Injection Of Sodium Salicylate Research Articles

Beneficial effect of metformin on tolerance to analgesic effects of sodium salicylate in male rats.

Tolerance to the analgesic effects of opioids and non-steroidal anti-inflammatory drugs (NSAIDs) is a major concern for relieving pain. Thus, it is highly valuable to find new pharmacological strategies for prolonged therapeutic procedures. Biguanide-type drugs such as metformin (MET) are effective for neuroprotection and can be beneficial for addressing opioid tolerance in the treatment of chronic pain. It has been proposed that analgesic tolerance to NSAIDs is mediated by the endogenous opioid system. According to the cross-tolerance between NSAIDs, especially sodium salicylate (SS), and opiates, especially morphine, the objective of this study was to investigate whether MET administration can reduce tolerance to the anti-nociceptive effects of SS. Fifty-six male Wistar rats were used in this research (weight 200-250 g). For induction of tolerance, SS (300 mg/kg) was injected intraperitoneally for 7 days. During the examination period, animals received MET at doses of 50, 75, or 100 mg/kg for 7 days to evaluate the development of tolerance to the analgesic effect of SS. The hot plate test was used to evaluate the drugs' anti-nociceptive properties. Salicylate injection significantly increased hot plate latency as compared to the control group, but the total analgesic effect of co-treatment with SS + Met50 was stronger than the SS group. Furthermore, the effect of this combination undergoes less analgesic tolerance over time. It can be concluded that MET can reduce the analgesic tolerance that is induced by repeated intraperitoneal injections of SS in Wister rats.

The increase in the degree of neural forward masking of cochlea following salicylate application

BackgroundHigh doses of salicylate are known to reduce cochlear response amplitude and raise threshold. However, its effect on the cochlear forward masking, reflecting temporal resolution, is still unclear. MethodsThe neural forward masking of cochlea was evaluated using double-tone stimulation. The first tone burst (5ms) was named the “masker” and the second tone burst (5 ms) was named the “probe”. The frequency and intensity of the masker and probe were equal, and the masker-probe interval varied from 2 to 32 ms. The reduction (%) of the probe-evoked cochlear compound action potential caused by the addition of the masker tone was used to represent cochlear forward masking. The data obtained before and 2 h following the injection of sodium salicylate (250 mg/kg) were compared. ResultsThe neural forward masking of cochlea in the normal rats increased as the masker-probe interval decreased. At 16 kHz, for example, it increased from ~5% to 32ms masker-probe interval to ~85% at 2ms masker-probe interval. Two hours post salicylate injection, the neural forward masking was significantly enhanced except at 32 ms masker-probe interval. Interestingly, this enhancement was only observed in the limited frequency range of 16–30 kHz. DiscussionThe enhancement of forward masking of cochlea following salicylate administration may reflect defective neurotransmitter release. This frequency-dependent injury in the cochlea may lead to the development of central plasticity observed after salicylate administration, likely through the increase in central gain, leading to perceptual consequences.

In Vivo Determination of Reduced Thiols in Rat Cerebellum Paraflocculus Following Salicylate-Induced Tinnitus by Fluorescence

ABSTRACTThe increasing number of patients suffering from tinnitus may be explained by an imbalance in the antioxidant defense system and reactive oxygen species formation, suggesting the importance of the redox homeostasis in this condition. Endogenous biothiols play important roles in maintaining redox homeostasis. Hence, to understand the role of biothiols in the pathological process of tinnitus, this study demonstrates an in vivo method for monitoring the concentrations of biothiols in the paraflocculus of the rat cerebellum during tinnitus induced by the injection of salicylate. Resorufin-based fluorescent probe 1 was used as the selective probe with in vivo microdialysis. Probe 1 was premixed with microdialysates from the paraflocculus of the rat cerebellum and transferred into a cuvette for continuous-flow fluorescence. A linear relationship between the fluorescence and the concentrations of cysteine, homocysteine, and glutathione was from 1 to 15 µM, with detection limits of 128, 148, and 183 nM, respectively. The basal level of total reduced biothiols in the paraflocculus of the rat cerebellum microdialysate was determined to be 10.62 ± 1.34 µM based on the calibration curve for homocysteine. The injection of sodium salicylate into the animals significantly decreased the reduced biothiol concentrations in the paraflocculus of the rat cerebellum from 60 min, reaching 39.5 ± 6.20% of the basal level. In contrast, at 120, 180, and 300 min, the concentrations of reduced biothiols were 55.73 ± 9.35, 58.26 ± 9.56, and 91.69 ± 6.91% of the basal level, respectively. These results imply that the decrease in reduced biothiols in the paraflocculus of the rat cerebellum may be associated with salicylate-induced tinnitus. This study offers a new platform for in vivo monitoring of reduced biothiols in the paraflocculus of the rat cerebellum following salicylate-induced tinnitus and may be useful for the investigation of this condition.

Flufenamic acid prevents behavioral manifestations of salicylate-induced tinnitus in the rat.

IntroductionTinnitus is defined as a phantom auditory sensation, the perception of sound in the absence of external acoustic stimulation. Given that flufenamic acid (FFA) blocks TRPM2 cation channels, resulting in reduced neuronal excitability, we aimed to investigate whether FFA suppresses the behavioral manifestation of sodium salicylate (SSA)-induced tinnitus in rats.Material and methodsTinnitus was evaluated using a conditioned lick suppression model of behavioral testing. Thirty-one Wistar rats, randomly divided into four treatment groups, were trained and tested in the behavioral experiment: (1) control group: DMSO + saline (n = 6), (2) SSA group: DMSO + SSA (n = 6), (3) FFA group: FFA (66 mg/kg bw) + saline (n = 9), (4) FFA + SSA group: FFA (66 mg/kg bw) + SSA (400 mg/kg bw) (n = 10). Localization of TRPM2 to the plasma membrane of cochlear nucleus neurons was demonstrated by confocal microscopy.ResultsPavlovian training resulted in strong suppression of licking, having a mean value of 0.05 ±0.03 on extinction day 1, which is below the suppression training criterion level of 0.20 in control tinnitus animals. The suppression rate for rats having both FFA (66 mg/kg bw) and SSA (400 mg/kg bw) injections was significantly lower than that for the rats having SSA injections (p < 0.01).ConclusionsWe suggest that SSA-induced tinnitus could possibly be prevented by administration of a TRPM2 ion channel antagonist, FFA at 66 mg/kg bw.

A randomised controlled trial of subcutaneous sodium salicylate therapy for osteoarthritis of the thumb

BackgroundCurrent treatment for osteoarthritis (OA) is limited. Many patients with OA of the hand have areas of tender subcutaneous thickening in the forearm and upper scapular region. A pilot study...

Differential gene expression profiles in salicylate ototoxicity of the mouse

Conclusion. This study demonstrated differential gene expression profiles in salicylate ototoxicity with oligonucleotide microarray. This study may also provide basic information on candidate genes associated with hearing loss and/or tinnitus or recovery after salicylate-induced cochlear dysfunction. Objectives: Salicylate ototoxicity is accompanied by temporary hearing loss and tinnitus. The purpose of the present study was to evaluate the gene expression profiles in the mouse cochlea with salicylate ototoxicity using DNA microarray. Materials and methods: The subject mice were injected intraperitoneally with 400 mg/kg of sodium salicylate; an approximate 30 dB threshold shift that was observed by auditory brainstem response was achieved 3 h after an injection of sodium salicylate and the hearing threshold returned to within normal range at 3 days. Differential gene expression profiles at 3 h after salicylate injection in comparison to the normal cochlea were analyzed with DNA microarray technology. Results: No ultrastructural changes in the mice cochlea were observed by TEM at 3 h after salicylate injection. Microarray revealed that 87 genes were up-regulated twofold or more in the mouse cochlea with salicylate ototoxicity in comparison to the normal cochlea. Among these genes, increased expression levels of 30 functional genes were confirmed by semi-quantitative RT-PCR.

Exogenous calcium protects postweanling rats from salicylate-induced changes in auditory conditioning

During Days 26–32 (postnatal), 18 rats drank more of a 0.05-M calcium-enriched solution when it was given to them ad lib or 1 h daily, but not when it was given 15 min daily, compared with 18 pups with similar access to plain water only. In a second experiment, acquisition and extinction of auditory conditioned suppression were observed in thirty-six 25-day-old pups, half of them reared with the calcium supplement throughout gestation and preweanling, and the other half reared with tap water. Twenty-two hours before training, the subjects were fluid deprived and exposed to continuous noise of 60 dB (SPL). Two hours prior to each session, the subjects received either injections of sodium salicylate before both sessions (n = 6 for each fluid type), saline before acquisition and salicylate before the extinction session (n= 6), or saline before both sessions (n = 6). Suppression of the approach to drink at the end of an alleyway paired the offset of the 60-dB noise and footshock. Calcium afforded subjects protection from salicylate-induced changes in auditory behavior during both acquisition and extinction.

The avian microcrystal arthritis II. Central versus peripheral effects of sodium salicylate, acetaminophen and colchicine. 1974.

An acute inflammation was elicited in pigeons by the injection of urate crystals (UC) into the intertarsal joint. From the resulting inflammation two parameters were recorded simultaneously: temperature-rise in the inflamed tissue and nociception, a correlate of pain. The effects of sodium salicylate, acetaminophen and colchicine on both parameters were investigated. All reduced nociception when administered at appropriate times and in suitable doses. However, only colchicine prevented temperaturerise in the inflamed area. After the injection of sodium salicylate an increase in temperature was also seen in noninflamed control tissue. Acetaminophen did not produce this effect. From these results it is concluded that colchicine acts peripherally at the site of inflammation whilst acetaminophen acts primarily, on nociception leaving local events at the site of inflammation unimpaired. For sodium salicylate a peripheral effect cannot be ruled out. The temperature effect of this drug appears to be of interest for the understanding of its antipyretic action.

Role of prostaglandins in exercise-induced core temperature elevation in female Sprague-Dawley rats.

Female Sprague-Dawley rats (12:12-h photoperiod; body temperature, BT, measured with biotelemetry) with access to running wheels for 6 wk have an elevated BT (compared with rats with no access to exercise wheels, i.e, sedentary) both during the period of voluntary exercise (nighttime) (0.5 degree C, P = 0.0001) and the nonexercise period (daytime) (0.3 degree C, P = 0.002). To determine whether prostaglandin (PG) E was responsible for any portion of this daytime rise in BT, we injected a dose of sodium salicylate (300 mg/kg), which was shown to produce complete antipyresis in rats injected with lipopolysaccharide (LPS), into exercised and sedentary rats 4 h after the onset of the lights-on period. The injections of sodium salicylate led to a fall in body temperature in both the exercised and sedentary rats of similar amounts (-0.88 degree C vs. -0.61 degree C at 2 h postinjection, P = 0.59). We conclude that the increase in daytime BT of exercised female rats is not mediated by prostaglandins.

Phantom auditory sensation in rats: an animal model for tinnitus.

In order to measure tinnitus induced by sodium salicylate injections, 84 pigmented rats, distributed among 14 groups in five experiments, were used in a conditioned suppression paradigm. In Experiment 1, all groups were trained with a conditioned stimulus (CS) consisting of the offset of a continuous background noise. One group began salicylate injections before Pavlovian training, a second group started injections after training, and a control group received daily saline injections. Resistance to extinction was profound when injections started before training, but minimal when initiated after training, which suggests that salicylate-induced effects acquired differential conditioned value. In Experiment 2 we mimicked the salicylate treatments by substituting a 7 kHz tone in place of respective injections, resulting in effects equivalent to salicylate-induced behavior. In a third experiment we included a 3 kHz CS, and again replicated the salicylate findings. In Experiment 4 we decreased the motivational level, and the sequential relation between salicylate-induced effects and suppression training was retained. Finally, no salicylate effects emerged when the visual modality was used. These findings support the demonstration of phantom auditory sensations in animals.

Parenteral aspirin and sodium salicylate are equally injurious to the rat gastric mucosa

The effects of parenteral aspirin (ASA) or sodium salicylate (SA) on the gastric mucosa were investigated in anesthetized pylorus-ligated rats 3 h after a bolus intravenous injection of ASA or SA, 150 mg/kg, or NaCl (control). Aspirin or SA produced similar extensive gross mucosal hemorrhagic lesions and similar microscopic damage in the presence of luminal acid (luminal pH 1.3 ± 0.05). Neither ASA nor SA produced gastric mucosal injury with intragastric instillation of saline (luminal pH 3.7 ± 0.5). Pretreatment for 1 h with luminal or subcutaneous 16,16-dimethyl prostaglandin E2 completely prevented the formation of red streaks in ASA-treated rats but not in SA-treated rats, although prostaglandin E2 pretreatment significantly reduced the gross lesion area in SA-treated rats (p < 0.05). We conclude the following: (a) Intravenous SA is as damaging as intravenous ASA as long as luminal acid is present, (b) 16,16-Dimethyl prostaglandin E2 completely protected the gastric mucosa from injury by intravenous ASA, and to a lesser extent by intravenous SA. (c) In view of the damaging effects of SA on the gastric mucosa and the rapid conversion of ASA to SA, the mechanism of the gastric mucosal injury by intravenous ASA is much more complex than simple inhibition of endogenous prostaglandin synthesis.

Hypothalamic temperature and the 22 kHz vocalization of the male rat

Following ejaculation the male rat emits a 22 kHz vocalization that has been hypothesized to play a communicative role. We found previously that this vocalization is often accompanied by rapid and selective hypothalamic cooling, and we hypothesized that the vocalization or, more precisely, the thoracic-laryngeal maneuver underlying the vocalization, is primarily a thermoregulatory behavior. Accordingly, one prediction made herein was that heating the brain of the isolated male, through the infusion of prostaglandin E 2, would be accompanied by the vocalization. Another was that cooling the brain of the copulating male through the injection of sodium salicylate would significantly reduce the post-ejaculatory vocalization. Both predictions were confirmed.

Absorption enhancement of growth hormone from the gastrointestinal tract of rats

An increased interest in non-injectable dosage forms for polypeptides has led to identification of some compounds which can increase absorption of these drugs. Sodium salicylate administered in rectal suppositories with recombinant methionyl human growth hormone (met-hGH) lead to measurable serum concentrations and demonstratable biological activity of the polypeptide. Sodium salicylate and mineral oil were tested in the ligated stomach, duodenum, ileum and colon of rats for their ability to enhance absorption of met-hGH. Rats were injected in one of the segments of the gastrointestinal tract with 3 mg kg of met-hGH with or without sodium salicylate in aqueous buffer or mineral oil vehicle. Blood samples were collected at various time points and assayed for hGH. Absolute bioavailabilities calculated for each formulation in each intestinal segment indicated that the only treatment with greater than 3% bioavailability was injection of sodium salicylate in mineral oil into the ileum (7%) and colon (9.5%). Statistical analysis proved the surprising interaction of salicylate and mineral oil to be synergistic in absorption enhancement. This is a promising finding but several issues must be addressed and pharmaceutical formulations must be optimized before it can be developed into an oral dosage form for polypeptide drugs.

Thermal control of maternal contact bouts: The interbout interval

Cooling mother rats by means of sodium salicylate injections did not curtail the intervals between maternal contact bouts. To the contrary, the interbout intervals were prolonged, suggesting that the relief from hyperthermia is a necessary but not a sufficient condition for the reinitiation of pup contact by mother rats. The ability of sodium salicylate to suppress maternal temperature suggests that pyrogenic and lactational increases in temperature may have some common feature.

Central thermosensitivity during fever produced by intra-PO/AH and intravenous injections of pyrogen

LIPTON, J. M. AND J. I. KENNEDY. Central thermosensitivity during fever produced by intra-PO/AH and intravenous injections of pyrogen. BRAIN RES. BULL. 4(1) 23–34, 1979.—Squirrel monkeys with thermodes implanted in the preoptic/ anterior hypothalamic (PO/AH) region and the medulla oblongata were used to examine three questions about central thermoresponsiveness in fever: Does thermoresponsiveness of the PO/AH region and medulla change during fevers caused by injection of bacterial endotoxin IV or directly into the PO/AH region? Does thermosensitivity of these brain regions determine the upper fever limit? Is thermoresponsiveness of the PO/AH region affected by local injections of salicylate? Changes in rectal temperature and oxygen consumption in response to heating and cooling the PO/AH region were reduced during fever caused by intra-PO/AH injections of bacterial endotoxin compared with changes produced during afebrile periods. PO/AH thermosensitivity was also reduced during fever caused by IV administration of bacterial pyrogen. Prolonged cooling of the PO/AH region or the medulla oblongata during fever produced by peripheral and central pyrogen injections did not cause rectal temperature (T re) to rise above 41.1°C although local heating reduced T re or limited the fever maximum. From the latter result it is concluded that both pools of central thermoreceptors can limit maximal fever by reacting to local high temperature but that lowered temperature in neither region can raise T re above a level determined by antagonistic input from thermoreceptors in other parts of the body. Injections of sodium salicylate into the PO/AH region had no effect on thermoresponsiveness of the region. This finding reinforces the idea that salicylates do not produce antipyresis by acting directly on thermosensitive cells of the central temperature control system.

Fever and antipyresis in the lizard Dipsosaurus dorsalis.

Lizards (Dipsosaurus dorsalis) were placed in a desertlike environment in which the ambient temperature (Ta) at night (1800-0600 h) was 12 degrees C and the day (0600-1800 h) Ta was between 30 and 55 degrees C depending on the location within the chamber. When dead Aeromonas hydrophila (4 X 10(9) organisms) was injected into nine lizards, an elevation in body temperature (Tb) of 2.7 degrees C was observed during the same day. On the day after bacterial injection the lizards' body temperatures averaged 41.6 degrees C, an increase of 4.2 degrees C over their control day Tb. Further investigations on the febrile response of D. dorsalis were conducted at the University of Wisconsin's Biotron, where there exists a simulated desert environment with the light intensity, temperature, and humidity closely parelleling a typical spring day in the southwestern desert of the United States (the natural habitat of Dipsosaurus). In this environment injection of dead bacteria into seven lizards led to an average febrile response of similar magnitude (Tb = 40.5 degrees C) but with a longer latency than that found at the University of Michigan. Injection of 13 lizards with live A. hydrophila (5 X 10(9) organism subcut.) in the simulated desert at Michigan led to a daytime fever averaging 2.3 degrees C (mean Tb = 40.6 degrees C) over a 5-day period. During the 6th and 7th day the lizards' body temperature returned to the normal or afebrile level. Injections of sodium salicylate along with dead A. hydrophila resulted in a dose-dependent attenuation of the febrile response. These results demonstrate that the reptilian febrile response is strikingly similar to avian and mammalian fever and suggest a common origin and perhaps function for the febrile mechanism.

The effect of sodium salicylate on bile secretion in the dog.

1. The I.V. injection of sodium salicylate (100 mg/kg) in the dog caused a rapid and maintained choleresis of the order of 300-600 percent of control levels. 2. The total amount of salicylate excreted in bile was only 1-2 percent of that injected. 3. The secretion of bile salt into bile was not increased by salicylate. 4. The choleresis caused by salicylate was associated iwth a decrease in the concentrations of sodium and of bile salt in bile, and with an increase in the concentration of chloride; the biliary concentration of bicarbonate was either temporarily increased or unchanged. 5. The choleresis could not be inhibited by the intra-portal injection of of ouabain (0-1 mg/kg). 6. The secretion of bromsulphthalein into bile was not potentiated by the choleresis. 7. The choleretic efficiency of sodium taurocholate was not increased in the presence of salicylate. 8. The injection of acetazolamide (20 mg/kg) in the presence of a salicylate choleresis, caused an increase in the osmolaity of bile and an increase in biliary sodium concentration, such that the composition of bile more nearly approached that of plasma. 9. The possible mechanisms underlying the choleretic effect of sodium salicylate are discussed.

Salicylate: action on normal body temperature in rats.

Rats receiving intraperitoneal injections of sodium salicylate (30 to 300 milligrams per kilogram of body weight) showed a decline in rectal temperature of up to 5.5 degrees C when placed in a 5 degrees C environment. High dosages of salicylate lowered the rectal temperatures of rats kept in a 23 degrees C environment. The finding that salicylate can lower nonfebrile body temperature suggests that this class of antipyretic agents does affect normal temperature regulation.

The effects of salicylate on temperature regulation in the rabbit.

1. A stable pyrexia has been produced in rabbits by intravenous injection of leucocyte pyrogen followed by a continuous infusion.2. Intravenous sodium salicylate, given 4 hr after the start of pyrogen infusion, induced rapid and progressive defervescence. The rate of fall of temperature was dose dependent.3. Intravenous injection of sodium salicylate had no effect on the temperature of afebrile rabbits.4. The intraventricular injection of small doses of sodium salicylate, given 4 hr after the start of a pyrogen infusion, caused a rapid, dose-dependent defervescence, but had no significant effect on the temperature of afebrile rabbits.5. Salicylates exert at least part of their antipyretic activity through an action on the central nervous system.

Effect of salicylate on the activity of plasma enzymes in the rabbit.

ELEVATIONS of glutamic-oxaloacetic and glutamic-pyruvic transaminases have been reported to occur in sera from more than 50 per cent of children with rheumatic fever treated with either aspirin or sodium salicylate1. The injection of sodium salicylate in the rat caused an increased activity of xanthine dehydrogenase in the blood but a decreased activity of the enzyme in the liver, and it was suggested that the salicylate caused liver and other tissue damage leading to an increased rate of release of enzyme protein into the circulation2. We have therefore studied the effects of prolonged oral administration of salicylate on the activities of five plasma enzymes and on tissue histology in the rabbit.