STUDY OF ANTINOCICEPTIVE EFFECT OF MELATONIN ALONE AND IN COMBINATION WITH PETHIDINE IN SWISS ALBINO MICE (original) (raw)
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Melatonin in Antinociception: Its Therapeutic Applications
Current Neuropharmacology, 2012
The intensity of pain sensation exhibits marked day and night variations. Since the intensity of pain perception is low during dark hours of the night when melatonin levels are high, this hormone has been implicated as one of the prime antinociceptive substances. A number of studies have examined the antinociceptive role of melatonin in acute, inflammatory and neuropathic pain animal models. It has been demonstrated that melatonin exerts antinociceptive actions by acting at both spinal cord and supraspinal levels. The mechanism of antinociceptive actions of melatonin involves opioid, benzodiazepine, α 1 -and α 2 -adrenergic, serotonergic and cholinergic receptors. Most importantly however, the involvement of MT 1 /MT 2 melatonergic receptors in the spinal cord has been well documented as an antinociceptive mechanism in a number of animal models of pain perception. Exogenous melatonin has been used effectively in the management of pain in medical conditions such as fibromyalgia, irritable bowel syndrome and migraine and cluster headache. Melatonin has been tried during surgical operating conditions and has been shown to enhance both preoperative and post-operative analgesia. The present review discusses the available evidence indicating that melatonin, acting through MT 1 /MT 2 melatonin receptors, plays an important role in the pathophysiological mechanism of pain.
Studies on the Anti-Inflammatory and Anti-Nociceptive Effects of Melatonin in the Rat
Pharmacological Research, 2002
The present study aimed to evaluate the anti-inflammatory and anti-nociceptive effects of melatonin in the rat. Acute inflammation was induced by sub-plantar injection of carrageenan (1%) in the rat hind paw. The rats received vehicle or drug 30 min before carrageenan administration and were evaluated for paw oedema at 1, 2, 3, and 4 h post-carrageenan. The induced inflammation and the formation of oedema were determined by measurement of the paw thickness. Nociception was tested by determining vocalization following electrical stimulation of the tail. Given intraperitoneally (i.p.) 30 min before carrageenan, melatonin caused significant and a dose-dependent reduction of hind paw swelling induced by carrageenan. At doses of 0.5 and 1 mg kg −1 , melatonin inhibited the carrageenan-induced oedema by 20.5 and 29.6% versus control values at 4 h post-carrageenan, respectively. Melatonin (0.5 and 1 mg kg −1 , i.p.) 30 min beforehand displayed anti-nociceptive effect in the electric stimulation of the rat tail test, increasing nociceptive thresholds to electrically-induced pain at 4 h post-treatment by 29.6 and 39.5%, respectively. Melatonin given simultaneously with the non-selective COX-1 and COX-2 inhibitor indomethacin (5 mg kg −1 , i.p.) 30 min prior to carrageenan, enhanced the anti-inflammatory effect of the latter in the carrageenan-induced paw oedema model by 23%. Melatonin (0.5 mg kg −1 , i.p.) increased the anti-nociceptive effect of indomethacin (5 mg kg −1 , i.p.). Meanwhile, the anti-inflammatory and anti-nociceptive effect of the highly selective COX-2 inhibitor rofecoxib (2.25 mg kg −1 , i.p.) was only slightly increased by melatonin administration at 0.5 mg kg −1 . Melatonin enhanced the anti-inflammatory effect of cysteamine (300 mg kg −1 , s.c.) in the carrageenan-induced paw oedema. Melatonin (20 and 40 µg per paw) given prior to carrageenan into the rat hind paw was devoid of anti-inflammatory effect. These results indicate that melatonin possesses anti-inflammatory and anti-nociceptive properties in the rat and enhance those of indomethacin. This effect is likely to be centrally mediated.
Antinociceptive effects of novel melatonin receptor agonists in mouse models of abdominal pain
World journal of gastroenterology : WJG, 2014
To characterize the antinociceptive action of the novel melatonin receptor (MT) agonists, Neu-P11 and Neu-P12 in animal models of visceral pain. Visceral pain was induced by intracolonic (ic) application of mustard oil or capsaicin solution or by intraperitoneal (ip) administration of acetic acid. Neu-P11, Neu-P12, or melatonin were given ip or orally and their effects on pain-induced behavioral responses were evaluated. To identify the receptors involved, the non-selective MT1/MT2 receptor antagonist luzindole, the MT2 receptor antagonist 4-P-PDOT, or the μ-opioid receptor antagonist naloxone were injected ip or intracerebroventricularly (icv) prior to the induction of pain. Orally and ip administered melatonin, Neu-P11, and Neu-P12 reduced pain responses in a dose-dependent manner. Neu-P12 was more effective and displayed longer duration of action compared to melatonin. The antinociceptive effects of Neu-P11 or Neu-P12 were antagonized by ip or icv. administered naloxone. Intracer...
Mechanisms involved in the antinociception caused by melatonin in mice
Journal of Pineal Research, 2006
The pregnane compound MV8612 isolated from the rhizome of the plant Mandevilla velutina administered by intraperitoneal (i.p.), intrathecal (i.t.) or by intracerebroventricular (i.c.v.) routes caused graded and complete inhibition of the thermal hyperalgesia caused by i.t. injection of bradykinin (BK) in mice with mean ID values of 7.8 mmol / kg, 33.6 and 4.6 nmol / site, respectively. Compound 50 MV8612 (i.p.) also inhibited both the neurogenic and inflammatory pain responses to formalin with mean ID values of 5.6 and 10.6 50 mmol / kg, respectively. Given i.t., MV8612 produced significant inhibition of both phases of the formalin-induced licking (inhibition of 3465 and 3664%, respectively). Given by i.c.v. route MV8612 inhibited both phases of formalin-induced pain (3266 and 6365%) with mean ID of 8.4 nmol / site against the late phase. MV8612, given by i.p., i.c.v. or i.t. routes, also inhibited capsaicin-induced pain 50 1 (5164, 2568 and 3966%, respectively). The i.t. injection of potassium (K ) channel blockers, apamin and charybdotoxin given 15 min before, markedly prevented the antinociception of MV8612 against both phases of formalin-induced nociception. In contrast, tetraethylammonium (TEA) or glibenclamide had no effect. The i.c.v. treatment with pertussis toxin resulted in a significant inhibition of both MV8612-and morphine-induced antinociception against both phases of formalin-induced pain. Taken together these results confirm and also extend our previous data by demonstrating that the greater part of the antinociception caused by MV8612 seems to be associated 21 1
PLOS ONE, 2013
Background: Previous studies have suggested that melatonin may produce antinociception through peripheral and central mechanisms. Based on the preliminary encouraging results of studies of the effects of melatonin on pain modulation, the important question has been raised of whether there is a dose relationship in humans of melatonin on pain modulation. Objective: The objective was to evaluate the analgesic dose response of the effects of melatonin on pressure and heat pain threshold and tolerance and the sedative effects. Methods: Sixty-one healthy subjects aged 19 to 47 y were randomized into one of four groups: placebo, 0.05 mg/kg sublingual melatonin, 0.15 mg/kg sublingual melatonin or 0.25 mg/kg sublingual melatonin. We determine the pressure pain threshold (PPT) and the pressure pain tolerance (PPTo). Quantitative sensory testing (QST) was used to measure the heat pain threshold (HPT) and the heat pain tolerance (HPTo). Sedation was assessed with a visual analogue scale and bispectral analysis. Results: Serum plasma melatonin levels were directly proportional to the melatonin doses given to each subject. We observed a significant effect associated with dose group. Post hoc analysis indicated significant differences between the placebo vs. the intermediate (0.15 mg/kg) and the highest (0.25 mg/kg) melatonin doses for all pain threshold and sedation level tests. A linear regression model indicated a significant association between the serum melatonin concentrations and changes in pain threshold and pain tolerance (R 2 = 0.492 for HPT, R 2 = 0.538 for PPT, R 2 = 0.558 for HPTo and R 2 = 0.584 for PPTo). Conclusions: The present data indicate that sublingual melatonin exerts well-defined dose-dependent antinociceptive activity. There is a correlation between the plasma melatonin drug concentration and acute changes in the pain threshold. These results provide additional support for the investigation of melatonin as an analgesic agent.
Melatonin administration reduces inflammatory pain in rats
Journal of Pain Research, 2012
In view of the broad range of effects attributed to melatonin, this study evaluated its analgesic effect on inflammatory pain induced by complete Freund's adjuvant (CFA) in Wistar rats. Inflammation was induced by intradermal CFA injection in the hind paw of all animals, which were then divided into two groups that received either 60 mg/kg of melatonin or vehicle (1% alcohol in saline), intraperitoneally, for three days. The analgesic effect of melatonin was assessed by the hot-plate test, immediately and thereafter at 30, 60, 90, and 120 minutes after the first administration and 24 hours after once-daily administration for 2 more days. After CFA injection, melatonin administration increased withdrawal latency at 60 minutes after the first dose. After the end of treatment, melatonin showed a significant analgesic effect on inflammatory pain. This study paves the way for exploration of how brief courses of treatment could improve this analgesic effect in the late phases of inflammatory pain.
Pineal opioid receptors and analgesic action of melatonin
Journal of Pineal Research, 1998
Physicians have noted since antiquity that their patients complained of less pain and required fewer analgesics at night times. In most species, including the humans, the circulating levels of melatonin, a substance with analgesic and hypnotic properties, exhibit a pronounced circadian rhythm with serum levels being high at night and very low during day times. Moreover, melatonin exhibits maximal analgesic effects at night, pinealectomy abolishes the analgesic effects of melatonin, and mu opioid receptor antagonists disrupt the day-night rhythm of nociception. It is believed that melatonin, with its sedative and analgesic effects, is capable of providing a pain free sleep so that the body may recuperate and restore itself to function again at its peak capacity. Moreover, in conditions when pain is associated with extensive tissue injury, melatonin's ability to scavenge free radicals and abort oxidative stress is yet another beneficial effect to be realized. Since melatonin may behave as a mixed opioid receptor agonist-antagonist, it is doubtful that a physician simply could potentiate the analgesic efficacy of narcotics such as morphine by coadministering melatonin. Therefore, future research may synthesize highly efficacious melatonin analogues capable of providing maximum analgesia and hopefully being devoid of addiction liability now associated with currently available narcotics.
Time-dependent melatonin analgesia in mice: inhibition by opiate or benzodiazepine antagonism
European Journal of Pharmacology, 1991
The aim of this study was to determine whether melatonin-induced analgesia in mice exhibits the time dependency known to occur for several other effects of the hormone, and to analyze to what extent the activity of melatonin can be inhibited by the opiate antagonist naloxone or the central-type benzodiazepine (BZP) antagonist Ro 15-1788. Analgesia was assessed with the hot plate procedure. There was a significant diurnal variation in the pain threshold, with an increase in latency during the dark phase of the daily photo period. Melatonin (20-40 mg/kg i.p.) exhibited maximal analgesic effects at late evening (20:00 h). The administration of naloxone or Ro 15-1788 at 20:00 h, although unable by themselves to modify pain threshold, blunted the analgesic response to melatonin. Significant increases in the latency of the hot plate response were found after diazepam injection, an effect blocked by Ro 15-1788 or naloxone. These results indicate that time-dependent melatonin analgesia is sensitive to opioid or central-type BZP antagonism.
Pain, 2015
Anti-nociceptive effects of melatonin have been documented in a wide range of experimental animal models. The aim of this study was to investigate the analgesic, anti-hyperalgesic and anti-inflammatory properties of melatonin employing a validated burn injury (BI) model in healthy male volunteers. The design was a randomized, double-blind, placebo-controlled, three-arm crossover study. Each volunteer participated in three identical study sessions with intravenous administration of either placebo, melatonin 10 mg or melatonin 100 mg. Sixty minutes after bolus injection of study medication, a BI was induced by a computerized contact thermode (47.0°C, 420 s, 5.0 x 2.5 cm). Pain ratings during the BI, and quantitative sensory testing (QST) at baseline, and, 1, 2, 4 and 6 hours after the BI, were performed. The QST included assessments of secondary hyperalgesia areas, mechanical and thermal thresholds in the BI-area, and pressure algometry. Furthermore, markers of inflammation, skin-refl...