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Biomedical subjects

J W Holaday

Publications and source records attributed to J W Holaday.

At least 91 records · Page 5Linked to original sources

Ultradian glucocorticoid rhythms in monkeys and rats continue during stress.

Previously we showed that rhesus monkeys have ultradian cortisol rhythms with periods of about 90 min that persist during the infusion of large amounts of adrenocorticotropin. The experiments reported here showed that rats exhibit ultradian corticosterone rhythms with a similar period (median period 61 min). However, rat ultradian corticosterone rhythms were distorted by large slow trends that had to be removed before the rhythm could be adequately assessed. The need for sophisticated trend removal suggests that physiological variables that have been described as exhibiting episodic fluctuations (e.g., human cortisol) may actually be periodic and ultradian. The ultradian glucocorticoid rhythm persisted during stress both in monkeys (median period 80 min) and rats (median period 52 min). However, the glucocorticoid stress response appeared to produce large slow trends in both monkeys and rats, indicating that environmental influences may introduce slow trends that make raw data difficult to evaluate. More importantly, the fact that ultradian glucocorticoid rhythms persist during stress provides further evidence of limits on the classical concept that glucocorticoid secretion is tightly and inseparably linked to hormonal events in the hypothalamic-pituitary unit.

Adrenal Glands↗

Naloxazone pretreatment modifies cardiorespiratory, temperature, and behavioral effects of morphine.

Behavioral and cardiorespiratory responses to a lethal dose of morphine were evaluated in rats pretreated with saline or naloxazone, an antagonist of high-affinity mu 1 opioid receptors. Pretreatment with naloxazone significantly blocked morphine analgesia, catalepsy and hypothermia at a dose which completely eliminated high-affinity binding in brain membranes. Moreover, naloxazone significantly attenuated the morphine-induced hypotension and respiratory depression, whereas morphine-induced bradycardia was less affected. Results indicate that subpopulations of mu receptors may mediate selective behavioral and cardiorespiratory responses to morphine.

Animals↗

Naloxazone lacks therapeutic effects in endotoxic shock yet blocks the effects of naloxone.

Cardiovascular effects of the high affinity, irreversible opiate antagonist, naloxazone, were investigated in conscious rats subjected to endotoxic shock. Unlike other less selective opiate antagonists such as naloxone, naloxazone failed to block or reverse the hemodynamic effects of endotoxemia. However, naloxazone pretreatment prevented the usual therapeutic effects of naloxone in endotoxic shock. Results indicate that high affinity (mu 1-site) opiate binding is not involved in the pathophysiological actions of endogenous opiates in shock, and suggest that interactions among opioid receptor subtypes may occur in vivo.

Animals↗

Evidence for delta-receptor involvement in the post-ictal antinociceptive responses to electroconvulsive shock in rats.

Studies were conducted with the putative delta-opioid receptor antagonist lCl 154,129 (lCl) and the putative mu-receptor antagonist beta-funaltrexamine (beta-FNA) to investigate their ability to block the acute opioid-like effects of a single electroconvulsive shock (ECS). lCl, but not beta-FNA, attenuated the increase in hot-plate escape latencies seen following ECS. From these data, we conclude that ECS activates endogenous opioids which act upon delta rather than mu receptors to result in an increase in hot-plate escape latencies.

Animals↗

A selective role for delta-receptors in the regulation of opioid-induced changes in seizure threshold.

In an effort to identify delta-receptor-specific properties for opioid modulation of seizure activity, studies were conducted with ICI 154,129, a putative delta-receptor antagonist, in the rat flurothyl test. Rats were pretreated i.c.v. with ICI 154,129 (50 micrograms) which, at this dose, does not alter normal seizure thresholds. Mean seizure thresholds for control groups (i.c.v. saline) ranged between 323-349 sec. In this test, D-Ala2-D-Leu5 enkephalin (20 micrograms, i.c.v.), metkephamid (40 mg/kg, s.c.), and etorphine (20 micrograms/kg, s.c.) raised seizure thresholds by 117, 128, and 140% of control, respectively. Meperidine (25 mg/kg, s.c.) lowered seizure thresholds by 14% less than control. Pretreatment with ICI 154,129 failed to antagonize the proconvulsant action of meperidine or the anticonvulsant and behavioral depressant actions of etorphine. The increases in seizure threshold produced by DADL and metkephamid (two delta-directed ligands) were significantly attenuated by ICI 154,129. However, the DADL-induced wet-shakes, rigid immobility, and behavioral depression were insensitive to ICI 154,129. These data indicate that ICI 154,129 possesses delta-receptor antagonistic properties in this in vivo model of seizure activity. Furthermore, since only the changes in seizure threshold were antagonized, it may be inferred that opioid-induced behavioral depression and DADLE wet-shakes are not a function of delta-receptor activity.

Animals↗

Multiple opioid receptors: evidence for mu-delta binding site interactions in endotoxic shock.

Using antagonists with selectivity for the delta (ICI 154,129) and mu (beta-funaltrexamine) binding sites, evidence was obtained to indicate that delta receptors within the brain mediate the endogenous opioid component of endotoxic hypotension. The therapeutic actions of intravenous ICI 154,129 were dose related, with effective doses between 15-60 mg/kg. Evidence for a functional interaction between mu and delta binding sites was obtained: prior occupancy of the mu binding site by beta-funaltrexamine prevented the usual therapeutic response to the delta antagonist ICI 154,129 in endotoxemic rats. These data indicate that mu and delta binding sites may be a part of the same macromolecular complex which interact through allosteric coupling.

Animals↗

Thyrotropin releasing hormone: autonomic effects upon cardiorespiratory function in endotoxic shock.

These studies define potential sites and mechanisms by which thyrotropin releasing hormone (TRH) stimulates cardiorespiratory function in normotensive rats as well as in rats subjected to endotoxic shock. Changes in mean arterial pressure, pulse pressure, heart rate, and respiratory rate were determined in conscious animals following injection of TRH into the lateral, third, or fourth ventricular spaces. Injections of TRH into the third ventricular space resulted in a greater increase in cardiorespiratory variables than did fourth ventricular injection. In endotoxin-treated rats, the cardiorespiratory effects of intracerebroventricular (icv) TRH and its analog MK 771 were assessed. TRH and MK 771 were shown to act within the brain to reverse endotoxic shock hypotension; at the doses used, the pressor effects of these two tripeptides were achieved through selectively different actions upon heart rate and pulse pressure. Adrenal demedullated and sham-operated control rats subjected to endotoxic shock were injected with icv and intravenous (iv) TRH in order to evaluate the potential involvement of sympatho-medullary function in cardiorespiratory responses. The cardiovascular effects of icv TRH were dependent upon adrenal medullary integrity; effects of iv TRH were not. Doses of iv TRH which effectively reverse shock neither altered nociceptive latencies nor interfered with analgesic responses to morphine. Collectively, these studies reinforce the potential therapeutic utility of TRH and its analogs in the treatment of shock and indicate potential sites and mechanisms which mediate these salutary effects.

Animals↗

Comparison of thyrotropin-releasing hormone (TRH), naloxone, and dexamethasone treatments in experimental spinal injury.

We have shown that early treatment with either naloxone or thyrotropin-releasing hormone (TRH) significantly improves neurologic outcome after experimental spinal injury. Because these previous studies used different injury variables, no conclusion could be made about the relative effectiveness of the two drugs. In the present study naloxone and TRH treatment (each 2 mg per kilogram bolus, 2 mg per kilogram per hour for 4 hours) were directly compared; other cats received either dexamethasone (0.5 mg per kilogram bolus, 0.5 mg per kilogram per hour) or saline. The spinal cord was traumatized at C-7, using the Allen method; treatment was begun 1 hour after injury. Neurologic function was graded between 0 and 10, using an ordinal rating scale. Both TRH- and naloxone-treated animals had significantly better functional scores than saline controls at 6 weeks postinjury. Moreover, TRH-treated cats also showed significantly better neurologic recovery than either naloxone- or dexamethasone-treated animals. These findings confirm the therapeutic benefit of TRH and naloxone in experimental spinal injury and indicate that TRH treatment is most effective. In contrast, corticosteroid treatment was of no benefit in the present model.

Animals↗

Adrenalectomy blocks pressor responses to naloxone in endotoxic shock: evidence for sympathomedullary involvement.

The effects of naloxone on endotoxic hypotension in adrenalectomized and selectively adrenal demedullated rats were evaluated. In sham-operated rats, naloxone administered intracerebroventricularly (ICV) and intravenously (IV) produced an elevation of arterial pressure in this conscious rat model of endotoxemia. By contrast, both adrenalectomy and selective adrenal demedullation (wherein cortical function remained) not only enhanced the sensitivity to endotoxin-induced hypotension at least 10- to 15-fold, but also completely prevented the pressor response to ICV or IV naloxone. These results indicate that 1) adrenal enkephalins are probably not the endogenous opiates responsible for shock hypotension since their removal enhances shock susceptibility; 2) pituitary-derived endorphins in the circulation also appear to be uninvolved since naloxone fails to reverse shock hypotension despite reported elevations of circulating beta-endorphin in adrenalectomized rats; 3) since evidence indicates that naloxone acts centrally in intact endotoxemic rats and fails to do so following adrenal demedullation, we suggest that endotoxic shock results in an endogenous opiate inhibition of central autonomic sites regulating sympatho-medullary outflow. Naloxone, by reversing these actions, may result in the increased release of pressor substances from the adrenal medulla.

Adrenal Medulla↗

Naloxone or TRH fails to improve neurologic deficits in gerbil models of "stroke".

The effects of naloxone or thyrotropin releasing hormone (TRH) upon neurologic outcome were evaluated in gerbil models of cerebral ischemia. Following temporary bilateral carotid occlusion, hypotension was transiently reversed by these endorphin antagonists. However, neither drug altered time to awaken, time to death, or the severity of neurologic signs (ptosis, movement, retracted paws, circling, righting reflexes, seizures, or opisthotonus) when evaluated by a blinded rater. Hot plate escape and roto-rod performance were also unaltered by naloxone or TRH; TRH, but not naloxone, increased respiratory rates. Thus, the transient improvement of cardiorespiratory function produced by these drugs is unrelated to the morbidity and mortality associated with temporary cerebral ischemia in the gerbil. Additional studies evaluating the effects of naloxone or TRH upon neurologic outcome following permanent unilateral carotid occlusion also failed to show any therapeutic effects of these drugs. Both morphine and TRH exacerbated the effects of ischemia. Of gerbils which developed neurologic impairment, the deficit was usually ipsilateral to the occluded carotid. Collectively, these results indicate that neither naloxone nor TRH prevents ischemic deficits in the gerbil. Further studies with different cerebral ischemia models in other species are required to clarify the possible therapeutic effects of these drugs in experimental stroke.

Animals↗