Join Date: Jul 2001
Location: New Brunswick, NJ, USA
Here are some additional studies on the subject of sleep and melatonin in people with spinal cord injury:
- Norrbrink Budh C, Hultling C and Lundeberg T (2005). Quality of sleep in individuals with spinal cord injury: a comparison between patients with and without pain. Spinal Cord. 43: 85-95. Spinalis SCI unit, Karolinska University Hospital, Stockholm, Sweden. STUDY DESIGN: A cross-sectional descriptive study of self-reported quality of sleep in individuals with a spinal cord injury (SCI). OBJECTIVES: To assess and describe subjective quality of sleep in patients with SCI, with and without pain. SETTING: Spinalis SCI unit, Stockholm, Sweden. METHODS: A total of 230 patients with an SCI were mailed a questionnaire containing queries about pain intensities, pain unpleasantness, mood, and sleep quality (Basic Nordic Sleep Questionnaire) to assess quality of sleep in patients with SCI with and without pain. RESULTS: Of the 192 questionnaires that were returned (response rate 83.4%), 191 were analysed. Patients were divided into three groups: (1) those who reported no pain (n=50), (2) those who reported intermittent pain (n=42), and (3) those who suffered from continuous pain (n=99). Patients suffering from continuous pain rated pain intensity and unpleasantness significantly higher than those who only suffered from intermittent pain. The group with continuous pain also reported the poorest quality of sleep and the highest ratings of anxiety and depression of the three groups. Anxiety, together with pain intensity and depression, were the main predictors for poor sleep quality. CONCLUSIONS: Poor subjective sleep quality was associated with higher ratings of pain intensity, anxiety, and depression. It is possible that melatonin serves as a modulator of these different aspects.
- Li Y, Jiang DH, Wang ML, Jiao DR and Pang SF (1989). Rhythms of serum melatonin in patients with spinal lesions at the cervical, thoracic or lumbar region. Clin Endocrinol (Oxf) 30: 47-56. The neural pathway essential for the diurnal rhythm of serum melatonin was studied in humans. Blood samples from 17 patients with chronic lesions of cervical (n = 8), low thoracic or lumbar (n = 9) spinal cord were collected at 0200, 0400, 1000 and 1400 h of their normal light-dark cycle. Blood samples were also collected from eight control subjects at 0200 and 1400 h. No special treatment of food, drug or photoperiod was implemented. Serum melatonin was extracted by dichloromethane and determined by radioimmunoassay. In patients with cervical spinal lesions (C3-C7), it was found that serum melatonin levels were low and no diurnal rhythm was observed. Conversely, diurnal rhythm of circulating melatonin with significantly higher levels (P less than 0.01) in the dark period were observed in individuals with injuries at the low thoracic or lumbar regions (T9-L2). In the second experiment, blood samples from two other patients were collected for three consecutive days during acute period of spinal injuries (cervical or upper thoracic region) and serum melatonin concentrations were determined. Again, there were low levels of serum melatonin with no observable diurnal rhythm in the patient with cervical lesion (C4-5). However, diurnal rhythms were maintained with high levels in the dark period in the patient with upper thoracic spinal (T2-3) transection. Our data suggest that the cervical region of the spinal cord is part of the neural pathway essential for the diurnal rhythm of pineal melatonin secretion in human beings. Department of Physiology, University of Hong Kong. http://www.ncbi.nlm.nih.gov/entrez/q...t_uids=2776355
- Kneisley LW, Moskowitz MA and Lynch HG (1978). Cervical spinal cord lesions disrupt the rhythm in human melatonin excretion. J Neural Transm Suppl 311-23. To determine whether spinal cord lesions disrupt the diurnal activity of the human pineal, urinary melatonin levels were measured over 24 hours (4 or 8-hourly intervals) in male patients with clinical evidence of cervical spinal cord transection. During the waking state, levels of melatonin in these subjects ranged from 3.2--13.5 ng/4 hours; during sleep and darkness, values ranged from 1.8--10.5 ng/4 hours. Levels of serum cortisol, aldosterone, and growth hormone showed rhythmic variations in these subjects. The absence of significant nocturnal melatonin increases distinguishes quadriplegic subjects from normal males and from one subject with a lesion of the lumbar spinal cord. These differences may be caused by "decentralization" of the pineal organ due to a lesion within the cervical spinal cord interrupting descending sympathetic fibers. If so, the human pineal, like that of other mammals, is regulated, at least in part, by activity within the central nervous system via sympathetic nervous connections. http://www.ncbi.nlm.nih.gov/entrez/q...st_uids=288855
Melatonin is also potentially important as a treatment of acute spinal cord injury.
- Zeitzer JM, Ayas NT, Shea SA, Brown R and Czeisler CA (2000). Absence of detectable melatonin and preservation of cortisol and thyrotropin rhythms in tetraplegia. J Clin Endocrinol Metab 85: 2189-96. The human circadian timing system regulates the temporal organization of several endocrine functions, including the production of melatonin (via a neural pathway that includes the spinal cord), TSH, and cortisol. In traumatic spinal cord injury, afferent and efferent circuits that influence the basal production of these hormones may be disrupted. We studied five subjects with chronic spinal cord injury (three tetraplegic and two paraplegic, all neurologically complete injuries) under stringent conditions in which the underlying circadian rhythmicity of these hormones could be examined. Melatonin production was absent in the three tetraplegic subjects with injury to their lower cervical spinal cord and was of normal amplitude and timing in the two paraplegic subjects with injury to their upper thoracic spinal cord. The amplitude and the timing of TSH and cortisol rhythms were robust in the paraplegics and in the tetraplegics. Our results indicate that neurologically complete cervical spinal injury results in the complete loss of pineal melatonin production and that neither the loss of melatonin nor the loss of spinal afferent information disrupts the rhythmicity of cortisol or TSH secretion. Department of Medicine, Harvard Medical School, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA. http://www.ncbi.nlm.nih.gov/entrez/q..._uids=10852451
- Genovese T, Mazzon E, Muia C, Bramanti P, De Sarro A and Cuzzocrea S (2005). Attenuation in the evolution of experimental spinal cord trauma by treatment with melatonin. J Pineal Res. 38: 198-208. Department of Clinical and Experimental Medicine and Pharmacology, School of Medicine, University of Messina, Italy. Melatonin is the principal secretory product of the pineal gland and its role as an immuno-modulator is well established. Recent evidence shows that melatonin is a scavenger of oxyradicals and peroxynitrite and exerts protective effects in septic shock, hemorrhagic shock and inflammation. In the present study, we evaluated the effect of melatonin treatment, in a model of spinal cord injury (SCI). SCI was induced by the application of vascular clips (force of 50 g) to the dura via a four-level T5-T8 laminectomy. SCI in rats resulted in severe trauma characterized by edema, neutrophil infiltration and apoptosis (measured by terminal deoxynucleotidyl transferase-mediated dUTP nick-end-labeling staining). Infiltration of spinal cord tissue with neutrophils (measured as increase in myeloperoxidase activity) was associated with enhanced lipid peroxidation (increased tissue levels of malondialdehyde). Immunohistochemical examination demonstrated a marked increase in immunoreactivity for nitrotyrosine and Poly(ADP-ribose) (PAR) in the spinal cord tissue. In contrast, the degree of (a) spinal cord inflammation and tissue injury (histological score), (b) nitrotyrosine and PAR formation, (c) neutrophils infiltration and (d) apoptosis was markedly reduced in spinal cord tissue obtained from rats treated with melatonin (50 mg/kg i.p., 30 min before SCI, 30 min, 6 hr, 12 hr and 24 hr after SCI). In a separate set of experiment we have clearly demonstrated that melatonin treatment significantly ameliorated the recovery of limb function (evaluated by motor recovery score). Taken together, our results demonstrate that treatment with melatonin reduces the development of inflammation and tissue injury events associated with spinal cord trauma.
- Cayli SR, Kocak A, Yilmaz U, Tekiner A, Erbil M, Ozturk C, Batcioglu K and Yologlu S (2004). Effect of combined treatment with melatonin and methylprednisolone on neurological recovery after experimental spinal cord injury. Eur Spine J. 13: 724-32. Department of Neurosurgery, Inonu University Medical Faculty, PK 230, Malatya, Turkey. email@example.com. Spinal cord injury (SCI) results in the loss of function below the lesion. Secondary injury following the primary impact includes a number of biochemical and cellular alterations leading to tissue necrosis and cell death. Methylprednisolone (MP), by reducing edema and protecting the cell membrane against peroxidation, is the only pharmacological agent with a proven clinically beneficial effect on SCI. Melatonin, known as a free radical scavenger, has been shown to have an effect on lipid peroxidation following experimental SCI. The purpose of this study was to examine the effect of MP and melatonin on neurological, ultrastructural, and electrophysiological recovery. Female albino rats weighing 200-250 g were randomized into five groups of 18 rats each and six rats for the control group. Weight-drop trauma was performed for each group and a 30-mg/kg single dose of MP for rats in group 1, a 10-mg/kg single dose of melatonin for rats in group 2, and MP and melatonin in the same doses for rats in group 3 were administered immediately after trauma. The rats in group 4 were the vehicle group (treated with ethanol) and group 5 was the trauma group. The motor and somatosensory evoked potentials were recorded at the 4th hour, the 24th hour, and on the 10th day of the study for six rats in each group. Posttraumatic neurological recovery was recorded for 10 days using "motor function score" and inclined plane test. After electrophysiological study the rats were terminated for an analysis of lipid peroxidation level of the injured site of the spinal cord. Electron microscopic studies were performed to determine the effects of melatonin, MP, and the combined treatment with MP and melatonin on axons, neurons, myelin, nucleus, and intracytoplasmic edema. The groups treated with MP, melatonin, and a combination of both had significantly enhanced electrophysiological, biochemical, and neurological recovery and also showed better ultrastructural findings than the trauma and vehicle groups. Although combined treatment was significantly more effective on lipid peroxidation than melatonin or MP treatments alone, at the 10th day, neurobehavioral, electrophysiological, and ultrastructural recovery were at the same level. In conclusion, MP, melatonin, and MP and melatonin combined treatment modalities improved functional recovery at the same level. Future studies involving different doses of melatonin and different dose combinations with MP could promise better results since each drug has a different anti-oxidative mechanism of action.
- Erten SF, Kocak A, Ozdemir I, Aydemir S, Colak A and Reeder BS (2003). Protective effect of melatonin on experimental spinal cord ischemia. Spinal Cord. 41: 533-8. Department of Neurosurgery, Faculty of Medicine, Inonu University, Malatya, Turkey. STUDY DESIGN: Experimental animal model to assess ischemic spinal cord injury following occlusion of the thoraco-abdominal aorta. OBJECTIVES: To measure whether melatonin administered to rabbits before and after occlusion exerts an effect on the repair of ischemia-reperfusion (IR) injury. SETTING: Medical Biology Laboratory, Inonu University, Malatya, Turkey. METHODS: Rabbits were divided into three IR treatment groups and one sham-operated (ShOp) control group. The three treatment groups had their infrarenal aorta temporarily occluded for 25 min, while the ShOp group had laparotomy without aortic occlusion. Melatonin was administered either 10 min before aortic occlusion or 10 min after the clamp was removed. Physiologic saline was administered to the control animals. After treatment, the animals were euthanized and lumbosacral spinal cord tissue was removed for the determination of relevant enzyme activities. RESULTS: Malondialdehyde levels, indicating the extent of lipid peroxidation, were found to be significantly increased in the nonmelatonin treated (IR) group when compared to the ShOp group. Melatonin, whether given to pre- or post occlusion groups, suppressed malondialdehyde levels below that of the ShOp group. Catalase (CAT) and glutathione peroxidase (GSH-Px) enzyme activities were increased in the IR group compared to the ShOp group. Melatonin given preocclusion resulted in a significant decrease in both CAT and GSH-Px enzyme levels. The superoxide dismutase (SOD) enzyme activity was decreased in the ischemia-reperfusion treatment group. However, the melatonin treatment increased SOD enzyme activity to levels approximating that of the ShOp group. CONCLUSION: To our knowledge, this is the first study that shows the effects of melatonin administered both pre- and postischemia on induced oxidative damage to injured spinal cords. Our data also expands on reports that melatonin administration may significantly reduce the incidence of spinal cord injury following temporary aortic occlusion.
- Topsakal C, Kilic N, Ozveren F, Akdemir I, Kaplan M, Tiftikci M and Gursu F (2003). Effects of prostaglandin E1, melatonin, and oxytetracycline on lipid peroxidation, antioxidant defense system, paraoxonase (PON1) activities, and homocysteine levels in an animal model of spinal cord injury. Spine 28: 1643-52. STUDY DESIGN: Investigation of the effects of prostaglandin E1, melatonin, and oxytetracycline on lipid peroxidation, antioxidant and paraoxonase activities, and homocysteine levels in an experimental model of spinal cord injury. OBJECTIVES: To determine the antioxidant efficacy of prostaglandin E1, melatonin, and oxytetracycline and whether paraoxonase and homocysteine can be used as monitoring parameters in the acute oxidative stress of spinal cord injury. SUMMARY OF BACKGROUND DATA: Melatonin has been found useful in spinal cord injury in previous studies. No study exists investigating the effects of melatonin, prostaglandin E1, and oxytetracycline as well as the response type of paraoxonase enzyme and homocysteine levels in the acute oxidative stress of spinal cord injury. METHODS: Sixty-three male albino Wistar rats were anesthetized with 400 mg/kg chloral hydrate and divided into 5 groups. The G1 (n = 7) control group provided the baseline levels. G2-G5 underwent T3-T6 total laminectomies and spinal cord injuries by clip compression at the T4-T5 levels. Medications were applied to G3-G5 right after clip compression. Hence, G2 constituted laminectomy + injury, G3 laminectomy + injury + prostaglandin E1; G4 laminectomy + injury + melatonin, and G5 laminectomy + injury + oxytetracycline groups. Animals were decapitated either the first or fourth hour after injury. Spinal cord tissue and blood malonyldialdehyde and plasma homocysteine levels, plasma glutathione peroxidase, superoxide dismutase, paraoxonase activities were assayed. The SPSS 9.0 program was used for statistical analysis and graphics. Intergroup comparisons were made by Bonferroni corrected Mann Whitney U test (P < 0.025) and intragroups comparisons by Wilcoxon Rank test (P < 0.03). RESULTS: In injury groups, plasma homocysteine levels decreased and paraoxonase activities increased as erythrocyte superoxide dismutase levels and plasma glutathione peroxidase activities decreased in parallel to increases of tissue and blood malonyldialdehyde levels. These alterations were relatively suppressed by prostaglandin E1, melatonin, and oxytetracycline administrations in varying degrees. Melatonin was the most powerful agent, particularly at the fourth hour. Oxytetracycline was also effective, both at the first and fourth hour. Prostaglandin E1 was effective in comparison to injury group, but not as much as melatonin and oxytetracycline. CONCLUSIONS: Melatonin and oxytetracycline are effective in preventing lipid peroxidation in spinal cord injury. Paraoxonase and homocysteine can be used in monitoring the antioxidant defense system as well as superoxide dismutase and plasma glutathione peroxidase, both in injury and medicated groups. Department of Neurosurgery, Firat University School of Medicine, Elazig, Turkey. firstname.lastname@example.org http://www.ncbi.nlm.nih.gov/entrez/q..._uids=12897486
- Kaptanoglu E, Tuncel M, Palaoglu S, Konan A, Demirpence E and Kilinc K (2000). Comparison of the effects of melatonin and methylprednisolone in experimental spinal cord injury. J Neurosurg 93: 77-84. OBJECT: Melatonin is a very effective antioxidant agent. This study was performed to investigate the effects of melatonin in experimental spinal cord injury (SCI). The authors also compared its effects with those of methylprednisolone, which also protects the spinal cord from secondary injury because of its antioxidant effect on membrane lipids. METHODS: Adult male albino rats were used for the study, and paraplegia was produced using a previously described weight-drop technique. Melatonin and methylprednisolone were given intraperitoneally by bolus injections of 100 mg/kg and 30 mg/kg, respectively, immediately after induction of trauma. The animals were killed, and 1-cm samples of injured spinal cord were obtained at 1, 24, and 48 hours postinjury. Lipid peroxidation was estimated by thiobarbituric acid test. Electron microscopic studies were performed to determine the effects of melatonin on neurons, axons, and subcellular organelles after experimental SCI. A grading system was used for quantitative evaluation. Following SCI, there was significant increase in lipid peroxidation. In melatonin- and methylprednisolone-treated groups, lipid peroxidation was found to decrease to the baseline (preinjury) levels. There was a significant difference between trauma-alone and treatment groups, but no statistical difference was found between the melatonin- and methylprednisolone-treated groups. Electron microscopic findings showed that SCI produced by the weight-drop technique resulted in profound tissue damage. CONCLUSIONS: Both melatonin and methylprednisolone have been shown to protect neuron, axon, myelin, and intracellular organelles including mitochondrion and nucleus. However, this study provides quantitative evidence that this protection of neurons and subcellular organelles of spinal cord after secondary injury is much more obvious in melatonin-treated rats than those treated with methylprednisolone. In view of these data, melatonin has been shown to be very effective in protecting the injured spinal cord from secondary injury. Department of Neurosurgery, Ankara Numune Hospital, Turkey. http://www.ncbi.nlm.nih.gov/entrez/q..._uids=10879762
- Fujimoto T, Nakamura T, Ikeda T and Takagi K (2000). Potent protective effects of melatonin on experimental spinal cord injury. Spine 25: 769-75. STUDY DESIGN: Experimental biochemical, behavioral, and histologic investigations of spinal cord injury in rats. OBJECTIVE: To investigate the effects of melatonin, a pineal hormone, in compression ischemic-induced spinal cord injury. SUMMARY OF BACKGROUND DATA: The implication of activated neutrophils in the worsening of spinal cord injury has been shown. Melatonin was shown to play an important role in protecting animal cells from neutrophil-induced toxicity and damage by free radicals. There is no report on using melatonin for spinal cord injury. METHODS: Spinal cord injury was induced by placing 25 g of weight extradurally on the rat spinal cord at T12 for 20 minutes. The rats were randomly divided into three groups. Sham rats had only laminectomy. Melatonin rats were injected with melatonin (2.5 mg/kg) intraperitoneally (intraperitoneal) five times: at 5 minutes, then 1, 2, 3, and 4 hours after the injury. Correspondingly, the control rats were injected with saline. Measured levels of lipid peroxidation estimated thiobarbituric acid reactive substances (TBARS) and the accumulation of leukocytes at the site of trauma, which were evaluated by measuring tissue myeloperoxidase activity. The recovery was assessed by using three clinical scoring systems, and histologic changes of the damaged spinal cord were examined. RESULTS: The thiobarbituric acid reactive substances content in the spinal cord increased after the injury, with two peaks (at 1 and 4 hours), and nitrogen mustard-induced leukocytopenia significantly attenuated the thiobarbituric acid reactive substances content in four 4 after injury. Also in these 4 hours, myeloperoxidase activity increased and melatonin injection reduced thiobarbituric acid reactive substances content and myeloperoxidase activity, which attenuated the motor deficits as well. Histologic findings showed that the melatonin group had less cavity formation than the control group. CONCLUSION: Results showed that injection of melatonin reduced thiobarbituric acid reactive substances content and myeloperoxidase activity, facilitating recovery of the damaged spinal cord. Department of Orthopedic Surgery, Kumamoto University School of Medicine, Kumamoto, Japan. email@example.com http://www.ncbi.nlm.nih.gov/entrez/q..._uids=10751286
Melatonin may also be potentially helpful for neuropathic pain
- Tu Y, Sun RQ and Willis WD (2004). Effects of intrathecal injections of melatonin analogs on capsaicin-induced secondary mechanical allodynia and hyperalgesia in rats. Pain. 109: 340-50. Department of Anatomy and Neurosciences, Marine Biomedical Institute, University of Texas Medical Branch, 301 University Blvd., Galveston, TX 77555-1069, USA. Melatonin, its agonists/antagonists were administered intrathecally (i.t.) before/after intradermal injection of capsaicin. Capsaicin produced an increase in the paw withdrawal frequency (PWF) in the presumed area of secondary mechanical allodynia and hyperalgesia. Melatonin agonists in the absence of a capsaicin injection decreased the PWF significantly, whereas melatonin antagonists given intrathecally alone were ineffective in the absence of a capsaicin injection. Pre-treatment with a melatonin agonist i.t. caused a reduction in the PWF after capsaicin. In contrast, the PWF increased after capsaicin with pre-administration of a melatonin antagonist i.t. Combined pre-treatment with melatonin and a melatonin antagonist i.t. prevented the change in PWF induced by melatonin alone after capsaicin. Intrathecal post-treatment with a melatonin agonist reduced the enhanced PWF that followed an injection of capsaicin, but treatment with a combination of a melatonin agonist and its antagonist did not alter the responses. The PWF was unaffected when melatonin analogs were applied i.t. at the T6 level or were injected intramuscularly adjacent to the L4 vertebra. In spinal rats, the data showed comparable effects of melatonin analogs on capsaicin-induced secondary mechanical hyperalgesia. Animal motor function tested by 'activity box' showed that motion activity was not affected by i.t. melatonin or its antagonist. These results suggest that activation of the endogenous melatonin system in the spinal cord can reduce the generation, development and maintenance of central sensitization, with a resultant inhibition of capsaicin-induced secondary mechanical allodynia and hyperalgesia.
- Ulugol A, Dokmeci D, Guray G, Sapolyo N, Ozyigit F and Tamer M (2005). Antihyperalgesic, but not antiallodynic, effect of melatonin in nerve-injured neuropathic mice: Possible involvements of the l-arginine-NO pathway and opioid system. Life Sci The present study was undertaken to determine the effects of intracerebroventricular (i.c.v.) and intraperitoneal (i.p.) melatonin on mechanical allodynia and thermal hyperalgesia in mice with partial tight ligation of the sciatic nerve, and how the nitric oxide (NO) precursor l-arginine and the opiate antagonist naloxone influence this effect. A plantar analgesic meter was used to assess thermal hyperalgesia, and nerve injury-induced mechanical hyperalgesia was assessed with von Frey filaments. 1-5 weeks following the surgery, marked mechanical allodynia and thermal hyperalgesia developed in neuropathic mice. Intracerebroventricular and intraperitoneal melatonin, with its higher doses, produced a blockade of thermal hyperalgesia, but not mechanical allodynia. Administration of both l-arginine and naloxone, at doses which produced no effect on their own, partially reversed antihyperalgesic effect of melatonin. These results suggest that although it has different effects on neuropathic pain-related behaviors, melatonin may have clinical utility in neuropathic pain therapy in the future. It is also concluded that l-arginine-NO pathway and opioidergic system are involved in the antihyperalgesic effect of melatonin in nerve-injured mice. Department of Pharmacology, Faculty of Medicine, Trakya University, 22030-Edirne, Turkey. http://www.ncbi.nlm.nih.gov/entrez/q..._uids=16107259
Last edited by Wise Young; 09-21-2005 at 12:12 AM.