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Piromelatine exerts antinociceptive effect via melatonin, opioid, and 5HT1A receptors and hypnotic effect via melatonin receptors in a mouse model of neuropathic pain

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Abstract

Rationale

An effective and safe treatment of insomnia in patients with neuropathic pain remains an unmet need. Melatonin and its analogs have been shown to have both analgesic and hypnotic effects; however, capacity of them on sleep disturbance with neuropathic pain as well as the precise mechanism is unclear.

Objective

The present study evaluated effects of piromelatine, a novel melatonin receptor agonist, on sleep disturbance in a neuropathic pain-like condition as well as the underlying mechanisms.

Methods

A mouse model of chronic neuropathic pain induced by partial sciatic nerve ligation (PSL) was employed. The antinociceptive and hypnotic effects of piromelatine were evaluated by measurement of thermal hyperalgesia, mechanical allodynia, and electroencephalogram (EEG) recordings in PSL mice. Pharmacological approaches were used to clarify the mechanisms of action of piromelatine.

Results

PSL significantly lowered thermal and mechanical latencies and decreased non-rapid eye movement (NREM) sleep, and PSL mice exhibited sleep fragmentation. Treatment with 25, 50, or 100 mg/kg of piromelatine significantly prolonged thermal and mechanical latencies and increased NREM sleep. Moreover, the antinociceptive effect of piromelatine was prevented by melatonin antagonist luzindole, opioid receptor antagonist naloxone, or 5HT1A receptor antagonist WAY-100635. The hypnotic effect of piromelatine was blocked by luzindole but neither by naloxone nor WAY-100635.

Conclusions

These data indicate that piromelatine is an effective treatment for both neuropathic pain and sleep disturbance in PSL mice. The antinociceptive effect of piromelatine is likely mediated by melatonin, opioid, and 5HT1A receptors; however, the hypnotic effect of piromelatine appears to be mediated by melatonin receptors.

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Acknowledgments

This study was supported in part by grants-in-aid for scientific research from the National Basic Research Program of China (2011CB711000, 2009ZX09303-006), the National Natural Science Foundation of China (30901797, 31171010, 31171049, 31121061, 31271164), the Shanghai Committee of Science and Technology (13140903100, 13dz2260700, 13ZR1403200), the Shanghai Leading Academic Discipline Project (B119), and the Ph.D. Programs Foundation of Ministry of Education of China (20110071110033).

Conflict of interest

Moshe Laudon is an employee of Neurim Pharmaceuticals Ltd, and provided piromelatine without any financial supports. All other authors declare that they have no conflicts of interest.

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Authors and Affiliations

  1. Department of Pharmacology, School of Basic Medical Sciences, Fudan University, Shanghai, 200032, China

    Yuan-Yuan Liu, Li Chen, Wei-Min Qu, Chang-Rui Chen & Zhi-Li Huang

  2. Department of Pharmacology, College of Pharmaceutical Science, Fudan University, Shanghai, China

    Dou Yin & Neng-Neng Cheng

  3. Institutes of Brain Science, Fudan University, Shanghai, China

    Wei-Min Qu & Zhi-Li Huang

  4. State Key Laboratory of Medical Neurobiology, Fudan University, Shanghai, China

    Zhi-Li Huang

  5. Neurim Pharmaceuticals Ltd, Tel-Aviv, Israel

    Moshe Laudon

  6. Department of Molecular Behavioral Biology, Osaka Bioscience Institute, Suita, Osaka, Japan

    Yoshihiro Urade

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  1. Yuan-Yuan Liu
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  2. Dou Yin
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  3. Li Chen
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  4. Wei-Min Qu
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  8. Yoshihiro Urade
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  9. Zhi-Li Huang
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Corresponding authors

Correspondence to Wei-Min Qu, Neng-Neng Cheng or Zhi-Li Huang.

Additional information

Liu Yuan-Yuan and Yin Dou equally contributed to this work.

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Liu, YY., Yin, D., Chen, L. et al. Piromelatine exerts antinociceptive effect via melatonin, opioid, and 5HT1A receptors and hypnotic effect via melatonin receptors in a mouse model of neuropathic pain. Psychopharmacology 231, 3973–3985 (2014). https://doi.org/10.1007/s00213-014-3530-5

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  • DOI: https://doi.org/10.1007/s00213-014-3530-5

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