Modulation of melatonin to the thalamic lesion-induced pain and comorbid sleep disturbance in the animal model of the central post-stroke hemorrhage

Abstract

The devastating chronic central post stroke pain is associated with variety of comorbidities. Disrupted sleep is a severe comorbidity, causing an increase in the suicide rate, due to CPSP's pain symptom. Melatonin is a well-known jet-lag compound, which helps in entrainment of sleep cycle. Accordingly, whether melatonin as a therapeutic measurement for the regulation of sleep disturbance related to central post stroke pain remains unclear. Exogenous melatonin administration entrained the disrupted 24 h circadian cycle, more effectively after 2 and 3 week of administration. The effect of melatonin was persisted on 4th week too, when melatonin administration was discontinued. Also, melatonin ameliorated the pain due to distorted sleep-activity behavior after melatonin administration for 3 weeks. The low levels of melatonin in blood plasma due to CPSP were restored after 3 weeks of melatonin administration. After 30 mg/kg melatonin administrations for 3 weeks, all the disrupted resting and activity behaviors were reduced during light and dark periods. The results suggested that melatonin significantly ameliorated CPSP's pain symptoms and comorbid sleep disturbance showing in activity behavior.

Keywords: activity behavior; hemorrhagic stroke; hyper-excitability; melatonin; pain; sleep.

Figure 1.

Experimental design.

Figure 2.

(a) Discrete activity behavior of Control (normal) rats during light and dark periods. Immobility: (control) rats being nocturnal showed significantly high resting behavior during day. Low activity: The normal rats did not show any difference in low activity. High activity: control rats have significantly higher exploratory behavior during night. Two-way ANOVA post Bonferroni test. (b) CPSP induction: showing Nissl stain of CPSP rat after 3 weeks of lesion. (c) shows Von Frey mechanical hyperalgesia in control and lesioned rats. (d) shows total amount of sleep and wakefulness in 24 h in control and lesioned rats. Two-way ANOVA followed by Bonferroni’s post hoc test (p < 0.05) control (n = 8), CPSP (n = 8).

Figure 3.

Effect of exogenous melatonin on rest activity (immobility) during light and dark periods. Immobility data during the 12:12 h-dark period in control, lesion, mlt, and without mlt groups. Two-way ANOVA followed by the Tukey’s post-test (p < 0.05). n = 8, dose of mlt:30 mg/kg (i.p.) O.D.

Figure 4.

Effect of exogenous melatonin on “decreased exploratory behavior” (low activity). Low activity data during the 12:12 h-dark period in control, lesion, mlt, and without mlt groups. Two-way ANOVA followed by the Tukey’s post-test (p < 0.05). n = 8, dose of mlt:30 mg/kg (i.p.) O.D.

Figure 5.

Effect of melatonin on high activity behavior during light and dark periods. High activity data during the 12:12 h -dark period in control, lesion, mlt, and without mlt groups. Two-way ANOVA followed by the Tukey’s post-test (p < 0.05). n = 8, dose of mlt:30 mg/kg (i.p.) O.D.

Figure 6.

(a) Effect of MT1 non selective antagonist Luzindole (Luz) and selective MT2 antagonist 4P-PDOT (4P) on Day activity in melatonin treated (2 week) animals: Both Luz and 4P have significantly blocked immobility and high activity effects of melatonin, while there was no difference in low activity effect. (b) Effect of MT1 non selective antagonist Luzindole (Luz) and selective MT2 antagonist 4P-PDOT (4P) on Night activity in melatonin treated (2 week) animals: Both Luz and 4P have significantly blocked immobility and low activity effects of melatonin, while high activity was only blocked by Luz significantly. From the night activity data, we have seen Luz has effectively blocked the effects of melatonin than 4P.

Figure 7.

Pain behavior test, mechanical hyperalgesia, done after 1, 2, 3 week of melatonin injection. Two-way ANOVA followed by the Tukey’s post-test (p < 0.05). n = 8, dose of mlt:30 mg/kg (i.p.) O.D.

Figure 8.

Figure showing 24-h activity (per hour) in control (a), CPSP (b) and melatonin treated 1 week (c), 2 week (d), 3 week (e) animals, 4 week-without melatonin treatment (f).

Figure 9.

Flow chart showing effect of exogenous melatonin on sleep disruption and central post stroke pain.