown that orexin-A contributes to the behavioral symptoms of naloxone-induced morphine withdrawal, partly by reducing the activity of GABAergic neurons, suggesting that orexin-A may negatively modulate fast GABAergic neurotransmission during morphine withdrawal. We used whole-cell patch-clamp recordings of LC neurons in brainstem slices to investigate the effect of orexin-A on bicuculline-sensitive GABAergic inhibitory postsynaptic currents (IPSCs) during naloxone-induced morphine withdrawal. Male Wistar rats (P14–P21) were given morphine (20 mg/kg, i.p.) daily for seven consecutive days to create dependency on the drug. The application of naloxone (1 µM) to brain slices of morphine-treated rats reduced the amplitude of evoked IPSCs (eIPSCs) as well as spontaneous IPSCs (sIPSCs) frequency but did not change sIPSCs amplitude. Orexin-A (100 nM) significantly enhanced the suppressive effect of naloxone on eIPSCs amplitude and sIPSCs frequency but had no effect on the presence of the orexin type 1 receptor (OX1R) antagonist, SB-334867. Orexin-A alone had no significant effect on eIPSCs and sIPSCs in the absence of naloxone. In summary, our results show that orexin-A, via OX1R, potentiates the suppressive effect of naloxone on GABAergic IPSCs of LC neurons in morphine-treated rats. We conclude that orexins may have a critical role in regulating GABAergic neurotransmission to LC neurons during naloxone-induced morphine withdrawal.


Orexin Orexin type 1 receptor GABAA-IPSCs Locus coeruleus Naloxone-induced morphine withdrawal 



This work was supported by the Cognitive Sciences and Technologies Council of Iran (CSTC, Grant no. 95P31), Iran National Science Foundation (INSF) and the Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran. The authors also wish to thank Dr. Alexander Davies for his English correction of this manuscript and Dr. Amir Shojaei for his technical help.


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Copyright information

© The Physiological Society of Japan and Springer Japan KK, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of Physiology, Faculty of Medical SciencesTarbiat Modares UniversityTehranIran

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