[Show abstract][Hide abstract] ABSTRACT: 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.
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.
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.
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.
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.
[Show abstract][Hide abstract] ABSTRACT: Synchronized electroencephalogram (EEG) activity is observed in pathological stages of cognitive impairment and epilepsy. Modafinil, known to increase the release of catecholamines, is a potent wake-promoting agent, and has shown some abilities to desynchronize EEG,but its receptor mechanisms by which modafinil induces desynchoronization remain to be elucidated. Here we used a pharmacological EEG synchronization model to investigate the involvement of adrenergic α1 receptors (R, α1R) and dopamine (DA) D1 and D2 receptors (D1Rs and D2Rs) on modafinil-induced desynchronization in mice.
Mice were treated with cholinergic receptor antagonist scopolamine and monoamine depletor reserpine to produce experimental EEG synchronization characterized by continuous large-amplitude synchronized activity, with prominent increased delta and decreased theta, alpha, and beta power density. The results showed that modafinil produced an EEG desynchronization in the model. This was characterized by a general decrease in amplitude of all the frequency bands between 0 and 20 Hz, a prominent reduction in delta power density, and an increase in theta power density. Adrenergic α1R antagonist terazosin (1 mg/kg, i.p.) completely antagonized the EEG desynchronization effects of modafinil at 90 mg/kg. However, DA D1R and D2R blockers partially attenuated the effects of modafinil. The modafinil-induced decrease in the amplitudes of the delta, theta, alpha, and beta waves and in delta power density were completely abolished by pretreatment with a combination of the D1R antagonist SCH 23390 (30 µg/kg) and the D2R antagonist raclopride (2 mg/kg, i.p.).
These results suggest that modafinil-mediated desynchronization may be attributed to the activation of adrenergic α1R, and dopaminergic D1R and D2R in a model of EEG synchronization.
PLoS ONE 10/2013; 8(10):e76102. DOI:10.1371/journal.pone.0076102 · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The mechanisms involved in the anti-seizure property of piperine (1-[5-(1, 3-benzodioxol-5-yl)-1-oxo-2, 4-pentadienyl]-(E, E)-piperidine, C17H19NO3) are still unclear. Piperine could activate transient receptor potential cation channel subfamily V member 1 (TRPV1) receptor, and the rapid activation of whole-cell currents is antagonized by the competitive TRPV1 antagonist capsazepine. Interestingly, recent studies have reported that TRPV1 may be a novel anti-epileptogenic target which led us to hypothesize that the anti-seizure property of piperine involves the TRPV1 receptor. To test this hypothesis, we examined the effect of piperine on seizures induced in mice and identified the receptors involved in the suppression of seizure caused by maximal electroshock (MES) and pentylenetetrazol (PTZ) models. Piperine, administered at doses of 40 and 80mg/kg, significantly delayed the onset of myoclonic jerks and generalized clonic seizures, and decreased the seizure stage and mortality compared with the vehicle-treated animals. Piperine also significantly reduced the incidence of MES-induced tonic hindlimb extension (THE) and PTZ-induced Fos immunoreactivity in the dentate gyrus. The anti-seizure effects of piperine were blocked by a TRPV1-selective antagonist capsazepine. Taken together, these data support the further investigation of piperine as a TRPV1 agonist for anti-seizure therapy.
European journal of pharmacology 07/2013; 714(1-3). DOI:10.1016/j.ejphar.2013.07.041 · 2.53 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Magnolol (6,6',7,12-tetramethoxy-2,2'-dimethyl-1-beta-berbaman, C(18)H(18)O(2)), an active ingredient of the bark of Magnolia officinalis, has been reported to exert potent anti-epileptic effects via the GABA(A) receptor. The receptor also mediates sleep in humans and animals. The aim of this study was to determine whether magnolol could modulate sleep behaviors by recording EEG and electromyogram in mice. The results showed that magnolol administered i.p. at a dose of 5 or 25 mg/kg could significantly shorten the sleep latency, increase the amount of non-rapid eye movement (non-REM, NREM) and rapid eye movement (REM) sleep for 3 h after administration with an increase in the number of NREM and REM sleep episodes. Magnolol at doses of 5 and 25 mg/kg increased the number of bouts of wakefulness but decreased their duration. On the other hand, magnolol increased the number of state transitions from wakefulness to NREM sleep and subsequently from NREM sleep to wakefulness. Immunohistochemical study showed that magnolol increased c-Fos expression in the neurons of ventrolateral preoptic area, a sleep center in the anterior hypothalamus, and decreased c-Fos expression in the arousal tuberomammillary nucleus, which was located in the caudolateral hypothalamus. The sleep-promoting effects and changes in c-Fos induced by magnolol were reversed by flumazenil, an antagonist at the benzodiazepine site of the GABA(A) receptor. These results indicate that magnolol increased NREM and REM sleep via the GABA(A) receptor.
[Show abstract][Hide abstract] ABSTRACT: BACKGROUND AND PURPOSE Decoctions of the Chinese herb houpu contain honokiol and are used to treat a variety of mental disorders, including depression. Depression commonly presents alongside sleep disorders and sleep disturbances, which appear to be a major risk factor for depression. Here, we have evaluated the somnogenic effect of honokiol and the mechanisms involved. EXPERIMENTAL APPROACH Honokiol was administered i.p. at 20:00 h in mice. Flumazenil, an antagonist at the benzodiazepine site of the GABA(A) receptor, was administered i.p. 15 min before honokiol. The effects of honokiol were measured by EEG and electromyogram (EMG), c-Fos expression and in vitro electrophysiology. KEY RESULTS Honokiol (10 and 20 mg·kg(-1) ) significantly shortened the sleep latency to non-rapid eye movement (non-REM, NREM) sleep and increased the amount of NREM sleep. Honokiol increased the number of state transitions from wakefulness to NREM sleep and, subsequently, from NREM sleep to wakefulness. However, honokiol had no effect on either the amount of REM sleep or EEG power density of both NREM and REM sleep. Honokiol increased c-Fos expression in ventrolateral preoptic area (VLPO) neurons, as examined by immunostaining, and excited sleep-promoting neurons in the VLPO by whole-cell patch clamping in the brain slice. Pretreatment with flumazenil abolished the somnogenic effects and activation of the VLPO neurons by honokiol. CONCLUSION AND IMPLICATIONS Honokiol promoted NREM sleep by modulating the benzodiazepine site of the GABA(A) receptor, suggesting potential applications in the treatment of insomnia, especially for patients who experience difficulty in falling and staying asleep.
British Journal of Pharmacology 04/2012; 167(3):587-598. DOI:10.1111/j.1476-5381.2012.02010.x · 4.84 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Curcumin, a phenolic compound present in Curcuma longa, has been reported to exert antinociceptive effects in some animal models, but the mechanisms remain to be elucidated. This work aimed to investigate the antinociceptive action of curcumin on neuropathic pain and the underlying mechanism(s). Chronic constriction injury (CCI), a canonical animal model of neuropathic pain, was produced by loosely ligating the sciatic nerve in mice and von Frey hair or hot plate test was used to assess mechanical allodynia or thermal hyperalgesia (to heat), respectively. Chronic, but not acute, curcumin treatment (5, 15 or 45 mg/kg, p.o., twice per day for three weeks) alleviated mechanical allodynia and thermal hyperalgesia in CCI mice, accompanied by increasing spinal monoamine (or metabolite) contents. Chemical ablation of descending noradrenaline (NA) by 6-hydroxydopamine (6-OHDA), or depletion of descending serotonin by p-chlorophenylalanine (PCPA), abolished curcumin's antinociceptive effect on mechanical allodynia or thermal hyperalgesia, respectively. The anti-allodynic action of curcumin on mechanical stimuli was totally blocked by chronic co-treatment with the β(2)-adrenoceptor antagonist ICI 118,551, or by acute co-treatment with the delta-opioid receptor antagonist naltrindole. Meanwhile, co-treatment with the 5-HT(1A) receptor antagonist WAY-100635 chronically, or with the irreversible mu-opioid receptor antangonist β-funaltrexamine acutely, completely abrogated the anti-hyperalgesic action of curcumin on thermal stimuli. Collectively, these findings indicate that the descending monoamine system (coupled with spinal β(2)-adrenoceptor and 5-HT(1A) receptor) is critical for the modality-specific antinociceptive effect of curcumin in neuropathic pain. Delta- and mu-opioid receptors are likely rendered as downstream targets, accordingly. This article is part of a Special Issue entitled 'Post-Traumatic Stress Disorder'.