Piromelatine exerts antinociceptive effect via melatonin, opioid, and 5HT1A receptors and hypnotic effect via melatonin receptors in a mouse model of neuropathic pain.
BACKGROUND
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.
Department of Pharmacology, School of Basic Medical Sciences, Fudan University, Shanghai, 200032, China.
Yuan-Yuan
YY
Liu
Dou
D
Yin
Li
L
Chen
Wei-Min
WM
Qu
Chang-Rui
CR
Chen
Moshe
M
Laudon
Neng-Neng
NN
Cheng
Yoshihiro
Y
Urade
Zhi-Li
ZL
Huang
D000700:Analgesics / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D004195:Disease Models, Animal; D006930:Hyperalgesia / Q000188:drug therapy / Q000209:etiology / Q000378:metabolism; D006993:Hypnotics and Sedatives / Q000494:pharmacology / Q000627:therapeutic use*; D007211:Indoles / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; D008550:Melatonin / Q000494:pharmacology; D051379:Mice; D009270:Naloxone / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology; D009437:Neuralgia / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism; D010147:Pain Measurement; D059348:Peripheral Nerve Injuries / Q000150:complications; D010879:Piperazines; D011714:Pyrans / Q000494:pharmacology / Q000627:therapeutic use*; D011725:Pyridines; D044282:Receptor, Serotonin, 5-HT1A / Q000378:metabolism*; D044094:Receptors, Melatonin / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011957:Receptors, Opioid / Q000378:metabolism*; D012584:Sciatic Nerve / Q000293:injuries; D012702:Serotonin Antagonists / Q000494:pharmacology; D012893:Sleep Wake Disorders / Q000188:drug therapy* / Q000378:metabolism; D014363:Tryptamines / Q000494:pharmacology
D000700:Analgesics; D006993:Hypnotics and Sedatives; D007211:Indoles; D009292:Narcotic Antagonists; D010879:Piperazines; D011714:Pyrans; D011725:Pyridines; D044094:Receptors, Melatonin; D011957:Receptors, Opioid; D012702:Serotonin Antagonists; D014363:Tryptamines; D044282:Receptor, Serotonin, 5-HT1A; C057154:luzindole; D009270:Naloxone; C090413:N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide; D008550:Melatonin; C581609:N-(2-(5-methoxy-indol-3-yl)-ethyl)-4-oxo-4H-pyran-2-carboxamide