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Biomedical subjects

J W Holaday

Publications and source records attributed to J W Holaday.

At least 73 records · Page 4Linked to original sources
PubMed1986

Dynorphin A (1-13): in vivo opioid antagonist actions and non-opioid anticonvulsant effects in the rat flurothyl test.

Dynorphin A (1-13) acutely elevated the seizure threshold (ST) to the convulsant flurothyl, and this action was not blocked by naloxone. Increases in ST were also observed following i.c.v. injections of the non-opioid fragment dynorphin A (3-13). Pretreatment with dynorphin A (1-13), but not dynorphin A (3-13), non-competitively blocked the anticonvulsant effect of the mu selective opioid DAGO. Furthermore, pretreatment with dynorphin A (1-13) antagonized the delta antagonist properties of naloxone or ICI 154,129 in this seizure model. Thus, in addition to its non-opioid anticonvulsant effects, dynorphin A (1-13) exhibits unique antagonist actions which appear to be specific for the active opioid fragment.

Animals↗
PubMed1986

U50,488, a highly selective kappa opioid: anticonvulsant profile in rats.

Subcutaneous or i.c.v. administration of U50,488, a highly selective kappa opioid agonist, resulted in a dose-and time-dependent anticonvulsant action in rats. The anticonvulsant effect was seizure-specific; thus, U50,488 protected against supramaximal electroshock seizures but failed to raise the threshold of flurothyl-induced convulsions. The ED50 for s.c. U50,488 was 8.6 mg/kg, with a duration of action longer than 8 hr. In contrast, the ED50 for i.c.v. U50,488 was 103.8 micrograms, lasting approximately 1 hr. The anticonvulsant effect of U50,488 was partially antagonized by high (10.0 mg/kg), but not low (1.0 mg/kg), doses of s.c. administered naloxone. Results indicate that U50,488 is an efficacious, long-acting anticonvulsant against supramaximal, but not chemical threshold, seizures in rats. Furthermore, the results with naloxone suggest that this effect of U50,488 is mediated by non-mu (probably kappa) binding sites. This structurally novel nonpeptide opioid may offer new insights into the development of therapeutically effective agents in the treatment of grand mal or partial epilepsies.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗
PubMed1986

Effects of naloxone and thyrotropin-releasing hormone on plasma catecholamines, corticosterone, and arterial pressure in normal and endotoxemic rats.

To investigate the possible involvement of the adrenal cortex and medulla in the cardiovascular effects of naloxone and thyrotropin-releasing hormone (TRH) in endotoxic shock, plasma epinephrine, norepinephrine, dopamine, and corticosterone were measured along with hemodynamic variables during naloxone and TRH treatment of normal and endotoxemic rats. In the absence of endotoxemia, naloxone (3 mg/kg, iv) did not significantly alter mean arterial pressure or plasma catecholamine or corticosterone levels. In contrast, following TRH administration (4 mg/kg, iv), an increase in mean arterial pressure was associated with significant increases in plasma epinephrine, norepinephrine, and corticosterone. TRH also produced a transient increase in plasma glucose levels. Endotoxic shock was associated with marked increases in plasma catecholamine levels, with epinephrine levels showing the greatest change, and significant though less pronounced increases in corticosterone. Both naloxone and TRH significantly elevated mean arterial pressures of endotoxemic rats, although neither of these compounds significantly altered the plasma catecholamine and corticosterone responses to endotoxin. Naloxone and TRH also failed to alter endotoxin-induced changes in plasma glucose levels. These results indicate that the cardiovascular effects of naloxone and TRH in endotoxic shock do not simply arise from an enhancement of adrenal catecholamine or corticosterone secretion.

Animals↗
PubMed1986

Central glucagon antagonizes morphine- and stress-induced antinociception in the mouse.

Previously, we have demonstrated that glucagon antagonizes morphine-induced antinociception in the rat (Malcolm et al. 1985). In the present studies we have shown that central injection of glucagon antagonizes morphine- and stress-induced antinociception in the mouse. Since stress-induced antinociception is mediated by the activation of endogenous opioid systems, these findings provide the first evidence for glucagon's ability to antagonize endogenous opioid actions.

Analgesia↗
PubMed1985

The anticonvulsant effects of DADLE are primarily mediated by activation of delta opioid receptors: interactions between delta and mu receptor antagonists.

Dose-response comparisons of the ability of the selective delta antagonist ICI 154,129 (12.5-50 nmol), the nonselective antagonist naloxone (29-290 nmol), and the irreversible selective mu antagonist beta-fNA (1.3-21 nmol) to alter the threshold response to DADLE or etorphine was studied in the rat flurothyl seizure test. DADLE (35 nmol, i.c.v.) and etorphine (122 nmol/kg, s.c.) both caused increases in seizure threshold which were differentially antagonized by pretreatment (i.c.v.) with the respective antagonists. For DADLE, only ICI 154,129 and naloxone produced a dose-related blockade of the increase in seizure threshold, with ICI 154,129 being more potent than naloxone. In contrast, the anticonvulsant action of etorphine was not antagonized by ICI 154,129 (50 nmol), but was blocked by a low dose of naloxone (29 nmol) or beta-fNA (21 nmol). In addition, prior occupancy of mu-sites with beta-fNA (21 nmol) significantly diminished the abilities of either ICI 154, 129 (50 nmol) or naloxone (290 nmol) to antagonize the anticonvulsant action of DADLE. The results of this study demonstrated that the effects of DADLE to increase seizure threshold in the rat were primarily mediated by activation of a delta-opioid receptor system. Furthermore, evidence has been provided for a functional interaction between delta and mu receptors in the opioid regulation of seizure threshold.

Animals↗
PubMed1985

Endogenous opioid systems: physiological role in the self-limitation of seizures.

Immediately following a seizure, the severity of subsequent seizures is significantly reduced. The involvement of endogenous opioid systems as a physiological regulator of this postseizure inhibition was studied in rats using repeated maximal electroshock (MES) seizures. Both the opiate antagonist (-)-naloxone and morphine tolerance abolished the progressive seizure protection associated with repeated MES. We propose that endogenous opioids, activated by a prior seizure, provide a central homeostatic inhibitory mechanism which may be responsible for the initiation of a postictal refractory state in the epileptic.

Animals↗
PubMed1985

Blood-brain barrier: endogenous modulation by adrenal-cortical function.

The blood-brain barrier restricts the passage of molecules from the blood to the brain. The permeability of the barrier to iodine-125-labeled bovine serum albumin was examined in rats that had undergone adrenalectomy, adrenal demedullation, and corticosterone replacement. Adrenalectomy, but not adrenal demedullation, increased the permeability of brain tissue to the isotopically labeled macromolecule; corticosterone replacement reversed this effect. These results indicate that the blood-brain barrier may be hormonally regulated; that is, the pituitary-adrenal axis may physiologically modulate the permeability of the brain microvasculature to macromolecules.

Adrenal Cortex↗
PubMed1985

Determination of chlorpromazine and its major metabolites by gas chromatography/mass spectrometry: application to biological fluids.

A method for the quantitative determination of chlorpromazine and five of its major metabolites in a single sample of biological fluid in the ng/ml range has been developed utilizing gas chromatography/mass spectrometry with selected ion recording. The assay is highly specific and quantification is accomplished by an inverse stable isotope dilution technique, using deuterium-labeled variants of the compounds as internal standards. In this way the concentrations of chlorpromazine and five of its major metabolites (the sulfoxide, the N-oxide, the monodemethylated, the didemethylated, and the 7-hydroxylated compounds) can be determined in biological fluids. Levels in humans have been measured both in plasma and in red blood cells and are compared to those found in related in vitro studies.

Biotransformation↗
PubMed1985

Opioid effects on plasma concentrations of luteinizing hormone and prolactin in the adult male rhesus monkey.

The role of endogenous opioid peptides (EOP) in the neuroendocrine control of primate gonadotropin and PRL secretion was studied in nonrestrained adult male rhesus monkeys. Morphine (0.5-1.0 mg/kg) was used as the prototype opiate, beta-endorphin (beta-END; 10-20 micrograms/kg) and [D-Ala2,D-Leu5] enkephalin (DADLE; 5-20 micrograms/kg) were used as representatives of EOP, and naloxone (0.5-2.0 mg/kg) was used as an opiate receptor blocker. Drugs were administered and blood was collected (at 20-min intervals for 4 h) through an indwelling jugular catheter. LH and PRL levels were measured in plasma by RIA. Intravenous administration of morphine (1.0 mg/kg) and DADLE (10 micrograms/kg) produced decreases in LH levels of 64% and 40%, respectively. These decreases occurred within 1 h after drug injections and lasted for approximately 3 h. beta-END had no effect on LH levels. Naloxone, at all doses studied, significantly increased LH levels (5- to 8-fold). The LH rises occurred within 20 min and lasted for up to 2 h. Both morphine and beta-END produced immediate increases in PRL, which remained elevated for 3 h. DADLE did not alter PRL levels. Naloxone (1.0 and 2.0 mg/kg) decreased PRL concentrations (45% and 60%, respectively). Pretreatment with morphine or DADLE did not alter the LH response to GnRH (100 micrograms) stimulation, indicating a hypothalamic site of action for the opioid inhibition of LH release. Naloxone administration reversed the inhibitory effects of morphine and DADLE on LH. The stimulatory effect of morphine on PRL levels was also reversed by naloxone. These studies further define the postulated physiological role of EOP in primate reproductive neuroendocrinology. Based on receptor selectivities of these opioid agonists, the inhibition of LH may be mediated by delta-receptors, whereas PRL release appears to be mu-mediated.

Animals↗
PubMed1985

Opioids and neuropeptides: mechanisms in circulatory shock.

Endogenous opioid systems are activated in stressful situations such as circulatory shock. The opiate antagonist naloxone improves cardiovascular function in several models of shock caused by endotoxemia, hypovolemia, anaphylaxis, and spinal trauma. The ergotropic neuropeptide, thyrotropin-releasing hormone, in supraphysiological doses, also improves cardiovascular function in these shock models, but this effect does not result from action at the opiate receptor. For both these agents a central nervous system (CNS) site of action has been partially characterized. A variety of neuropeptides, including the opioids, seem capable of modulating autonomic function through their CNS actions. In addition, they may play a role in peripheral integration and transmission of autonomic nervous activity by actions at the ganglia and/or at nerve endings. Some neuropeptides also have direct autacoid effects on cells, including those of the microvasculature. This raises new questions concerning possible peripheral functions of neuropeptides during circulatory shock, and the nature of their interactions with other potential shock mediators such as monokines and arachidonic acid derivatives.

Adrenal Glands↗
PubMed1984

ICI 154,129, a delta-opioid receptor antagonist raises seizure threshold in rats.

Acute i.c.v. administration of ICI 154,129 (100-600 micrograms), a delta-opioid receptor antagonist, raised the seizure threshold in a dose-related manner in rats exposed to flurothyl, a volatile convulsant. Pretreatment with naloxone or beta-funaltrexamine (beta-FNA) antagonized this effect. Lower doses of ICI 154,129 (12.5-50 micrograms), which did not influence seizure threshold, selectively antagonized the anticonvulsant action of [D-Ala2,D-Leu5]enkephalin (DADLE) in the same procedure. Consequently, it may be inferred that ICI 154,129 at high doses has mu-agonist and at low doses delta-antagonist properties in the rat flurothyl test.

Animals↗
PubMed1984

Electroencephalographic assessment of the role of delta receptors in opioid peptide - induced seizures.

DPDPE ([D-Pen2, D-Pen5]-Enkephalin) and DPLPE ([D-Pen2, L-Pen5]-Enkephalin) are conformationally-constrained cyclic analogs of enkephalin with high selectivity for delta opioid receptors. Intracerebroventricular (i.c.v.) administration of each analog acutely produces a complex EEG response in rats characterized by a dose-related increase in spectral power and HVSA (peak frequency of 5.0 Hz) during behavioral stupor, and a theta driving (5.25-8.0 Hz) associated with intense behavioral arousal. These effects were antagonized by high (10 mg/kg), but not low (1.0 mg/kg), doses of naloxone. Both analogs failed to cause EEG or convulsive seizures. In contrast, i.c.v. administration of DADLE ([D-Ala2, D-Leu5]-Enkephalin), an enkephalin analog with activity at both mu and delta binding sites, caused initial nonconvulsive EEG seizures followed by HVSA (3.0 Hz); theta driving was not evident. The incidence of the seizures was dose-related and antagonized by very low doses of naloxone (0.01-1.0 mg/kg). Collectively, the inability of DPDPE and DPLPE to cause seizure activity, and the marked sensitivity of DADLE-induced EEG seizures to naloxone, suggest that delta receptors are not directly responsible for DADLE-induced EEG seizure activity. Furthermore, these data implicate mu opioid receptors as the primary sites responsible for enkephalin-induced seizures.

Animals↗
PubMed1984

ICI 174864, a putative delta opioid antagonist, reverses endotoxemic hypotension: pretreatment with dynorphin 1-13, A kappa agonist, blocks this action.

The putative delta opioid receptor antagonist ICI 174864 (3 mg/kg, i.v.) significantly reversed endotoxic shock hypotension at a dose which lacked significant pressor actions in normotensive, non-endotoxemic rats. In contrast, dynorphin 1-13, when administered either before (0.1 or 1.0 mg/kg, i.v.) or following (1.0 mg/kg, i.v.) injection of endotoxin, failed to alter the course of ensuing circulatory shock. Additionally, pretreatment with dynorphin 1-13 prevented the subsequent reversal of endotoxemic hypotension by ICI 174864. It is concluded that: 1) delta opioid receptors mediate the endogenous opioid component of endotoxic shock hypotension; and 2) functional interactions occur between ligands for mu, delta, and kappa opioid receptor subtypes, which may predict potential interactions with a common macromolecular opioid receptor complex.

Animals↗
PubMed1984

Opiate antagonists in shock and trauma.

Circulatory shock and pain were associated as frequent consequences of surgery and trauma prior to the development of anesthetics. The recent discovery of the endogenous opioid systems affords the opportunity to link the occurrence of pain and circulatory shock at a functional level. The involvement of opioid systems in endogenously and exogenously induced analgesia is well established. In this review, evidence is presented indicating that endogenously activated opioid systems contribute to the pathophysiology of circulatory shock following such diverse causes as endotoxemia, hemorrhage, and spinal cord trauma. The opiate antagonist naloxone (Narcan), acting to oppose endogenous opiates, rapidly reverses the hemodynamic, metabolic, and biochemical sequelae of shock in experimental animal models. Additionally, naloxone has been shown to prevent paralysis following acute cervical spinal cord injury. As with all drugs, several physiologic and pathophysiologic circumstances limit the usefulness of naloxone in reversing shock and improving tissue perfusion. They include acidosis, hypothermia, interactions with administered steroids, and the potential for antagonizing opioid-induced analgesia, which may exacerbate pain in the traumatized patient. Two approaches have yielded potential ways to circumvent these limitations: first, the development of specific opioid-receptor antagonists, which reverse shock without affecting opioid analgesia, and second, the pharmacologic use of thyrotropin releasing hormone (TRH), which acts through its own effector system, independent of endogenous opioid receptors, to produce autonomic effects that reverse shock in experimental animals without affecting analgesia.

Animals↗
PubMed1984

Multiple opioid receptors in endotoxic shock: evidence for delta involvement and mu-delta interactions in vivo.

The use of selective delta and mu opioid antagonists has provided evidence that delta opioid receptors within the brain mediate the endogenous opioid component of endotoxic shock hypotension. The selectivity of these delta and mu antagonists was demonstrated by their differing effects upon morphine analgesia and endotoxic hypotension. The mu antagonist beta-funaltrexamine, at doses that antagonized morphine analgesia, failed to alter shock, whereas the delta antagonist M 154,129: [N,N-bisallyl-Tyr-Gly-Gly-psi-(CH2S)-Phe-Leu-OH] (ICI) reversed shock at doses that failed to block morphine analgesia. Therefore, selective delta antagonists may have therapeutic value in reversing circulatory shock without altering the analgesic actions of endogenous or exogenous opioids. Additional data revealed that prior occupancy of mu binding sites by irreversible opioid antagonists may allosterically attenuate the actions of antagonists with selectivity for delta binding sites. For endogenous opioid systems, this observation provides an opportunity to link in vivo physiological responses with receptor-level biochemical interactions.

Allosteric Regulation↗