Injection Of Salicylate Research Articles

Salicylate-induced changes in auditory thresholds of adolescent and adult rats.

Shifts in auditory intensity thresholds after salicylate administration were examined in postweanling and adult pigmented rats at frequencies ranging from 1 to 35 kHz. A total of 132 subjects from both age levels were tested under two-way active avoidance or one-way active avoidance paradigms. Estimated thresholds were inferred from behavioral responses to presentations of descending and ascending series of intensities for each test frequency value. Reliable threshold estimates were found under both avoidance conditioning methods, and compared to controls, subjects at both age levels showed threshold shifts at selective higher frequency values after salicylate injection, and the extent of shifts was related to salicylate dose level.

The opposing effects of interleukin-1 β microinjected into the preoptic hypothalamus and the ventromedial hypothalamus on nociceptive behavior in rats

The effects of microinjections of recombinant human interleukin-1β (rhIL-1β) into the hypothalamus and neighboring basal forebrain on nociceptive behavior were studied using a hot-plate test in rats. The microinjection of rhIL-1β at doses between 5 pg/kg and 50 pg/kg into the medial part of the preoptic area (MPO) reduced the paw-withdrawal latency. The maximal reduction was obtained 30 min after the injection of rhIL-1β at 20 pg/kg. RhIL-1β (20 pg/kg)-induced hyperalgesia was completely blocked by the simultaneous injection of IL-1 receptor antagonist (IL-1ra, 20 ng/kg), Na salicylate (200 ng/kg) or α-melanocyte-stimulating hormone (α-MSH, 20 ng/kg). The intra-MPO injection of rhIL-1β at doses of less than 5 pg/kg or more than 50 pg/kg (up to 2 ng/kg) had no effect on nociceptive behavior. The microinjection of rhIL-1β (20 pg/kg) into the lateral part of the preoptic area, the median preoptic nucleus and the diagonal band of Broca also reduced the latency. On the other hand, the microinjection of rhIL-1β (20 pg/kg) into the paraventricular nucleus, the lateral hypothalamic area and the septal nucleus had no effect on nociception. The microinjection of rhIL-1β (20 pg/kg–50 pg/kg) into the ventromedial hypothalamus produced a prolongation of the paw-withdrawal latency. A maximal prolongation was obtained 10 min after the injection of rhIL-1β at 50 pg/kg. This reaction was also blocked by the simultaneous injection of IL-1ra (50 ng/kg) and Na salicylate (500 ng/kg). These findings indicate that IL-1β in the MPO and the VMH produces hyperalgesia and analgesia, respectively, while, in addition, both effects are mediated by IL-1 receptors and the synthesis of prostaglandins.

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.

Salicylate-induced changes in cat auditory nerve activity.

The purpose of this study was to measure, in the cat, spontaneous auditory nerve (AN) activity before and after injection with sodium salicylate. Ten cats were anesthetized, and the AN and round window (RW) were surgically exposed. Electrodes were applied to allow recording from three channels, including bipolar electrodes and monopolar electrodes located directly on the auditory nerve, in addition to an RW electrode. Spectral averaging of the spontaneous activity was performed before and during salicylate treatment. An increase in spectral activity near 200 Hz was noted in all cats by 3 hours after salicylate injection. This activity was present in bipolar, monopolar, and RW records, and was temporarily diminished or eliminated by injection of lidocaine. No such spectral changes were found in saline-injected control animals. These results show promise of developing a noninvasive, objective, quantitative measure of tinnitus for studies in animals and in man.

Effects of intra-cochlear perfusion of salicylates on cochlear microphonic and other auditory responses in the guinea pig

The ototoxic action of salicylate was investigated in the guinea pig by perfusion of both salicylate and bromosalicylate through scala tympani. The results qualitatively confirmed experiments using intravenous administration in cats (Stypulkowski, 1990), showing dose-dependent elevations in compound action potential (CAP) thresholds, increases in cochlear microphonics (CM) and level-dependent reductions in 2ƒ 1 −ƒ 2 acoustic distortion products. The endocochlear potential was not significantly affected and iontophoretic injection of salicylate into scala media had no measurable effect on CAP thresholds, consistent with an action on the basolateral walls of the hair cells. Perfusion with indomethacin produced effects similar to those of the salicylates, but at non-physiological doses. Together with the great effectiveness of 5-bromosalicylate, this suggests that salicylate does not act by inhibiting prostaglandin synthesis. The results are qualitatively consistent with the proposition that salicylates act on the basolateral walls of the outer hair cells. However, the magnitude of the CM increases, particularly at high drug concentrations, and the fact that salicylate reduced, but did not eliminate the effects of olivocochlear efferent stimulation on CM amplitude indicate that a simple explanation for salicylate effects based solely on a conductance increase in the outer hair cell membranes may be inadequate.

Quinine-Induced Tinnitus in Rats

Quinine ingestion reportedly induces tinnitus in humans. To expand our salicylate-based animal model of tinnitus, a series of conditioned suppression experiments was performed on 54 male-pigmented rats using quinine injections to induce tinnitus. Quinine induced changes in both the extent of suppression and recovery of licking, which followed a pattern that paralleled those produced after salicylate injections, and which may be interpreted as the result of tinnitus perception in animals. These changes depended on the dose and time schedule of quinine administration. Additionally, the calcium channel blocker, nimodipine, abolished the quinine-induced effect in a dose-dependent manner.

Effects of noise and salicylate on auditory evoked-response thresholds in the chinchilla

The combined effects of noise and sodium salicylate on auditory sensitivity were examined in the chinchilla. Sensitivity was monitored by recording the evoked response recorded with an electrode implanted in the inferior colliculus. Sodium salicylate (300 mg/kg/day), an octave band of noise centered at 500 Hz (80 or 105 dB SPL), or both of these agents were delivered for 15 days. Threshold testing was performed at 7 frequencies before, during, and after exposure to the ototraumatic agent(s). The salicylate alone caused an average temporary threshold shift of less than 10 dB and essentially no permanent shift. Animals exposed to noise alone had temporary and permanent threshold shifts which were not significantly different from those observed in animals exposed to noise plus salicylate. The data suggest that a single daily injection of sodium salicylate, resulting in peak serum salicylate concentrations of 28 to 34 mg% 2 to 4 hours after delivery, does not exacerbate the temporary or permanent threshold shifts induced by 15-day, 24-hour-per day exposure to either a moderate- or high-level, low-frequency noise. A second series of experiments utilizing a higher dose of salicylate (450 mg/kg/day) was not completed due to a high mortality rate among subjects that received salicylate and were exposed to noise. This result was consistent with other recent examinations of the interaction of these agents.

Effects of Intravenous Injection of Salicylate on the Spontaneous Discharge Rates of the Cochlear Nerve

Effects of Intravenous Injection of Salicylate on the Spontaneous Discharge Rates of the Cochlear Nerve

Arterial chemoreceptor involvement in salicylate-induced hyperventilation in rats.

1. The extent to which peripheral arterial chemoreceptors are involved in the respiratory stimulant action of salicylates has been investigated in rats. 2. Injection of sodium salicylate (200 mg kg-1, single dose i.v.) caused a rapid transient hyperventilation that was not obtained when the carotid chemoreceptors were denervated by section of the carotid sinus nerves. A delayed (10 min) increase in respiration occurred regardless of whether or not the carotid nerves were sectioned. 3. Intravenous infusions of sodium salicylate (0.5 or 4 mg kg-1 min-1) caused hyperventilation in barbiturate-anaesthetized rats. The threshold dose for respiratory stimulation was significantly lower when the carotid sinus nerves were intact than when they were bilaterally sectioned, and the same pattern was observed following intravenous injections of sodium salicylate (cumulative doses) in anaesthetized and conscious rats. 4. Bilateral sectioning of the vagosympathetic nerve trunks did not significantly affect hyperventilation evoked by salicylate, suggesting that this response does not involve actions of salicylate on sensory receptors innervated by these nerves. 5. Administration of salicylate close-arterial to a carotid body, by local perfusion or cross-perfusion of a carotid sinus, led to an increase in respiration when the ipsilateral carotid nerve was intact, but not when it was sectioned. 6. Neuropharmacological studies on anaesthetized rats showed that chemosensory discharge, recorded from a sectioned carotid nerve, increased in response to salicylate injections with a similar dose-response pattern to the hyperventilation. Salicylate had no effect on baroreceptor discharge. 7. We conclude from our experiments that arterial chemoreceptors do contribute to salicylate-induced hyperventilation, and are almost exclusively responsible for the initial phase of the response in rats. Later increases in breathing are independent of reflexes from arterial chemoreceptors and result from actions at other sites, including the CNS. The therapeutic implications of our results are discussed.

Modification of transplacental distribution of salicylate in rats by acidosis and alkalosis.

1. The basis for the existence of a lower concentration of salicylate in the foetal than in the maternal blood was investigated in rats on day 20 of gestation. 2. Bolus injections of sodium salicylate were made into the mother and of [14C]-salicylic acid into its foetuses and serial maternal and foetal blood samples were collected. When derived on the basis of serum salicylic acid uncorrected for differences in ionization in the maternal and foetal blood, the placental clearance was 2.2 fold greater from the foetal to maternal side than that from the maternal to foetal side. 3. The greater foetal placental clearance relative to the maternal placental clearance was not due to any active placental transfer, since there was no evidence of saturation of this process and it was not affected by pretreatment with probenecid. Moreover, salicylic acid was not concentrated by placental slices in vitro and its placental uptake was not affected by dinitrophenol or by cooling. 4. Maternal blood pH was 0.19 units higher than the foetal blood pH. Administration of ammonium chloride or of sodium bicarbonate into the mother increased the foetal to maternal ratio of salicylic acid from 0.6 to approximately 1. 5. It is concluded that a foetal to maternal serum salicylate concentration-ratio of less than 1 simply reflects lower ionization in the foetus than in the mother, because foetal blood pH is lower than the maternal blood pH.

Pigmentation, Anesthesia, Behavioral Factors, and Salicylate Uptake

In four experiments, 54 pigmented rats were used to examine the time course of sodium salicylate uptake in serum, cerebrospinal fluid, and perilymph. Subjects were tested under sodium pentobarbital anesthesia or while conscious. Compared with previously reported data from albino rats, pigmented subjects generally showed increased salicylate uptake. Moreover, the data suggested two different, time-dependent clearance mechanisms in conscious animals not observed in anesthetized rats. Daily injections of salicylate did not produce an accumulation of salicylate in serum. Systematically higher levels of salicylate were observed in perilymph compared with cerebrospinal fluid. Behavioral procedures, including water deprivation and conditioned suppression of ongoing drinking levels, had no effect on salicylate levels.

Effects of intravenous injection of salicylate on the cochlear nerve action potentials

It is not yet well understood the actions of salicylate on the auditory system. Our previous study has shown that injections of salicylate increases the spontaneous discharge rate of cochlear nerve fibers. This study was aimed to elucidate the effects of various doses of salicylate on the cochlear nerve by recording the compound action potentials (CAPs) which were evoked by electrical pulse applied to the cochlea through the round window membrane before and after intravenous injection of salicylate.After injection of 100mg/kg, 200mg/kg and 400mg/kg of salicylate, the amplitude of CAPs was decreased significantly, while their latency was increased significantly only after injection of 400mg/kg of salicylate. These results suggest that intravenous injection of salicylate acts directly on the cochlear nerve and causes increase of its excitability and that the amplitude changes of CAPs are better indicaters than the latency changes of CAPs.

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.

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.

Serial production of controlled periods of temporary heart block used to unmask and assess latent ventricular automaticity during experimental acute myocardial ischemia

This study examined the onset, time course of development and response to overdrive stimulation of ventricular tachycardia in 10 dogs that underwent a Harris two-stage ligation of the left anterior descending coronary artery. Transient (12 +/- 3 minutes) complete atrioventricular (AV) block was produced 2, 3, 4, 5, 8, 12, 16, 20 and 24 hours after onset of infarction through selective injection of physostigmine salicylate into the AV node artery. Seven of the 10 dogs had early transient arrhythmic episodes that occurred within 20 to 40 minutes after coronary occlusion but none of the dogs had any spontaneous ventricular tachycardia in the ensuing 2 hours. Two hours after left anterior descending coronary artery ligation, complete AV block unmasked in every dog a slow (37 +/- 9 beats/min) AV junctional rhythm readily suppressed by overdrive. Three hours after coronary ligation, AV block revealed a monomorphic ventricular tachycardia (106 +/- 10 beats/min) in 3 of the 10 dogs. Four and five hours after coronary ligation, five and eight dogs, respectively, had ventricular tachycardia during AV block and in three the tachycardia was polymorphic. The two remaining dogs did not develop ventricular tachycardia during the 24 hours of observation. Ventricular tachycardia always began abruptly, first with brief and then longer bursts. Soon after onset the rate of tachycardia began to increase to reach a plateau 2 to 3 hours later at frequencies 21 +/- 9% greater than the initial tachycardia rate. Concomitant with this increase in rate there was a steady decline of overdrive suppressibility and during the plateau phase there was little or no overdrive suppression.(ABSTRACT TRUNCATED AT 250 WORDS)

Comparative Behavioral Toxicity of Physostigmine in Ferrets and Rats

Marshall-bred ferrets( n = 10) and Sprague-Dawley derived rats ( N = 12) were monitored in a photocell cage for 20 minutes following an IP injection of physostigmine salicylate or vehicle. Doses ranged from 0.0125 to 0.4 mg/kg for ferrets and 0.05 to 0.8 mg/kg for rats in equal logarithmic intervals. A repeated measures Latin-square design was used with a minimum of 72 hours between tests. Vertical activity (rearing), horizontal activity (ambulation), and movement time were recorded. Both ferrets and rats showed a reduction in rearing at doses of 0.1 mg/kg or greater. Ambulation was significantly reduced from vehicle control levels at doses of 0.05 mg/kg or greater for ferrets and 0.1 mg/kg or greater for rats. Ferrets exhibited a significant decrease in movement time at doses of 0.025 mg/kg or greater, whereas rats did not show this reduction until doses of 0.1 mg/kg or larger were administered. It thus appears that, using these behavioral measures, ferrets are more responsive to the effects of the cholinesterase inhibitor, physostigmine, than are rats.

Pathways for the bioactivation of aliphatic nitriles to free cyanide in mice

Reports from several laboratories agree that many, but not all, aliphatic nitriles undergo hepatic biotransformation in mice and rats to release free cyanide, but the mechanisms at work in these reactions remain in doubt. We have used primarily n-butyronitrile, propionitrile, and their respective α-carbon-hydroxylated homologs, propionaldehyde cyanohydrin and lactonitrile, to examine this question in mice. Pretreatment of mice with the hepatic microsomal enzyme inducers, pregnenolone-16α-carbonitrile, troleandomycin, and isosafrole, or with the cytochrome P-450-depleting agent, cobaltous chloride, did not influence the mortality of mice given single doses of nitriles. Repeated injections of aspirin or sodium salicylate in water failed to protect mice against death by the nitriles. Dimethyl sulfoxide, however, was effective in reducing mortality after nitrile administration. Repeated injections of 4-methylpyrazole or disulfiram protected mice against death after nitriles. Most of the treatment regimens successful against the nitriles also protected against death due to the cyanohydrins. The cyanohydrins were more acutely toxic than their parent nitriles, produced death much more rapidly, and resulted in the same toxic signs, suggesting that they are intermediates in the bioactivation pathway leading to free cyanide. The cyanohydrins appeared to serveas weak substrates for yeast alchohol dehydrogenase, however, incubation of them with either yeast or horse liver alcohol dehydrogenase did not increase the rate of cyanide release over that in incubations where the enzymes were absent. The slow rate of cyanide release due to spontaneous hydrolysis interfered with the determinations of alcohol dehydrogenase activity, but it cannot account for the rapid action and high toxicity of the cyanohydrins in vivo, or for the efficacy of the treatment regimens which protected against death. It appears unlikely that prostaglandin synthetase or alcohol dehydrogenase are importantly involved in nitrile bioactivation. The same active process, however, appears to be responsible both for α-carbon hydroxylation and for the subsequent degradation of the resulting cyanohydrins to release free cyanide. It is far more efficient in mediating the latter reaction than the former.