Alteration of early T cell development by opioid and superantigen stimulation.
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Animals↗
Biomedical subjects
L E McCarthy
Publications and source records attributed to L E McCarthy.
Neurotoxicology of chronic infusion of the ganglioside GM1 in the ewe: phase I. intrathecal administration.
Gangliosides, including GM1, provide a measure of improved functional recovery after ischemic, toxic, and traumatic brain injuries in animal studies. Since systemically injected GM1 has provided equivocal results in a variety of human neurodegenerative conditions, the possibility exists that intrathecal or intracerebroventricular delivery might provide more effective concentrations along the neuroaxis. In preparation to consider clinical trials, the potential neurotoxicologic effects of chronic intrathecal GM1 were studied in ewes. Preliminary in vitro tests first demonstrated the stability and compatibility of GM1 in implanted pumps. Two groups of adult ewes were then implanted with either Therex or Infusaid continuous flow implantable pumps and chronic intrathecal catheters. Ewes were infused intrathecally with either preservative-free normal saline (n = 5) or GM1 (n = 7) 100 micrograms-10,000 micrograms/d for up to 24 wk. No abnormal behavioral responses were noted. Cerebrospinal fluid analyzed for GM1 concentrations by thin layer chromatography revealed no evidence of GM1 accumulation. After the animals were killed, spinal cords were removed, fixed, sectioned, and stained. Histologic analysis revealed no generalized pattern of neuronal damage, demyelination, gliosis, or axonopathy to distinguish intrathecal normal saline or GM1. In both treated and control groups, the only consistent finding was a pericatheter-associated compression of white matter with axonal dilation, vacuolation, and occasional neuronal loss. Catheter tracts in both groups were also associated with variable leptomeningeal fibroproliferative changes in adjacent dura and pia, at times in conjunction with more generalized duromeningeal thickening. In summary, chronic intrathecal GM1 in doses up to 10 mg/d had no definable neuropathologic consequences.
Animals↗
Differential c-fos-like protein expression in mechanically versus chemically induced visceral nociception.
The expression of c-fos-like protein has been suggested to be a marker for neuronal activity in nociceptive processing. The immunohistochemical detection of this protein was used to determine if different visceral noxious stimuli induce distinct patterns in the rat spinal cord. We have developed a mechanical visceral pain model which is based on the acute distention of the duodenum yielding a quantifiable behavioral endpoint, writhing-like activity. One hour following either intraperitoneal injection of acetic acid or the distention of the duodenum via a chronically implanted balloon catheter, the animals were processed for the immunocytochemical detection of c-fos-like protein in the spinal cord. Characteristic patterns of c-fos-like immunoreactivity were observed following each type of stimulus that differed in spinal laminar and segmental distribution, number of neurons expressing fos-like immunoreactivity and staining intensity. The chemical noxious stimulus induced c-fos bilaterally in laminae I and X predominantly in the thoraco-lumbar region of the spinal cord. In contrast, the mechanical noxious stimulus induced a greater number and more intense neuronal c-fos-like protein expression in laminae I-VI, IX and X. These data provide further evidence that there is a differential nociceptive modulation in mechanical noxious visceral stimulation.
Animals↗
Central respiratory inhibition by angiotensin II in anesthetized cats.
Observations were made on respiration, alveolar concentration of CO2, arterial blood pressure and heart rate in barbiturate-anesthetized cats subjected routinely to section of the vagus and carotid sinus nerves and maintained with pure O2 for inhalation. Bolus i.v. injection of angiotensin II (AII), 0.6 to 6.0 micrograms/kg, evoked a prompt shortlasting suppression of breathing, manifested mainly as a reduction in tidal volume susceptible to the development of tachyphylaxis if injections were spaced more closely than 30 min apart. Ablation of the area postrema failed to eliminate the respiratory effect of All. The response also persisted after midbrain transection, spinal cord transection at C8, dorsal rhizotomy of spinal segments C1 to C8 and interruption of cranial nerves V, VII, VIII, IX, X, XI and XII. No influence of All was evident on indirectly evoked tibialis muscle contractions and on pulmonary compliance. A reduction in phrenic nerve impulse traffic coincided with the respiratory response to All. Cranial i.a. injection of All initiated the respiratory effect in its first pass through the brain, before any change occurred in the blood pressure. The degree of All-induced respiratory inhibition was relatively constant at different magnitudes of breathing produced by CO2 inhalation or by electrical stimulation of the respiratory center in the medulla oblongata. It is concluded that All given by bolus intravascular injection causes respiratory inhibition through a direct central action at the final processing step in the CO2-tidal volume controller.
Anesthesia↗
Radioemetic protection at 24 h after 60Co irradiation in both normal and postremectomized cats.
The radioemetic dose-response relationships were established in 46 unanesthetized cats for each of two whole-body exposures, 24 h apart, to 60Co radiation at selected doses between 7.5 and 60 Gy. Individual episodes of vomiting were recorded for a period of 48 h as distinctive intrathoracic pressure deflections signaled through a catheter placed in the superior vena cava. Five cats with chronic lesions of the area postrema were included in the group exposed to 45 Gy. The lesioned animals were not detectably different in their radiation response behavior from the intact cats. Initial exposure in the entire cat series produced an increasing incidence of radioemesis from 25 to 80% over the specified dose range for the first observation period of 24 h. By contrast, the second exposure produced an inverse dose-related incidence of emesis varying from 63% to zero with an apparent crossover of radioemetic susceptibility for the two exposures at about 15 Gy. Complete protection during 12 h after the second exposure was obtained at 30, 45, and 60 Gy, and for all of 24 h at 45 and 60 Gy. In a separate group of 11 normal cats, the emetic drug xylazine invariably evoked vomiting when radioemetic protection was otherwise manifest after initial irradiation at 45 Gy. We conclude that the temporary recovery of well-being following acute lethal irradiation results selectively through increased radioemetic resistance, and it does not depend on the integrity of the area postrema.
Animals↗
High dorsal column cordotomy plus subdiaphragmatic vagotomy prevents acute ionizing radiation sickness in cats.
Our purpose was to determine the effects on acute radiation sickness of interrupting afferent neural pathways that converge upon the medullary vomiting center but which bypass the emetic chemoreceptor trigger zone in the area postrema. A comparison was made of the vomiting response and other signs of sickness in three groups of chronic cats surgically prepared as follows: high spinal cord section of the dorsal columns, subdiaphragmatic vagotomy, and the combination of procedures. Every cat was exposed over the whole body to 45 Gy 60Co gamma-radiation which was effective in evoking emesis in 11 of 12 normal cats. Neither cordotomy alone (8 cats) nor vagotomy alone (2 cats) reliably blocked the vomiting response but they separately delayed its onset. On the other hand, the cordotomy prevented the loss of appetite and behavioral malaise that was invariably caused by the irradiation in normal cats. Finally, the combination of cordotomy and vagotomy protected all of 3 cats against the entire radiation syndrome. These cats then vomited appropriately in response to the injection of deslanoside which induces emesis through an action on the area postrema. Histological examination of the lower medulla revealed no damage of the area postrema resulting from the cordotomies. We conclude that acute radiation sickness in the cat is signaled through afferent neural pathways originating in the abdomen and that the area postrema does not participate in the causation of this syndrome.
Animals↗
Acute radiation-induced vomiting in area postrema-ablated cats.
A dose-response relationship was established in normal unanesthetized cats for emetic incidence, latency to onset of vomiting, and duration of emetic activity over a period of 24 h after whole-body exposure to 60Co radiation at selected doses between 7.5 and 90 Gy. Each episode of vomiting, i.e., retching and expulsion, was recorded oscillographically as its characteristic intrathoracic pressure waveform by means of a catheter inserted some days before into the superior vena cava. The gamma-radiation dose of 45 Gy evoked vomiting optimally with an incidence of 92% and an average onset time of 98 min. When administered to animals prepared chronically with surgical ablation of the area postrema, the same dose of radiation evoked vomiting in four of five test cases and with an average time to onset that was not by either measure significantly different from normal. Vomiting was also elicited in all of six normal cats exposed to an intestinal dose of 45 Gy X radiation with the head shielded. The same form of irradiation evoked vomiting in two of three chronically postremectomized cats. Successful ablation of the area postrema was determined functionally by emetic refractoriness to an injection of digitalis and confirmed for completeness by histological examination. It is concluded that the area postrema is not an essential element in the reflex mechanism of radiation-induced vomiting and, therefore, no physiological basis exists for dependence on a centrally acting chemogenic factor in radioemesis.
Animals↗
Neurological analysis of respiratory, cardiovascular and neuromuscular effects of brevetoxin in cats.
Effects of brevetoxin were evaluated in cats anesthetized with pentobarbital under conditions of controlled end-expiratory pCO2 and constant body temperature. Recordings were made of arterial blood pressure, heart rate, respiratory pattern, diaphragm EMG, evoked tibialis muscle twitch and evoked contraction of the nictitating membrane. Electrical stimulation was employed for periodic excitation of the medullary respiratory center, the phrenic nerve, the peroneal nerve and the cervical sympathetic nerve. Brevetoxin was prepared at a concentration of 1.0 mg/ml in an aqueous medium of 2.5% ethanol plus 2.5% Emulphor 620 (General Aniline and Film Corp., New York). Small i.v. bolus injections of the toxin (40 micrograms/kg) evoked, without tachyphylaxis, the Bezold-Jarisch reflex triad of bradycardia, hypotension and bradypnea. This effect was essentially abolished by vagotomy. Continued injections then resulted in pressor reactions and tachycardia, along with the development of respiratory dysrhythmia. Large doses of brevetoxin (160 micrograms/kg i.v.) caused somatomotor seizures accompanied by severe hypertension, that occurred even after decerebration and cervical spinal cord transection. Cranial intra-arterial and intra-cerebroventricular injections of brevetoxin produced hypertension and respiratory depression more effectively than did i.v. injections. Systemic cumulation of the toxin, with the respiration supported artificially, caused death from cardiovascular collapse, without significant blockade of neuromuscular and ganglionic transmission. It is concluded that brevetoxin exerts its major toxic effects on the circulation and respiration through reflex and central actions, largely sparing peripheral motor mechanisms.
Animals↗
Peripheral and central actions of sodium azide on circulatory and respiratory homeostasis in anesthesized cats.
In pentobarbital-anesthesized cats, bolus i.v. injections of sodium azide produced dose-dependent transient hypotension accompanied by a modest tachycardia and a brief hyperpnea. Intracerebroventricular injections of azide elicited graded effects similar to the i.v. doses, but the responses were slower in onset and could be delayed by occluding the cranial blood supply. This is interpreted to mean that intracerebroventricular azide acts systematically after escaping from the cerebrospinal fluid into the bloodstream. The hypotensive response to i.v. azide was not affected by cholinergic or adrenergic blockade or buffer nerve section. The tachycardia was blocked by sympathetic neural blockade or buffer nerve section indicating that it is a baroreflex response to the vasodepressor effect. Respiratory effects of bolus i.v. azide occurred independently of the hypotensive response and were abolished by peripheral chemodenervation. Infusion of azide facilitated CO2-tidal volume responsiveness in the steady state, an effect that was essentially eliminated by carotid sinus neurotomy. The azide did not affect the tidal volume-respiratory frequency relationship mediated by the pulmonary stretch receptors. Thus, the respiratory stimulant effect of azide in subtoxic doses is attributable to an excitatory action on the arterial chemoreceptors. Toxic doses of azide resulted in centrally mediated hypertension, tachycardia, cardiac arrhythmia, respiratory depression, seizures and death.
Animals↗
Cisplatin-induced vomiting eliminated by ablation of the area postrema in cats.
Cisplatin-induced emesis was characterized using the cat as an experimental model. The incidence, latency, and number of vomiting episodes which occurred over an 8-hour period were determined for iv doses ranging from 3 to 10 mg/kg. Oscillographic recording of physiologic pressures which produce vomiting served to document the observation that 7.5 mg/kg iv was the most effective dose. This dose produced vomiting in seven animals with a latency of 71 +/- 7.04 minutes (mean +/- SE) and subsequent emetic episodes (averaging 3.86/animal) followed a linear relationship with respect to the logarithm of time. The larger dose of 10 mg/kg appeared to be less effective, because not all animals responded. Those animals that vomited in response to this dose did so only after a significantly increased latency. Four animals with longstanding lesions of area postrema were tested with cisplatin (7.5 mg/kg); all four failed to vomit during a 6-hour observation period. In addition, none of the animals exhibited the sustained malaise associated with cisplatin administration to intact animals and only one displayed any prodromal emetic signs. These findings demonstrate that the area postrema, the anatomic site of the chemoreceptor trigger zone for emesis, is essential for cisplatin-induced vomiting. Elucidation of this action suggests a possible mechanism for other emetogenic anticancer agents.
Animals↗
Role of the area postrema in vomiting and related functions.
Before 1949, the vomiting center was said to be located in the dorsal vagal nuclei of the medulla, but it was uncertain whether two centers existed separately for the control of direct and reflex actions of emetic agents. Borison and Wang then used a stereotaxic technique with electrical stimulation to localize the vomiting center in the reticular formation at a measurable distance from the dorsal vagal nuclei. They also formulated the concept of a separate emetic chemoreceptor trigger zone (CTZ) so that the vomiting center itself is not sensitive to emetic agents and serves solely to coordinate the reflex process. The CTZ was soon identified with the area postrema (AP), but the question remains unanswered whether the CTZ constitutes part or all of tht circumventricular organ. Furthermore, different chemosensory functions, as for defecation and certain forms of autonomic expression, may be represented regionally within the AP. Species that are unable to vomit, e.g., rodents, show other postrema-mediated effects as radiation-induced gastric stasis and drug-induced conditioned taste aversion. In sheep, digitalis-induced arrest of rumination is prevented by postremectomy. It is suggested that these behavioral end points in nonvomiting species may serve for biological assay of antinauseant drugs. Finally, a tabular summary is given of known causes of vomiting in which the AP has been implicated.
Animals↗
Neuropharmacology of chemotherapy-induced emesis.
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Antiemetics↗
Respiratory and cardiovascular depressant effects of nabilone, N-methyllevonantradol and delta 9-tetrahydrocannabinol in anesthetized cats.
Drug effects were examined in cats anesthetized with a mixture of pentobarbital and barbital injected i.p. Respiratory observations were analyzed according to effects produced on 1) chemoregulatory responsiveness determined by changes in tidal volume resulting from CO2 inhalation or measured during isocapnic stabilization, and on 2) mechanoreflex control of respiratory frequency through the vagus nerves. Blood pressure and heart rate were recorded concomitantly. Cardiovascular effects were manifested as dose-related hypotension and bradycardia that were generally response-limited by contrast with the respiratory depressant effects which progressed ultimately to failure. Relative potency of the three agents to produce an elevation of 4% in resting alveolar CO2 fraction was 100 times for N-methyllevonantradol and 10 times for nabilone by comparison with delta 9-tetrahydrocannabinol. Marked slowing of respiratory frequency occurred in vagotomized as well as in nerve-intact cats. Apneustic respiration was not observed in any case. It is concluded that the effects of the cannabinoids resulted from 1) an upward shift in CO2 setpoint of the central chemorespiratory "detector"; 2) decreased gain of the CO2-tidal volume "controller"; 3) depression of the respiratory "oscillator" in the lower medulla; 4) depression of the vasomotor center; and 5) a central vagotonic action in addition to a direct cardiodecelerator action on the heart.
Anesthesia, General↗
Respiration unaffected by anemia in chemodenervated cats.
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Anemia↗
Noninvasive documentation of emesis in cats.
Chest and abdominal wall movements were assessed as objective indicators of emesis. Thirty-six vomiting episodes in one intact and four decerebrate cats were monitored either by an inductive plethysmograph or by magnetometers applied to the chest and abdomen. The plethysmographic method was found to be the more suitable of these two monitoring techniques because it produced stable, artifact-free recordings with excellent signal differentiation. The occurrence of emesis was validated by simultaneously recording thoracic central venous pressure. Unlike the intrathoracic pressure measurement, spasmodic movements of chest and abdomen did not differentiate retching from expulsion. However, rhythmic abdominal excursions recorded during vomiting were several times greater than those occurring during any other activity. Surprisingly, these movements indicated an increase in abdominal dimensions during vomiting in contrast to the reduction in size observed during sneezing and coughing. We believe that recording of abdominal movements that accompany vomiting might potentially serve as a noninvasive research tool for the study of emesis in cancer chemotherapy.
Abdominal Muscles↗
Vomiting induced by cyclophosphamide and phosphoramide mustard in cats.
Cyclophosphamide and phosphoramide mustard produce significant vomiting. Cyclophosphamide is metabolized to phosphoramide mustard, which may ultimately contribute to vomiting after cyclophosphamide administration. The role of the chemoreceptor trigger zone (CTZ) in vomiting caused by these agents is unknown. We studied the emetic syndromes produced by iv and intracerebroventricular cyclophosphamide and phosphoramide mustard in unanesthetized normal and CTZ-ablated cats. Iv cyclophosphamide produced vomiting unpredictably, with a mean latency of 54 +/- 9 mins (mean +/- SE) in cats that vomited. A dose-response relationship was found for phosphoramide mustard-induced emesis. A dose of 200 mg/kg was consistently effective, with a mean latency of 127 +/- 6 mins. Neither agent produced predictable emesis by the intracerebroventricular route of administration. One of four CTZ-ablated cats vomited after 300 mg/kg of cyclophosphamide. Since cyclophosphamide was an unpredictable emetic stimulus, it was not possible to further evaluate the effect of CTZ ablation on cyclophosphamide-induced vomiting. However, CTZ-ablated cats given 200 mg/kg of phosphoramide mustard vomited significantly less frequently (P = 0.05 by chi-square test) and with a longer latency than nonablated animals. A temporary, severe neurotoxic reaction was observed in cats receiving greater than or equal to 3400 mg/kg of cyclophosphamide, which may have had an inhibitory effect on emesis. Phosphoramide mustard was found to be a potent emetic stimulus in cats and may contribute to the emetic response following cyclophosphamide administration. Analysis of latency data suggests that in the cat other cyclophosphamide metabolites may also contribute to the emetic syndrome.
Animals↗
Emetic action of xylazine on the chemoreceptor trigger zone for vomiting in cats.
Xylazine is an effective sedative analgesic that induces vomiting in the cat. A consistently effective intramuscular emetic dose of xylazine was established in normal cats in this laboratory. Animals in which the area postrema of the medulla oblongata had been chronically destroyed did not exhibit emesis in response to the standard test dose of xylazine but continued to show sedation. By contrast, sham-operated cats responded normally. Refractoriness to deslanoside, a known specific emetic drug, was used as functional proof for successful ablation of area postrema, and the lesions were also validated histologically. We conclude that xylazine exerts its emetic action on the chemoreceptor trigger zone of the area postrema. It is suggested that this action may be mediated by an opiate type of molecular receptors.
Animals↗
Spatial interrelationship of pHa PACO2 and respiratory VT in chemodenervated decerebrate cats.
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Acid-Base Equilibrium↗