Oxidative Stress and Inflammation Biomarkers in Postoperative Pain Modulation in Surgically Treated Patients with Laryngeal Cancer-Pilot Study.

(1) Background: Surgical treatment of laryngeal carcinoma includes different types of laryngectomies with neck dissection. Surgical tissue damage triggers an inflammatory response, leading to the release of pro-inflammatory molecules. This increases reactive oxygen species production and decreases antioxidant defense mechanisms, leading to postoperative oxidative stress. The aim of this study was to assess the correlation between oxidative stress (malondialdehyde, MDA; glutathione peroxidase, GPX; superoxide dismutase, SOD) and inflammation (interleukin 1, IL-1; interleukin-6, IL-6; C-reactive protein, CRP) parameters and postoperative pain management in patients surgically treated with laryngeal cancer. (2) Methods: This prospective study included 28 patients with surgically treated laryngeal cancer. Blood samples were taken for the analysis of oxidative stress and inflammation parameters before the operative treatment and after the operative treatment (1st postoperative day and 7th postoperative day). The concentrations of MDA, SOD, GPX, IL-1, IL-6, and CRP in the serum were determined by coated enzyme-linked immunosorbent assay (ELISA). The visual analog scale (VAS) was used for pain assessment. (3) Results and conclusion: There was a correlation between oxidative stress and inflammation biomarkers and postoperative pain modulation in surgically treated patients with laryngeal cancer. Age, more extensive surgery, CRP values, and use of tramadol were predictors for oxidative stress parameters.

The Interactions of Magnesium Sulfate and Cromoglycate in a Rat Model of Orofacial Pain; The Role of Magnesium on Mast Cell Degranulation in Neuroinflammation.

Mast cell degranulation impacts the development of pain and inflammation during tissue injury. We investigated the antinociceptive effect of a combination of cromoglycate and magnesium in the orofacial model of pain and the histological profile of the effect of magnesium in orofacial pain. In male Wistar rats, formalin (1.5%, 100 µL) was injected subcutaneously into the right upper lip of rats after cromoglycate and/or magnesium. Pain was measured as the total time spent on pain-related behavior. Toluidine blue staining was used to visualize mast cells under the light microscope. In the formalin test, in phase 1, magnesium antagonized the antinociceptive effect of cromoglycate, while in phase 2, it potentiated or inhibited its effect. Magnesium significantly reduced mast cell degranulation in the acute phase by about 23% and in the second phase by about 40%. Pearson's coefficient did not show a significant correlation between mast cell degranulation and pain under treatment with magnesium. The cromoglycate-magnesium sulfate combination may prevent the development of inflammatory orofacial pain. The effect of a combination of cromoglycate-magnesium sulfate depends on the nature of the pain and the individual effects of the drugs. Magnesium reduced orofacial inflammation in the periphery, and this effect did not significantly contribute to its analgesic effect.

Magnesium Sulfate Reduces Carrageenan-Induced Rat Paw Inflammatory Edema Via Nitric Oxide Production.

Background: Magnesium is an antagonist of the N-methyl-D-aspartate receptor. This study aimed to investigate the anti-edematous effect of magnesium sulfate (MS) in different protocols of use and the possible mechanism of its action. Methods: In a rat model of carrageenan-induced paw inflammation, the anti-edematous activity of MS was assessed with a plethysmometer. The effects of the nonselective inhibitor (L-NAME), selective inhibitor of neuronal (L-NPA) and inducible (SMT) nitric oxide synthase on the effects of MS were evaluated. Results: MS administered systemically before or after inflammation reduced edema by 30% (5 mg/kg, P < .05) and 55% (30 mg/kg, P < .05). MS administered locally (.5 mg/paw, P < .05) significantly prevented the development of inflammatory edema by 60%. L-NAME, intraperitoneally administered before MS, potentiated (5 mg/kg, P < .05) or reduced (3 mg/kg, P < .05), while in the highest tested dose L-NPA (2 mg/kg, P < .01) and SMT (.015 mg/kg, P < .01) reduced the anti-edematous effect of MS. Conclusions: Magnesium is a more effective anti-edematous drug in therapy than for preventing inflammatory edema. The effect of MS is achieved after systemic and local peripheral administration and when MS is administered as a single drug in a single dose. This effect is mediated at least in part via the production of nitric oxide.

Ketamine, an Old-New Drug: Uses and Abuses.

Ketamine as an old-new drug has a variety of clinical implications. In the last 30 years, ketamine has become popular for acute use in humans. Ketamine in standard doses is principally utilized for the induction and maintenance of surgical procedures. Besides its use in anesthesia and analgesia, recent studies have shown that ketamine has found a place in the treatment of asthma, epilepsy, depression, bipolar affective disorders, alcohol and heroin addiction. Ketamine primarily functions as a noncompetitive antagonist targeting the N-methyl-D-aspartate (NMDA) receptor, but its mechanism of action is complex. It is generally regarded as safe, with low doses and short-term use typically not leading to significant adverse effects. Also, ketamine is known as a powerful psychostimulant. During the past decade, ketamine has been one of the commonly abused drugs.

Chloroquine Attenuates Oxidative Stress in Gentamicin-Induced Nephrotoxicity in Rats.

The wider application of gentamicin is limited by potential adverse effects (nephrotoxicity and ototoxicity). The goal of our study was to investigate the effects of chloroquine on biochemical and oxidative stress parameters in gentamicin-induced nephrotoxicity in rats. Animals were randomly divided into 1 of 5 groups. First was Sham group (0.9% NaCl) (n = 8); second group received gentamicin (n = 8); while third (n = 8), fourth (n = 8) and fifth group (n = 8) received gentamicin and chloroquine in a dose of 0.3, 1 and 3 mg/kg, respectively. The urea and creatinine levels were significantly lower in chloroquine treated groups in doses of 0.3 mg/kg and 1 mg/kg (P < 0.001). Total oxidant status and the oxidative stress index showed significantly lower values in all chloroquine treated groups (P < 0.001; P < 0.005). Malondialdehyde was lower in chloroquine treatment in doses of 0.3 mg/kg (P < 0.005) and 3 mg/kg (P < 0.05). Chloroquine treatment markedly reduced the level of superoxide dismutase in doses of 1 mg/kg (P < 0.01) and 3 mg/kg (P < 0.05). Our study showed that chloroquine attenuates gentamicin-induced nephrotoxicity in rats regarding biochemical and oxidative stress parameters.

Investigation of the Antinociceptive Activity of the Hydroethanolic Extract of Junglas nigra Leaf by the Tail-Immersion and Formalin Pain Tests in Rats.

Background: Juglans (J.) nigra leaf is obtained from a plant that is used in traditional medicine in some countries to alleviate inflammatory diseases. Aim: The aim of this study was to compare the effects of J. nigra extract on acute nociceptive and inflammatory pain in rats. Methods: Antinociceptive activity was examined in Wistar rats by the tail-immersion and formalin tests. Motor function was assessed using the rotarod test. Plant extract was administered intraperitoneally. Results: In the tail-immersion test, the maximal antinociceptive effect of the plant extract (100-330 mg/kg) was about 24-30% and is the result of the effect of a high concentration of ethanol. In the formalin test, the plant extract (41.3-330 mg/kg) significantly and dose-dependently inhibited nociception in both phases of the test with similar maximal effects of about 76% and 85%. Only the plant extract at the dose of 330 mg/kg caused a significant time-dependent reduction in time spent on the rotarod. Conclusions: In rats, the preventive systemic administration of the hydroethanolic extract of J. nigra leaf reduced chemically but not thermally induced pain. Higher efficacy was obtained in pain associated with inflammation and tissue injury. The antinociceptive effect is dose-dependent and may be limited by motor impairment.

Correlation of Ionized Magnesium with the Parameters of Oxidative Stress as Potential Biomarkers in Patients with Anxiety and Depression: A Pilot Study.

Background: Magnesium (Mg) is the second most abundant intracellular cation. Ionized Mg is the only active form of Mg. The concentration of ionized Mg could be a potentially novel biomarker for anxiety and depression. Aim: The aim of this study was to assess the serum concentration of ionized Mg and its correlation with biomarkers of oxidative stress and inflammation in patients with anxiety and depression. Methods: In this study included 93 respondents were divided into 3 groups: C (control group-18 respondents); A (patients with anxiety disorder, dissociative/conversion disorders and somatoform disorders-36 patients); D (patients with depression-39 patients). Clinical diagnosis was based on ICD-10 criteria. Blood samples were used for standard laboratory analysis, ionized Mg analysis, oxidative stress, and inflammatory parameters. Results: Statistical significance was recorded between healthy volunteers and patients (anxiety/depression) in ionized Mg values. In anxious patients, malondialdehyde (MDA) had a positive correlation between the parameters of oxidative stress with ionized Mg. In depressive patients, MDA had a positive correlation, and glutathione peroxidase 1 (GPX1) a negative correlation with the concentration of ionized Mg. Conclusion: Ionized Mg and its correlation with parameters of oxidative stress could be potential biomarkers in anxious and depressive patients.

Interactions between Ketamine and Magnesium for the Treatment of Pain: Current State of the Art.

BACKGROUND: Over the past three decades, NMDA-receptor antagonists have been shown to be efficient drugs for treating pain, particularly pain resistant to conventional analgesics. Emphasis will be on the old-new drugs, ketamine and magnesium, and their combination as a novel approach for treating chronic pain. METHODS: The MEDLINE database was searched via PubMed for articles that were published up to March 1, 2020, with the keywords 'ketamine', 'magnesium', and 'pain' (in the title/abstract). RESULTS: Studies in animals, as well as humans, have shown that interactions of ketamine and magnesium can be additive, antagonistic, and synergistic. These discrepancies might be due to differences in magnesium and ketamine dosage, administration times, and the chronological order of drug administration. Different kinds of pain can also be the source of divergent results. CONCLUSION: This review explains why studies performed with a combination of ketamine and magnesium have given inconsistent results. Because of the lack of efficacy of drugs available for pain, ketamine and magnesium in combination provide a novel therapeutic approach that needs to be standardized with a suitable dosing regimen, including the chronological order of drug administration.

Synthesis and pharmacological evaluation of novel cis and trans 3-substituted anilidopiperidines.

BACKGROUND: 4-Anilidopiperidine class of synthetic opioid analgesics, with it's representative fentanyl, are by far the most potent and clinically significant for the treatment of the severe chronic and surgical pain. However, side effects of µ-opioids are often quite serious. In order to improve the pharmacological profile of this class of opioid analgesics, a novel fentanyl analogs were designed, synthesized and evaluated in vivo for their antinociceptive activity. METHODS: The title compounds were prepared using known synthetic transformations, including N-bromoacetamide mediated Hofmann rearrangement, highly selective carbamate cleavage with trimethylsilyl iodide and dehydration of carboxamide group to nitrile in the presence of SOCl2. The antinociceptive activity of the synthesized compounds was determined by tail-immersion and formalin test. RESULTS: The scalable synthetic route towards novel fentanyl analogs bearing nitrogen groups in position C3 of piperidine ring is designed. In addition, Hofmann rearrangement was substantially improved for the more efficient synthesis of previously published 3-substituted fentanyl analogs. The series of ten fentanyl analogs was tested in vivo for their antinociceptive activity. The most potent compound of the series was found to be cis-4, based on the determined ED50 values in tail-immersion test. CONCLUSION: Of ten compounds tested for their antinociceptive activity, compound cis-4 is characterized by high potency, rapid beginning and short duration of action and due to this might be incorporated in different pharmaceutical forms.

Involvement of serotonergic and opioidergic systems in the antinociceptive effect of ketamine-magnesium sulphate combination in formalin test in rats.

BACKGROUND: Ketamine and magnesium sulphate showed synergic interaction in the tail-immersion test and additive interaction in the rat formalin test. Aim of study was to evaluate the influence of serotonergic and opioidergic system of this combination in the formalin test in rats. METHODS: Antinociceptive activity was assessed by the formalin test in male Wistar rats (200-250 g). Antagonists (naloxone and methysergide) were administrated 5 min before and magnesium sulphate 5 min after ketamine injection. Formalin (2.5%, 100 µL) was injected into the right hind paw surface (intraplantar) of rats 5 min after ketamine/magnesium combination. Data were recorded as the total time spent in pain related behavior after the injection of formalin or vehicle (0.9% NaCl). RESULTS: In the intermediate phase of the formalin test, methysergide at a dose of 0.2 mg/kg did not have any effect, but at doses of 0.5 and 1 mg/kg it had a pronociceptive effect. Methysergide (0.2, 0.5 and 1 mg/kg) inhibited the antinociceptive effect of ketamine-magnesium sulphate combination. In the intermediate phase, naloxone at a dose of 0.2 mg/kg did not have any effect, but at a dose of 3 mg/kg it produced a pronociceptive effect. Naloxone (0.2 and 3 mg/kg) antagonized the antinociceptive effect of the ketamine (5 mg/kg)-magnesium sulphate (5 mg/kg) combination. CONCLUSION: The results of the present study suggest that serotonergic and opioidergic systems are involved, at least in part, in the antinociceptive effect of the ketamine-magnesium sulphate combination in the model of inflammatory pain in rats.

Pain Management After Surgical Tonsillectomy: Is There a Favorable Analgesic?

The aim of this study was to examine how ibuprofen and paracetamol prevent pain after cold-steel extracapsular tonsillectomy in children. Also, we examined the relation between age, gender, nausea, postoperative bleeding, antibiotic use, type of diet, and postoperative pain intensity and the type of administered analgesic. A prospective study was conducted on 147 children (95 males and 52 females, aged 7-17 years) who underwent tonsillectomy in the Clinical-Hospital Center "Dragisa Misovic" from January 1 to June 30, 2016. The degree of pain was measured using a visual analog scale (VAS). We did not observe any significant differences in postoperative nausea, hospitalization rate postoperative bleeding, and antibiotic use between the paracetamol and ibuprofen groups. A test of within-patient effects showed that VAS scores changed significantly during the postoperative follow-up period (P = .00), but there were no significant differences between the groups (P = .778). After 12 hours, 29.3% of the patients on paracetamol and 21.8% on ibuprofen were transferred to a soft diet; after 24 hours, 84.8% of the paracetamol group and 85.5% of the ibuprofen group were on a soft diet (χ2 test, P < .05). There was a statistically significant correlation between VAS scores measured 4 hours after the surgery and the time of transference to the soft diet (Spearman ρ test, P < .001). The transfer to soft and normal diets was not significantly different between the 2 groups as assessed by the VAS scores (Pearson χ2 test, P = .565).There is still no consensus on the most effective postoperative pain-control regiment after tonsillectomy. This study showed that satisfactory pain management was achieved equally with both paracetamol and ibuprofen.

Preventive treatment with dizocilpine attenuates oedema in a carrageenan model of inflammation: the interaction of glutamatergic and nitrergic signaling.

Dizocilpine is a highly selective and potent non-competitive antagonist of the N-methyl-D-aspartate (NMDA) glutamate receptor. It is well known that dizocilpine has different neuroprotective effects in animal models of pain, epilepsy and oedema during trauma. The search for alternative antiinflammatory drugs is ongoing. We investigated the anti-oedematous effects of dizocilpine and the probable mechanism of action in a rat model that mimics local and persistent inflammation without tissue injury or damage. Male Wistar rats were injected with 100 µL of 0.5% carrageenan to the plantar surface of the hind paw. Anti-oedematous activity was assessed in the carrageenan-induced paw inflammatory oedema test with a plethysmometer. To assess possible mechanisms of dizocilpine action, we examined the effects of the selective inhibitor of neuronal [N-ω-propyl-L-arginine hydrochloride (L-NPA)] and inducible [S-methylisothiourea (SMT)] nitric oxide synthase (NOS). Dizocilpine after systemic (0.0005, 0.005 and 0.02 mg/kg, subcutaneous (s.c.)), but not after local peripheral administration, reduced the paw inflammatory oedema. The effect is not dose dependent, and the highest decrease by about 47% at the time of maximally developed oedema was achieved with 0.005 mg/kg. Intraperitoneally (i.p.) administered L-NPA (0.5, 1 and 2 mg/kg) or SMT (0.005, 0.01 and 0.015 mg/kg) before dizocilpine abolished or reduced the anti-oedematous effect of dizocilpine by about 70-85%. An acute single dose of dizocilpine administered before inducing oedema systemically reduced the development of inflammatory oedema. The mechanism of the anti-oedematous effect includes, at least partially, an increase in nitric oxide (NO) production.

Cannabinoids and Pain: New Insights From Old Molecules.

Cannabis has been used for medicinal purposes for thousands of years. The prohibition of cannabis in the middle of the 20th century has arrested cannabis research. In recent years there is a growing debate about the use of cannabis for medical purposes. The term 'medical cannabis' refers to physician-recommended use of the cannabis plant and its components, called cannabinoids, to treat disease or improve symptoms. Chronic pain is the most commonly cited reason for using medical cannabis. Cannabinoids act via cannabinoid receptors, but they also affect the activities of many other receptors, ion channels and enzymes. Preclinical studies in animals using both pharmacological and genetic approaches have increased our understanding of the mechanisms of cannabinoid-induced analgesia and provided therapeutical strategies for treating pain in humans. The mechanisms of the analgesic effect of cannabinoids include inhibition of the release of neurotransmitters and neuropeptides from presynaptic nerve endings, modulation of postsynaptic neuron excitability, activation of descending inhibitory pain pathways, and reduction of neural inflammation. Recent meta-analyses of clinical trials that have examined the use of medical cannabis in chronic pain present a moderate amount of evidence that cannabis/cannabinoids exhibit analgesic activity, especially in neuropathic pain. The main limitations of these studies are short treatment duration, small numbers of patients, heterogeneous patient populations, examination of different cannabinoids, different doses, the use of different efficacy endpoints, as well as modest observable effects. Adverse effects in the short-term medical use of cannabis are generally mild to moderate, well tolerated and transient. However, there are scant data regarding the long-term safety of medical cannabis use. Larger well-designed studies of longer duration are mandatory to determine the long-term efficacy and long-term safety of cannabis/cannabinoids and to provide definitive answers to physicians and patients regarding the risk and benefits of its use in the treatment of pain. In conclusion, the evidence from current research supports the use of medical cannabis in the treatment of chronic pain in adults. Careful follow-up and monitoring of patients using cannabis/cannabinoids are mandatory.

Evaluation of Prophylactic and Therapeutic Effects of Tramadol and Tramadol Plus Magnesium Sulfate in an Acute Inflammatory Model of Pain and Edema in Rats.

Background: Inflammatory pain is the most commonly treated clinical pain, since it develops following trauma or surgery, and accompanies rheumatic or arthritic diseases. Tramadol is one of the most frequently used opioid analgesics in acute and chronic pain of different origin. Magnesium is a widely used dietary supplement that was recently shown to be a safe analgesic drug in different models of inflammatory pain. Aim: This study aimed to evaluate the effects of systemically or locally injected tramadol with/without systemically injected magnesium sulfate in prophylactic or therapeutic protocols of application in a rat model of somatic inflammation. Methods: Inflammation of the rat hind paw was induced by an intraplantar injection of carrageenan (0.1 ml, 0.5%). The antihyperalgesic/antiedematous effects of tramadol (intraperitoneally or intraplantarly injected), and tramadol-magnesium sulfate (subcutaneously injected) combinations were assessed by measuring the changes in paw withdrawal thresholds or paw volume induced by carrageenan. The drugs were administered before or after inflammation induction. Results: Systemically administered tramadol (1.25-10 mg/kg) before or after induction of inflammation reduced mechanical hyperalgesia and edema with a maximal antihyperalgesic/antiedematous effect of about 40-100%. Locally applied tramadol (0.125 mg/paw) better reduced edema (50-100%) than pain (20-50%) during 24 h. Administration of a fixed dose of tramadol (1.25 mg/kg) with different doses of magnesium led to a dose-dependent enhancement and prolongation of the analgesic effect of tramadol both in prevention and treatment of inflammatory pain. Magnesium increases the antiedematous effect of tramadol in the prevention of inflammatory edema while reducing it in treatment. Conclusion: According to results obtained in this animal model, systemic administration of low doses of tramadol and magnesium sulfate given in combination is a potent, effective and relatively safe therapeutic option for prevention and especially therapy of somatic inflammatory pain. The best result is achieved when tramadol is combined with magnesium sulfate at a dose that is equivalent to the average human recommended daily dose and when the drugs are administered when inflammation is maximally developed.

Antiepileptic drugs as analgesics/adjuvants in inflammatory pain: current preclinical evidence.

Inflammatory pain is the most common type of pain that is treated clinically. The use of currently available treatments (classic analgesics - NSAIDs, paracetamol and opioids) is limited by insufficient efficacy and/or side effects/tolerance development. Antiepileptic drugs (AEDs) are widely used in neuropathic pain treatment, but there is substantial preclinical evidence on their efficacy against inflammatory pain, too. In this review we focus on gabapentinoids (gabapentin and pregabalin) and dibenzazepine AEDs (carbamazepine, oxcarbazepine, and recently introduced eslicarbazepine acetate) and their potential for relieving inflammatory pain. In models of somatic, visceral and trigeminal inflammatory pain, that have a translational value for inflammatory conditions in locomotor system, viscera and head/face, AEDs have demonstrated analgesic activity. This activity was mostly consistent, dependent on the dose and largely independent on the site of inflammation and method of its induction, nociceptive stimuli, species, specific drug used, its route of administration and dosing schedule. AEDs exerted comparable efficacy with classic analgesics. Effective doses of AEDs are lower than toxic doses in animals and, when expressed as equivalent human doses, they are largely overlapping with AEDs doses already used in humans for treating epilepsy/neuropathic pain. The main mechanism of antinociceptive/antihyperalgesic action of gabapentinoids in inflammatory pain models seems to be α2δ-dependent suppression of voltage-gated calcium channels in primary sensory neurons that leads to reduced release of neurotransmitters in the spinal/medullar dorsal horn. The suppression of NMDA receptors via co-agonist binding site primarily at spinal sites, activation of various types of K+ channels at spinal and peripheral sites, and activation of noradrenergic and serotonergic descending pain modulatory pathways may also contribute. Inhibition of voltage-gated sodium channels along the pain pathway is probably the main mechanism of antinociceptive/antihyperalgesic effects of dibenzazepines. The recruitment of peripheral adrenergic and purinergic mechanisms and central GABAergic mechanisms may also contribute. When co-administered with classic/other alternative analgesics, AEDs exerted synergistic/additive interactions. Reviewed data could serve as a basis for clinical studies on the efficacy/safety of AEDs as analgesics/adjuvants in patients with inflammatory pain, and contribute to the improvement of the treatment of various inflammatory pain states.

Inhibition of neuronal nitric oxide synthase attenuate the hypothermic effect of ketamine-magnesium sulfate combination in rats.

Ketamine and magnesium as NMDA receptor antagonists interact synergistically to decrease body temperature in rats. The mechanism of the hypothermic effect of the ketamine-magnesium sulfate combination has not been studied until now. The aim of this study was to examine whether nitric oxide (NO) has a role in the hypothermic effect of ketamine (10 mg/kg) and the combination of ketamine (5 mg/kg) and magnesium sulfate (5 mg/kg). The body temperature was measured by insertion of a thermometer probe 5 cm into the colon of unrestrained male Wistar rats (200-250 g). N(ω)-nitro-L-arginine methyl ester (L-NAME 2.5 and 5 mg/kg) as non-selective inhibitor of nitric oxide synthase at a dose of 5 mg/kg antagonized the effect of the ketamine-magnesium sulfate combination at 60 min (p < 0.05) and 90 min (p < 0.01). Ketamine induced hypothermia was not affected by administrating of L-NAME (2.5 and 5 mg/kg). Inhibitor of inducible nitric oxide synthase N6-(1-Iminoethyl)-L-lysine hydrochloride (L-NIL 1.25 mg/kg and 2.5 mg/kg, sc) did not significantly change the hypothermic response evoked by the ketamine-magnesium sulfate combination. Inhibitor of neuronal nitric oxide synthase N-ω-Propyl-L-arginine hydrochloride (L-NPA) at a dose of 2 mg/kg antagonized the combination at 60 min when it achieved the maximum effect. The NO pathway is not involved in the hypothermic effect of ketamine. Production of NO through neuronal NO synthase, might play a role in the mechanism of the hypothermic effect of the ketamine-magnesium sulfate combination.

Magnesium sulfate reduces formalin-induced orofacial pain in rats with normal magnesium serum levels.

BACKGROUND: In humans, orofacial pain has a high prevalence and is often difficult to treat. Magnesium is an essential element in biological a system which controls the activity of many ion channels, neurotransmitters and enzymes. Magnesium produces an antinociceptive effect in neuropathic pain, while in inflammatory pain results are not consistent. We examined the effects of magnesium sulfate using the rat orofacial formalin test, a model of trigeminal pain. METHODS: Male Wistar rats were injected with 1.5% formalin into the perinasal area, and the total time spent in pain-related behavior (face rubbing) was quantified. We also spectrophotometrically determined the concentration of magnesium and creatine kinase activity in blood serum. RESULTS: Magnesium sulfate administered subcutaneously (0.005-45mg/kg) produced significant antinociception in the second phase of the orofacial formalin test in rats at physiological serum concentration of magnesium. The effect was not dose-dependent. The maximum antinociceptive effect of magnesium sulfate was about 50% and was achieved at doses of 15 and 45mg/kg. Magnesium did not affect increase the levels of serum creatine kinase activity. CONCLUSIONS: Preemptive systemic administration of magnesium sulfate as the only drug can be used to prevent inflammatory pain in the orofacial region. Its analgesic effect is not associated with magnesium deficiency.

Additive and antagonistic antinociceptive interactions between magnesium sulfate and ketamine in the rat formalin test.

Because ketamine and magnesium block NMDA receptor activation by distinct mechanisms of action, we hypothesized that in a model of inflammatory pain in rats the combination of ketamine and magnesium might be more effective than ketamine alone. Antinociceptive activity was assessed by the formalin test in male Wistar rats (200-250 g). Animals were injected with 100 µL of 2.5% formalin to the plantar surface of the right hind paw. Data were recorded as the total time spent in pain-related behavior after the injection of formalin or vehicle (0.9% NaCl). Ketamine and magnesium sulfate given separately reduced nocifensive behavior in the second phase of the formalin test in rats. When ketamine was applied after magnesium sulfate, the log dose-response curves for the effects of ketamine and the magnesium sulfate-ketamine combination revealed antagonistic interaction, and about 1.6 (CL 1.2-2.4) fold increment in ketamine dosage. A low dose of magnesium sulfate (5 mg/kg, subcutaneously) administered after ketamine increased the antinociceptive effect of ketamine by a factor of only 1.2 (CL 0.95-1.38), indicating an additive interaction. There was a 1.8-fold reduction in dosage of ketamine when ketamine was administered before rather than after the magnesium sulfate. The present study revealed that both ketamine and magnesium reduced pain-related behavior in the second phase of the formalin test in rats. Ketamine, when administered before or after the magnesium, provided additive or antagonistic antinociceptive interactions, respectively. Whether there will be an additive or antagonistic antinociceptive interaction between ketamine and magnesium depends on the order of drug administration.

Magnesium in Pain Research: State of the Art.

Magnesium has been shown to produce an antinociceptive effect on animal models of neuropathic and inflammatory pain. It has also been shown to exert an analgesic effect on humans in conditions presenting acute (postoperative pain) and chronic (neuropathic) pain. As it is known that magnesium is a physiological antagonist of the N-methyl-Daspartate (NMDA) receptor ion channel, and that the NMDA receptor plays a key role in central sensitization, the primary mechanism through which magnesium produces its analgesic effect is believed to be blockade of the NMDA receptor in the spinal cord. In addition, magnesium blocks calcium channels and modulates potassium channels. The activation of the nitric oxide (NO) pathway could have an important role in the antinociceptive effects of systemic magnesium sulfate in the somatic, but not in the visceral model of inflammatory pain. Although it is known for some time that intramuscular, intravenous and subcutaneous injections of magnesium sulfate in humans, and intraperitoneal injection in rodents produce local pain sensation, the mechanism of this action was elucidated only recently. It was demonstrated that subcutaneous injection of an isotonic, pHadjusted (7.4) solution of magnesium sulfate (6.2%) to rats produces local peripheral pain via activation of peripheral TRPA1, TRPV1, TRPV4 and NMDA receptors and peripheral production of NO. In animal models of pain, magnesium has been shown to exert both antinociceptive and pronociceptive effects by acting on different ion channels and NO pathways, however, the precise mechanisms remain to be elucidated.