Activation of TLR4/STAT3 signaling in VTA contributes to the acquisition and maintenance of morphine-induced conditioned place preference

Behav Brain Res. 2017 Sep 29;335:151-157. doi: 10.1016/j.bbr.2017.08.022. Epub 2017 Aug 18.


Morphine, commonly used to relieve the acute or chronic pain, has a high potential for addiction and exerts rewarding effects via a critical role for mesolimbic dopamine system. Studies suggest that addiction-related behavior is highly associated with inflammatory immune response, but the mechanisms are poorly understood. The present study showed that intra-VTA microinjection of TLR4 antagonist LPS-RS prevented the acquisition and maintenance, but not the expression, of morphine-induced CPP in rats. In addition, chronic morphine treatment significantly activated STAT3 on day 6 and 11 in VTA, and bilateral microinjection of STAT3 inhibitor S3I-201 into the VTA suppressed the acquisition and maintenance of morphine-induced CPP in rats. Furthermore, local knockout of STAT3 by injection of the AAV-Cre-GFP into the VTA area of STAT3flox/flox mice also significantly impaired the acquisition of morphine CPP. Importantly, the TLR4 expression is colocalized with p-STAT3-positive cell in VTA, and repeated injection of LPS-RS significantly attenuated the STAT3 activation in VTA induced by chronic morphine treatment. Collectively, these data suggest that TLR4/STAT3 signaling pathway in VTA might play a critical role in the acquisition and maintenance of morphine CPP, and provides new evidence that TLR4/STAT3 signaling pathway might be a potential target for treatment of morphine addiction.

Keywords: Conditioned place preference; Morphine; STAT3; TLR4; VTA.

MeSH terms

  • Animals
  • Conditioning, Classical / drug effects*
  • Male
  • Morphine / pharmacology*
  • Morphine Dependence / immunology
  • Morphine Dependence / metabolism*
  • Narcotics / pharmacology
  • Rats
  • Rats, Sprague-Dawley
  • Reward
  • STAT3 Transcription Factor / genetics
  • STAT3 Transcription Factor / immunology
  • STAT3 Transcription Factor / metabolism*
  • Signal Transduction / drug effects
  • Toll-Like Receptor 4 / antagonists & inhibitors
  • Toll-Like Receptor 4 / immunology
  • Toll-Like Receptor 4 / metabolism*
  • Ventral Tegmental Area / drug effects*
  • Ventral Tegmental Area / immunology
  • Ventral Tegmental Area / metabolism*


  • Narcotics
  • STAT3 Transcription Factor
  • Stat3 protein, rat
  • Tlr4 protein, rat
  • Toll-Like Receptor 4
  • Morphine