| Diabetic neuropathic pain is one of the more common chronic complications of diabetes and is often untreated because of its insidious onset,which has a serious impact on patients’ life.Melatonin is a neuroendocrine hormone mainly secreted by the pineal gland,which exerts analgesic effects by its receptors.The group’s previous studies have demonstrated that the thalamic dorsal medial nucleus and ventral medial nucleus act as “promoters” of endogenous modulation of nociception,which control endogenous descending facilitation and inhibitory respectively.Recently,the group put forward that warm needle stimulation can selectively activate endogenous descending inhibition of nociception to relieve neuropathic pain.We aim to explore the role of melatonin in the endogenous regulation of thalamic-mediated nociception on the diabetic neuropathic pain model.Additionally,we try to probe into the effect of 43°C warm needle stimulation on the this model was further explored in the hope of providing new strategies and tools of physiotherapy for clinic of diabetic neuropathic pain.Purposes:1.To explore the role of the melaton in pineal gland in thalamus-mediated endogenous modulation of nociception in the rat;2.To explore the role of the melaton in pineal gland in the endogenous modulation of nociception in rats with diabetic neuropathic pain;3.To explore the effects of 43°C warm needle stimulation on the endogenous modulation of nociception in diabetic neuropathic pain rats;4.To explore the mechanism of melatonin receptor-mediated central modulation of diabetic neuropathic pain in the ventral medial nucleus of the thalamus.Methods:1.The SD female rats were subjected to pinealectomy and we measured the paw withdrawal mechanical threshold and paw withdrawal thermal latency of bilateral hind limbs before and 1-7 days after pinealectomy.We also mesured blood glucose changes of the model rats at the same time.Then,0.9% saline or 5.8% saline was injected intramuscularly in the rats and we observed the above-mentioned behavioral indicators at 30 minutes-4 hours and 1-7 days after injection.2.Rats were subjected to pinealectomy and diabetic neuropathic pain model was established by intraperitoneal injection of streptozocin 30 mg/kg for 7 days after surgery recovery.The rats were observed for changes in above-mentioned behavioral indicators and weight before and 1-14 days after the modeling.3.Rats were established to pinealectomy with diabetic neuropathic pain model and observed for changes in point 2.After 7 days,rats were given 43℃ warm needle stimulation for 30 minutes in the gastrocnemius muscle,and the changes of the paw withdrawal mechanical threshold and paw withdrawal thermal latency in the bilateral hind limbs,blood glucose changes and body weight s were observed 0.5-4 hours and1-7 days after the treatment.4.Rats were subjected pinealectomy with intracranial cannulation.After 7 days of recovery,a diabetic neuropathic pain model was established.On the 7th day after modeling,we treated model rats use 43℃ for 30 minutes in the gastrocnemius muscle.Then,different doses of melatonin were microinjected into the contralateral thalamic ventromedial nucleus on one day after the treatment.We monitored the changes of the paw withdrawal mechanical threshold and paw withdrawal thermal latency in the bilateral hind limbs,and blood glucose changes were observed between 0.5–4 hours after microinjection.Results:1.No statistically significant difference in the response to injurious mechanical and thermal stimulation of pinealectomy rats compared with that of na?ve rats(P >0.05).2.Intramuscular injection of 5.8% saline produced mechanical nociceptive hypersensitivity in pinealectomy rats range 0.5 hours to 4 days post-injection,with a statistically significant difference.We also observed a transient increase in blood glucose at 1 hour post-injection in pinealectomy rats.However,intramuscular injection of 5.8% saline produced mechanical nociceptive hypersensitivity in na?ve rats.We also observed a transient increase in blood glucose at 2 hours post-injection in na?ve rats.It should be mentioned that intramuscular injection of 5.8% saline had no effect on paw withdrawal thermal latency both in pinealectomy and na?ve rat,with no statistically significant difference(P > 0.05).3.Pinealectomy rats had elevated blood glucose after intraperitoneal injection of streptozocin 30 mg/kg for 1days increased to 16.7 mmol/L,resulting a model of diabetic neuropathic pain.The rats lost weight after modeling,which could be maintained for 14 days with statistically significant differences(P < 0.001).Rats in this model developed bilateral mechanical pain sensitivity after 3 days(P < 0.001)and bilateral thermal pain sensitivity after 5 days.Mechanical and thermal pain sensitivity both lasted for 14 days,a statistically significant difference(P < 0.001).4.Intramuscular 43°C warm needle stimulation for 30 minutes prolonged paw withdrawal thermal latency in diabetic neuropathic pain model with pinealectomy and maintained it for 1-3 days(P < 0.05).However,there was no significant effect on their paw withdrawal mechanical threshold,blood glucose and body weight(P > 0.05).5.Microinjection of different doses of melatonin into the thalamic ventromedial nucleus can enhanced the prolongation of paw withdrawal thermal latency dose-dependently in pinealectomy-diabetic neuropathic pain group of rats after intramuscular 43°C warm needle stimulation for 30 minutes(P < 0.05).Conclusions:1.Physiologically,pinealectomy did not affect the endogenous modulation of nociception in rats.2.Pinealectomy-diabetic neuropathic pain rats show enhanced descending facilitation and diminished descending inhibition.3.43°C intramuscular warm needle stimulation for 30 minutes activates descending inhibition in pinealectomy-diabetic neuropathic pain rats.4.Melatonin in thalamic ventromedial nucleus may be involved in the enhancement of descending inhibition by 43°C warm needle stimulation for 30 minutes in pinealectomy-diabetic neuropathic pain rats. |
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