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Biomedical subjects

J W Holaday

Publications and source records attributed to J W Holaday.

At least 55 records · Page 3Linked to original sources
PubMed1988

Neurologic deficits and neuronal injury in rats resulting from nonopioid actions of the delta opioid receptor antagonist ICI 174864.

The delta opioid receptor antagonist ICI 174864 produces postural abnormalities and barrel rolling after i.c.v. injection and hindlimb and tail flaccidity after spinal subarachnoid injection in rats. These effects appear to result from nonopioid characteristics of ICI 174864 because they are neither shared nor blocked by other opioid antagonists (naloxone, ICI 154129 and WIN 44,441-3) and are produced by two compounds (ICI 174644 and ICI 178173) that are structurally related to ICI 174864 but lack its delta antagonist properties. Barrel rolling and hindlimb paralysis are also produced by dynorphin A-related peptides; however, rats failed to demonstrate tolerance or cross-tolerance to the hindlimb paralytic actions of ICI 174864 or dynorphin A (1-13) after 7 days of continuous spinal intrathecal infusion of either of these compounds. Whereas hindlimb responses to low doses of ICI 174864 (1.6-6.2 nmol intrathecally) were usually transient, higher doses (6.2-25 nmol intrathecally) produced persistent hindlimb motor dysfunction, altered nociception, priapism, hindlimb edema, bladder infarction and atony and urinary incontinence. Neuronal and axonal changes in the lumbosacral spinal cords of rats with persistent and transient neurologic deficits provided direct evidence of the neuropathologic actions of ICI 174864 (3.1 and 6.2 nmol) and ICI 174644 (25 nmol). These results indicate that 1) use of ICI 174864 as a selective delta opioid receptor antagonist is potentially compromised by its nonopioid neuropathologic actions and 2) ICI 174864 and dynorphin A-related peptides are unique among opioid agonists and antagonists in sharing barrel rolling and hindlimb paralytic effects. A similar mechanism of action may underlie the shared nonopioid actions of these peptides.

Animals↗
PubMed1988

Naloxone potentiates epinephrine's pressor actions in endotoxemic rats.

Naloxone's pressor effects in shock may be mediated through antagonism of endogenous opioid inhibition of sympathoadrenal catecholaminergic systems. Since circulating catecholamine levels are not further elevated by naloxone in endotoxemic animals, it is possible that naloxone acts upon opiate receptors to enhance catecholamine actions at the receptor or postreceptor level. To investigate this hypothesis, we sought to determine whether naloxone treatment would augment the pressor actions of exogenous catecholamines (epinephrine) in normal and endotoxemic rats. Naloxone (3 mg/kg intravenous [i.v.] bolus followed by 3 mg/ml/hr infusion) significantly augmented the pressor response to 10, 20, and 50 micrograms/kg of i.v. epinephrine by 69%, 48% and 14%, respectively, in endotoxin (5 mg/kg, LD20, i.v.) -treated rats but not in normal rats. Likewise, the duration of the pressor response to epinephrine was significantly increased by naloxone. These findings suggest that the coadministration of naloxone and epinephrine may be of benefit in the treatment of shock.

Animals↗
PubMed1988

Hypercalcemia attenuates blood pressure response to epinephrine.

The potent alpha and beta adrenergic actions of epinephrine are probably mediated through an increase in free intracellular calcium concentration. Despite an absence of experimental evidence, many clinicians administer epinephrine with calcium to augment its cardiovascular effects. We evaluated the effects of calcium on epinephrine's pressor response in both normal and endotoxin-treated rats by administering epinephrine to animals made hypercalcemic with calcium chloride or hypocalcemic with the calcium chelator EGTA. EPI, given in incremental doses of 10, 20 and 50 micrograms/kg, produced incremental increases in mean arterial pressure. Calcium chloride infused i.v. at a rate of 50 mg/ml/hr significantly (P less than .05) blunted (50% decrease) the hypertensive response to 50 micrograms/kg epinephrine in normal animals. In endotoxin-treated rats, calcium chloride at 50 mg/ml/hr significantly blunted the hypertensive response to 10 micrograms/kg (73% decrease), 20 micrograms/kg (62% decrease) and 50 micrograms/kg (50% decrease) epinephrine. Endotoxemia plus calcium chloride at 25 mg/ml/hr also significantly blunted (30% decrease) the hypertensive response to 50 micrograms/kg EPI. By contrast, hypocalcemia produced by EGTA (30 mg/ml/hr) had no effect on epinephrine's hypertensive effects in normal or endotoxemic rats. Since calcium chloride significantly diminishes epinephrine's hypertensive effects in both normal and endotoxin-treated rats, the clinical use of calcium chloride along with epinephrine may not have a sound experimental basis.

Animals↗
PubMed1988

Morphine pellet-induced immunomodulation in mice: temporal relationships.

Morphine, an alkaloid known for its potent analgetic action, also affects a variety of immunologic functions. In the experiments reported here, the time course for the effect of 75-mg morphine pellet implants on spleen and thymus size and cellularity and in vitro proliferative responses of lymphocytes from male C3H/HeN mice is described. T lymphocyte proliferation in response to concanavalin A (Con A) was not significantly affected at 6 or 24 hr after morphine pellet implantation but was reduced at 48 and 72 hr. B lymphocyte proliferation in response to lipopolysaccharide was more sensitive to morphinization, as the response was reduced at the 24, 48 and 72 hr intervals after implantation of the morphine pellet. No differences in Con A- or lipopolysaccharide-induced proliferation were observed 96 hr after pellet implantation. Interestingly, a slight elevation of Con A-induced proliferation was observed 120 hr after morphine pellet implantation. By contrast with Con A proliferative data, lipopolysaccharide-induced proliferation of lymphocytes from morphine-treated mice was not different from placebo-pelleted mice at 120 hr. A marked atrophy of the spleen and thymus accompanied the reduced splenocyte proliferative responses of morphine-treated mice and was greatest at the 48 to 72 hr postimplantation interval. The attenuation of mitogen-induced proliferative responses and atrophy of immune organs was accompanied by hypothermia and a marked tolerance to the antinociceptive effect of morphine in morphine-pelleted mice at all of the time points that were monitored.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1987

Intrathecal dynorphin A1-13 and dynorphin A3-13 reduce rat spinal cord blood flow by non-opioid mechanisms.

Radiolabeled microspheres were used to examine the effects of paralytic intrathecal doses of dynorphin A (Dyn A1-13) and Dyn A3-13 on rat brain and spinal cord blood flows and cardiac output. Dyn A1-13 produced significant dose-related reductions in blood flow to lumbosacral and thoracic spinal cord without altering cardiac output and blood flow to brain and cervical spinal cord. Naloxone failed to block these effects. Dyn A3-13, which lacks opioid activity, also significantly reduced blood flow in lumbosacral spinal cord. Thus, the paralytic effects of Dyn A in the rat may involve reductions in spinal cord resulting from non-opioid actions of Dyn A.

Animals↗
PubMed1987

Release of multiple hormones by a direct action of interleukin-1 on pituitary cells.

Exposure to bacterial endotoxins has long been known to stimulate the release of anterior pituitary hormones; administration of endotoxin was at one time a common clinical test of anterior pituitary function. Endotoxin is a potent stimulus for production of the endogenous pyrogenic protein, interleukin-1 (IL-1), by macrophages and monocytes. The possibility that IL-1 has a direct effect on the secretion of hormones by rat pituitary cells in a monolayer culture was investigated. Recombinant human IL-1 beta stimulated the secretion of adrenocorticotropic hormone, luteinizing hormone, growth hormone, and thyroid-stimulating hormone. Increased hormone secretion into culture supernatants was found with IL-1 concentrations ranging from 10(-9) M to 10(-12) M. Prolactin secretion by the monolayers was inhibited by similar doses. These concentrations of IL-1 are within the range reported for IL-1 in serum, suggesting that IL-1 generated peripherally by mononuclear immune cells may act directly on anterior pituitary cells to modulate hormone secretion in vivo. Incubation of IL-1 solutions with antibody to IL-1 neutralized these actions. These pituitary effects of IL-1 suggest that this monokine may be an important regulator of the metabolic adaptations to infectious stressors.

Adrenocorticotropic Hormone↗
PubMed1987

Chronic morphine upregulates a mu-opiate binding site labeled by [3H]cycloFOXY: a novel opiate antagonist suitable for positron emission tomography.

CycloFOXY (17-cyclopropylmethyl-3,14-dihydroxy-4,5-alpha-epoxy-6-beta- fluoromorphinan) is a novel opiate antagonist synthesized as a ligand suitable for in vivo visualization of opiate receptors using positron emission transaxial tomography. In this paper we report that [3H]cycloFOXY labels two distinct opiate binding sites in rat brain membranes, tentatively identified as mu and kappa. Furthermore, chronic administration of morphine results in a selective up-regulation of the mu binding site. The implications of this finding for models of the opioid receptors and the mechanism of the sodium effect are discussed.

Alkylating Agents↗
PubMed1987

Immunosuppressive effects of chronic morphine treatment in mice.

In this report we describe the immunomodulatory effects of subcutaneous morphine pellets in mice, a model commonly used in the study of opiate tolerance and dependence. Mice given a single 75 mg morphine pellet displayed marked atrophy and reduced cellularity of the spleen and thymus, and an attenuated lymphocyte proliferative response to T- and B-cell mitogens (concanavalin A and bacterial lipopolysaccharide, respectively). These immunosuppressive effects were observed 72 hr following implantation of the pellet, a time point by which the mice also had developed tolerance to the antinociceptive effect of the pellet. Splenic and thymic atrophy with reduced mitogen-induced lymphocyte proliferative responses and opiate tolerance were also apparent in mice subjected to a multiple pellet implantation schedule. However, implantation of a pellet containing 37.5 mg morphine did not suppress mitogen-stimulated lymphocyte proliferation, which was slightly elevated in this group. These findings concur with other observations suggesting immunosuppression with morphine tolerance. Furthermore, we suggest that chronic morphine treatment acts as a pharmacologic stressor that mimics behavioral stress.

Animals↗
PubMed1987

Glucagon's chronotropic action is calcium dependent.

Evidence is increasing that many anesthetics and cardiovascular agents alter cellular Ca kinetics and flux. In prior work we demonstrated that the tachycardic effects of glucagon were significantly blunted by Ca channel blockade, but not by beta adrenergic receptor blockade. Thus, the chronotropic effects of glucagon may be dependent upon extracellular Ca levels. Based upon these observations, we tested the hypothesis that changes in circulating ionized Ca concentrations may alter glucagon's ability to increase heart rate in rats. In conscious normocalcemic rats, glucagon's tachycardic actions were dose related with peak effects obtained at 1 to 2 min and persisting approximately 10 min after 1.0 mg/kg of glucagon. The effects of altered Ca levels on glucagon tachycardia were evaluated in three groups of rats: 1) rats rendered hypercalcemic by the infusion of Ca chloride (10, 50 or 100 mg/ml/hr); 2) rats rendered hypocalcemic by infusion of the Ca chelator EDTA (15 or 30 mg/ml/hr); and 3) normocalcemic rats infused with saline. Normocalcemic rats had a mean ionized Ca level of 4.73 mg/dl. In rats, increasing Ca chloride doses resulted in increasing mean serum ionized Ca levels (5.24, 8.35 and 15.2 mg/dl, respectively), whereas increasing doses of EDTA produced progressive decreases in mean ionized Ca (3.62 and 2.13 mg/dl, respectively). Severe hypo (2.13 mg/dl)- or hypercalcemia (15.2 mg/dl) significantly blunted glucagon's chronotropic action (51 and 44%, respectively). From these data, we conclude that glucagon has its maximal tachycardic action at physiologic Ca levels (being blunted by both hyper- and hypocalcemia), indicating that this effect of glucagon is Ca dependent.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic beta-Antagonists↗
PubMed1987

Repeated electroconvulsive shock: effect on sodium dependency and regional distribution of opioid-binding sites.

The effects of single and repeated electroconvulsive shock (ECS) on the binding of [3H]diprenorphine to rat brain membranes was studied. Repeated but not single ECS significantly increased the Bmax of [3H]diprenorphine binding when measured in the absence but not in the presence of NaCl. On a regional basis the effect of ECS was greatest in the olfactory bulb, nucleus accumbens, and striatum. More modest increases were found in the hippocampus, amygdala, septum, hypothalamus, and pyriform cortex. No significant effect was found in the brainstem and frontal cortex. Although the regional rank order of receptor increase does not match the receptor distribution of brain enkephalins, the receptor increase does parallel the regional increases in brain enkephalins following ECS.

Animals↗
PubMed1987

Thyrotropin releasing hormone: effects in monkeys and dogs subjected to experimental circulatory shock.

We tested the hypothesis that thyrotropin releasing hormone (TRH) would improve cardiovascular function and survival in circulatory shock by opposing the adverse effects of endogenous opioids and other pathophysiologic mediators. Cynomolgus monkeys and mongrel dogs were anesthetized and catheterized to measure mean arterial pressure (MAP) and left ventricular contractility (LV dp/dtmax). Hemorrhagic shock was induced by bleeding into a reservoir to achieve and maintain MAP at 45 mm Hg for one hour. Endotoxic shock was produced by the iv injection of an LD80 dose of Escherichia coli lipopolysaccharide endotoxin (3 mg/kg in dogs and 5 mg/kg in monkeys). Animals were treated iv with either TRH (2 mg/kg plus 2 mg/kg X h) or equivolume saline. TRH significantly increased MAP and LV dp/dtmax in primate hemorrhagic and endotoxic shock. In primate hemorrhagic shock, TRH significantly (p = .02) improved survival (alive/total = 4/5 vs. 0/5). However, TRH had no effect on survival in endotoxemic primates. In contrast, TRH treatment in dogs produced only a transient hemodynamic response after endotoxemia and no significant hemodynamic effect after acute hemorrhage (even at twice the TRH dose). TRH did not affect survival in either dog model of circulatory shock. Based on extensive evidence with the opiate receptor antagonist naloxone in other studies, endogenous opioids play a role in the cardiovascular depression in primate and canine circulatory shock. From these studies with TRH, we conclude that TRH is relatively ineffective in canine circulatory shock, and physiologic antagonism of the adverse effects of opioids and other cardiodepressant substances by TRH administration may prove to be a useful alternative treatment of primate hemorrhagic shock.

Animals↗
PubMed1986

Morphine tolerance increases mu-noncompetitive delta binding sites.

In light of more recent knowledge concerning endogenous opioid peptides and their multiple opiate receptors, we reevaluated the effects of morphine tolerance on opiate receptor binding parameters. Rats were implanted with morphine or placebo pellets, and [3H][D-Ala2,D-Leu5]enkephalin ([3H]DADL) was used to label brain membranes. Utilizing the technique of binding surface analysis, we observed a selective 47% up-regulation of lower affinity [3H]DADL binding sites (mu-noncompetitive delta binding sites) in morphine pelleted rats. To corroborate these results, we treated brain membranes with the site directed alkylating agent FIT (N-phenyl-N-[1-(2-p-isothiocyanato)phenyl-ethyl)-4-piperidinyl] propanamide), which results in membranes highly enriched with the lower affinity [3H]DADL binding site. Scatchard plots of [3H]DADL binding to FIT-treated membranes also revealed that chronic morphine treatment produced a 60-65% up-regulation of the mu-noncompetitive delta binding site. These data indicate that chronic morphine alters a selective subpopulation of opiate receptors that may play a role in the mechanisms of opiate tolerance and physical dependence.

Animals↗
PubMed1986

Endogenous opioids in spinal cord injury: a critical evaluation.

Based upon evidence that opioid antagonists improve neurological outcome following either traumatic or ischemic spinal cord injury, endogenous opioids have been implicated in the pathophysiology of these disorders. Naloxone improved both spinal cord perfusion and neurological function following traumatic spinal cord injury in cats, and was subsequently observed to improve neurological outcome following ischemic spinal cord injury in rabbits. Using several opioid antagonists with varied selectivities for different types of opioid receptors, it was suggested that kappa opioid receptors are involved in both these models of spinal cord injury. In addition, spinal cord trauma in rats is associated with increased concentrations of the endogenous kappa agonist dynorphin A, and increased kappa opioid receptor binding capacity localized to the injury site. Furthermore, dynorphin A induces hindlimb and tail flaccidity following intrathecal injection in rats. Thus, the pathophysiological effects of endogenous opioids in spinal cord injury have been proposed to involve dynorphin A interactions with kappa opioid receptors. However, disparities between the actions of intrathecally injected dynorphin A in rats and the presumed actions of endogenous dynorphin A in cat and rabbit spinal cord injury have been revealed in recent experiments. Paralysis resulting from intrathecal dynorphin A is not altered by opioid receptor antagonists or TRH, produced by non-opioid dynorphin A fragments but not by other selective kappa opioid agonists, and associated with non-opioid mediated reductions in spinal cord blood flow. Furthermore, despite reports of endogenous opioid changes following rat spinal cord trauma, in contrast to cats and rabbits, naloxone failed to improve neurological outcome following traumatic rat spinal cord injury. Thus, the specific endogenous opioids and opioid receptor types involved in spinal cord injury remain to be resolved, and do not appear to be universal among different models of spinal cord injury in different species. Additionally, dynorphin A may participate in spinal cord injury mechanisms in the rat through non-opioid actions.

Animals↗
PubMed1986

Electroconvulsive shock activates endogenous opioid systems: behavioral and biochemical correlates.

From the evidence reviewed above, there is little doubt that ECS activates endogenous opioids and modifies their receptors. Thus, this form of SIA is accompanied by many other corollaries of opioid-like actions, including catalepsy, similar EEG patterns, common autonomic effects, and increases in opioid receptor binding sites. Investigations have further indicated that the amnestic effects of ECS can also be attenuated by naloxone, and that pituitary-derived opioids may play an important role as a predominant source of opioids that contribute to these opioid-like effects following ECS. It is hoped that these many attempts to correlate SIA with other behavioral and physiological endpoints following ECS will provide a more global perspective on the role of endogenous opioid systems in ECS. From these results, it is suggested that other forms of SIA may also share many of these properties in common with ECS-induced SIA. Nonetheless, ECS and other forms of SIA, such as cold water exposure and restraint, share with ECS a common history of clinical use in the treatment of human depression. It is possible that the common thread linking these experimental observations to endogenous opioid systems may provide new insights into the cause and treatment of mental disorders as well as the perception of pain.

Analgesia↗
PubMed1986

Glucagon: endocrine effects and calcium involvement in cardiovascular actions in dogs.

Although the cardiovascular effects of glucagon are understood, its mechanism(s) of action remains unclear. We studied the effects of increasing doses of glucagon (0.001, 0.01, 0.1 mg/kg) on cardiovascular responses in dogs relative to concurrent measurements of circulating glucagon, cyclic AMP, glucose, norepinephrine, epinephrine, triiodothyronine, thyroxine, and cortisol levels. Glucagon-induced increases in plasma cyclic AMP, glucose, and catecholamine concentrations paralleled the heart rate response to glucagon administration. Further studies were conducted to evaluate the role of beta-adrenergic function as well as calcium in mediating glucagon's actions. The tachycardic effects of glucagon (0.01 mg/kg) were unaltered by prior beta-adrenergic receptor blockade with propranolol (3.5 mg/kg total dose). The calcium antagonist verapamil (0.2 mg/kg bolus then 7.5 micrograms/kg/min/infusion) prevented glucagon-induced increases in heart rate. However, the coadministration of glucagon (0.01 mg/kg) with calcium (1.0, 5.0, 10.0, or 50.0 mg/kg) did not alter glucagon's cardiovascular effects. These data indicate that glucagon is a potent tachycardiac agent that also elevates circulating endocrine-related substances. The antagonism of glucagon's tachycardiac effects by verapamil suggests that glucagon's action may be via glucagon-induced calcium movement through calcium channels, although extracellular calcium changes do not alter glucagon's effect. Furthermore, the persistence of glucagon's cardiovascular actions following beta-adrenergic blockade indicates the potential clinical utility of glucagon in reversing the adverse effects of beta-blocker overdoses, and its potential usefulness in treating circulatory shock in "beta-blocked" patients.

Animals↗
PubMed1986

Upregulation of the mu-noncompetitive delta binding site by chronic morphine administration: effect of preincubating membranes in 400 nM sodium chloride.

Rats treated chronically with morphine were found to have an increased number of mu-noncompetitive delta binding sites. The increase in the Bmax was 39% and the enhancement was blocked by pre-incubation in 50 mM Tris, pH 7.4 with 400 mM NaCl for one hour at 25 degrees C. These findings are consistent with the removal of newly manifested binding sites being a specific property of sodium, by analogy with previous studies where sodium has been shown to extract extrinsic proteins from red cell ghosts.

Animals↗
PubMed1986

Intrathecal dynorphin A (1-13) and (3-13) reduce spinal cord blood flow by non-opioid mechanisms.

Dynorphin A (Dyn A)-related peptides have been implicated in the pathophysiology of spinal cord injury in part because their intrathecal (i.t.) injection causes hindlimb paralysis. The effects of paralytic doses of i.t. Dyn A (1-13) and Dyn A (3-13) on spinal cord blood flow and cardiac output were examined in rats using radiolabeled microspheres. Both Dyn A (1-13) and Dyn A (3-13) significantly reduced blood flow in lumbosacral spinal cord without altering cardiac output. Pretreatment with naloxone failed to block these reductions in blood flow. Thus, the paralytic effects of Dyn A may result from non-opioid actions of Dyn A to reduce spinal cord perfusion.

Animals↗