Mary Ann Werz - Academia.edu (original) (raw)

Papers by Mary Ann Werz

Neuropeptides, Dec 1, 1984

PubMed, Oct 1, 1987

The effects of selective mu, delta and kappa opioid agonists and antagonists were studied on soma... more The effects of selective mu, delta and kappa opioid agonists and antagonists were studied on somatic calcium-dependent action potentials recorded from mouse dorsal root ganglion (DRG) neurons grown in dissociated cell culture. The mu selective agonist, PL 017, and the delta selective agonist, [D-Pen2, L-Pen5] enkephalin (DPLPE), reduced action potential duration of a subpopulation (21/56) of DRG neurons. Leucine-enkephalin reduced action potential duration of all neurons sensitive to PL 017 or DPLPE, whereas 85% of neurons responding to leucine-enkephalin responded to either PL 017 or DPLPE. Only 15% of neurons responded to both PL 017 and DPLPE. There was no significant difference in the response to PL 017 or DPLPE when compared to leucine-enkephalin. In another experiment, the kappa selective agonist dynorphin A (DYN A), PL 017 and DPLPE reduced action potential duration of a subpopulation (15/67) of DRG neurons. There was a heterogeneous response among neurons to PL 017, DPLPE and DYN A inasmuch as 21.4% of neurons responded to all three agonists, 35.7% responded to PL 017 and DYN A, 35.7% responded only to PL 017 and 7.1% responded only to DYN A. Responses to the mu selective agonist PL 017 were antagonized by the reversible opioid antagonist naloxone and the selective mu antagonist SMS 201-995 in a concentration-dependent fashion. Responses to PL 017 were not altered by the selective delta antagonist ICI 174864. Responses to PL 017 were reduced by the irreversible, selective mu antagonists beta-funaltrexamine and naloxonazine in a concentration-dependent fashion.(ABSTRACT TRUNCATED AT 250 WORDS)

PubMed, Sep 1, 1985

Barbiturates have been shown to reduce presynaptic release of neurotransmitter. It is likely that... more Barbiturates have been shown to reduce presynaptic release of neurotransmitter. It is likely that barbiturates alter transmitter release by decreasing calcium entry since barbiturates decrease calcium influx into synaptosomes and reduce the maximal rate of rise and duration of calcium-dependent action potentials. The mechanisms of barbiturate action on neuronal calcium entry have been studied using mouse dorsal root ganglion neurons in cell culture. Dorsal root ganglion neuron action potentials have a calcium-dependent component which is decreased by the barbiturates, pentobarbital (50-500 microM) and phenobarbital (500-2000 microM). Calcium-dependent action potential after hyperpolarization was also decreased by barbiturates. Intracellular injection of the potassium channel blocker, cesium, enhanced barbiturate actions. In voltage-clamp studies, barbiturates reduced inward calcium current and calcium chord conductance without altering the leak conductance which is present after all calcium conductance was blocked by application of cadmium ions (100 microM). Calcium current inactivation was accelerated by barbiturates but unaffected by cadmium. We conclude that barbiturates reduce calcium conductance by enhancing calcium channel inactivation or by producing open channel block of calcium channels.

PubMed, Jul 1, 1985

Opioid peptides decrease somatic calcium-dependent action potential duration of a subpopulation o... more Opioid peptides decrease somatic calcium-dependent action potential duration of a subpopulation of mouse dorsal root ganglion (DRG) neurons grown in dissociated cell culture. Based on rank order of potency and naloxone sensitivity, both mu and delta opioid receptors were demonstrated on the somata of DRG neurons and were shown to have a heterogeneous distribution. The purpose of the present investigation was to determine the actions of dynorphin gene products, dynorphin A, dynorphin B, dynorphin A(1-8), dynorphin A(1-9), alpha-neoendorphin and beta-neoendorphin on DRG neuron somatic calcium-dependent action potentials and to compare the actions of dynorphin and neoendorphin peptides to the action of morphiceptin, a mu receptor-selective ligand, and Leu-enkephalin, a delta receptor-preferring ligand. We report that the dynorphin and neoendorphin peptides decreased DRG neuron somatic calcium-dependent action potential duration in a portion of DRG neurons, an action that was dose-dependent and was antagonized by naloxone. DRG neuron responses to the dynorphins and neoendorphins differed from responses to morphiceptin and Leu-enkephalin. First, many DRG neurons responded to dynorphin A but not to morphiceptin or Leu-enkephalin. Second, dynorphin A responses, unlike responses to morphiceptin or Leu-enkephalin, were present after intracellular injection of cesium, a potassium channel blocker. Dynorphin A effectiveness was decreased after deletions at the carboxy-terminus and Leu-enkephalin [dynorphin A(1-5)] was inactive at 10 microM. Thus, on DRG neurons in cell culture, dynorphins and neoendorphins act at opioid receptors distinct from mu and delta receptors, possibly kappa receptors.(ABSTRACT TRUNCATED AT 250 WORDS)

PubMed, Nov 1, 1983

Previously, it has been reported that opioid peptides decrease the calcium component of action po... more Previously, it has been reported that opioid peptides decrease the calcium component of action potentials in a dose-dependent and naloxone-reversible manner consistent with mediation by opiate receptors. To clarify the relation of mu and delta opiate receptors to decreases of somatic calcium-dependent action potential duration, we investigated the potency of two opioid peptides which have different affinities for mu and delta opiate receptors, Leu-enkephalin and morphiceptin. We predicted that Leu-enkephalin would be about 1000-fold more potent than morphiceptin on dorsal root ganglion (DRG) neurons if delta receptors mediated decreases of DRG neuron somatic calcium-dependent action potentials, but that these ligands would be approximately equipotent if mu receptors mediated opiate actions. Additionally, because naloxone has been reported to have a higher affinity for mu receptors in comparison with delta receptors, we investigated agonist sensitivity to naloxone antagonism. When morphiceptin and Leu-enkephalin were tested at equimolar concentrations on individual DRG neurons, a heterogeneous pattern of response to the two opioid peptides was obtained. The response pattern ranged from Leu-enkephalin and morphiceptin producing equal effects to Leu-enkephalin, but not morphiceptin, decreasing action potential duration. DRG neurons that responded only to Leu-enkephalin were approximately 100-fold less sensitive to naloxone antagonism than DRG neurons that responded equally well to both opioid peptides. DRG neurons that responded to both opioid peptides but better to Leu-enkephalin were intermediate in sensitivity to naloxone antagonism. Our results suggest that both mu and delta opiate receptors mediate decreases in somatic calcium-dependent action potentials of DRG neurons.(ABSTRACT TRUNCATED AT 250 WORDS)

Brain Research, Sep 1, 1984

The actions of diazepam and its p-chloro-derivative Ro 5-4864 were compared on mouse spinal cord ... more The actions of diazepam and its p-chloro-derivative Ro 5-4864 were compared on mouse spinal cord and dorsal root ganglion neurons in cell culture. Diazepam enhanced but Ro 5-4864 reduced iontophoretic GABA responses in a concentration-dependent manner. Both diazepam and Ro 5-4864 limited sustained, high frequency repetitive firing of spinal cord neurons but diazepam was more potent. Ro 5-4864 was, however, more potent than diazepam in inhibiting spontaneous neuronal activity of spinal cord neurons and reducing the duration of calcium-dependent action potentials of dorsal root ganglion neurons. The differing actions of diazepam and Ro 5-4864 may account for the contrasting pharmacological spectra of the two benzodiazepines.

The Society for Neuroscience Abstracts, Apr 24, 1984

The Journal of Physiology, 1986

1. Adenosine and several of its analogues produced a concentration-dependent shortening of calciu... more 1. Adenosine and several of its analogues produced a concentration-dependent shortening of calcium-dependent action potential (c.a.p.) duration of mouse dorsal root ganglion (d.r.g.) neurones in dissociated cell culture. The following rank order of potency was obtained: N6-(L-phenylisopropyl)adenosine > N6-(D-phenylisopropyl)adenosine > N6-cyclohexyladenosine > 2-chloroadenosine > 1-methylisoguanosine > adenosine. Effects of adenosine agonists on c.a.p. duration were blocked by methylxanthine adenosine antagonists. Adenosine monophosphate (AMP) and cyclic AMP shortened c.a.p.s in d.r.g. neurones, while ATP also depolarized cells. 2. Voltage-clamp analysis revealed that the effect arose from reduction of a voltage-dependent calcium conductance. Adenosine agonists reduced depolarizationevoked inward currents but did not alter membrane conductance following blockade of calcium channels by cadmium. Additionally, adenosine reduced the instantaneous current-voltage slope (chord conductance) during step commands that produced maximal activation of voltage-dependent calcium conductance. 3. If effects of adenosine on neuronal somata and synaptic terminals are similar, adenosine agonists may inhibit neurotransmitter release in the central nervous system by inhibiting a voltage-dependent calcium conductance. Since effects of adenosine agonists did not correspond with their relative potencies as modulators of adenylate cyclase activity or inhibitors of neurotransmitter release in peripheral tissues, a novel adenosine receptor may be involved in regulation of this conductance.

Epilepsy & Behavior, Feb 1, 2005

Loss of consciousness limited to exercise should suggest a cardiovascular etiology even when clon... more Loss of consciousness limited to exercise should suggest a cardiovascular etiology even when clonic activity is reported. Infrequently, epilepsy patients report a preponderance of their seizures related to exertion. In these patients, seizures also occur independent of exercise. This is a report of a normal young adult woman with episodes of loss of consciousness limited to exercise. During cardiac stress testing with simultaneous electroencephalography, she developed generalized paroxysms of epileptiform discharges preceding a generalized tonic-clonic seizure. This case demonstrates the utility of simultaneous cardiac stress testing with electroencephalography in confirming exercise-related seizures and distinguishing epilepsy from syncope.

Neuroscience Letters, Jul 1, 1987

Therapeutics and Clinical Risk Management, Oct 1, 2008

The goal in managing patients with epilepsy is complete seizure freedom. Pharmacotherapeutic mana... more The goal in managing patients with epilepsy is complete seizure freedom. Pharmacotherapeutic management of epilepsy is complicated by multiple syndromes, interindividual differences in drug sensitivities, inter-individual differences in drug disposition, and drug interactions. Most anti-epileptic drugs (AEDs) have a therapeutic window with only a 2-to 3-fold concentration range. Extended release formulations offer advantages over their immediate release counter parts with less fl uctuation in the serum concentration vs time curve and improved compliance. However, missed doses are more likely to result in prolonged "subtherapeutic serum concentrations". Best clinical outcome may sometimes require twice daily dosing of extended release formulations even though approved for once daily dosing, as this optimally balances pharmacokinetics against compliance. Lamotrigine (LTG) is a broad spectrum AED with effi cacy in partial and generalized epilepsy syndromes and good tolerability. Its metabolism is affected by co-medications which may be inducing, neutral or inhibiting of hepatic glucuronidation. Furthermore, though the average half-life in monotherapy is about 24 hours, there is a large inter-individual variation that may, including the extremes, approach a range of 10-fold. LTG-XR is expected to decrease fl uctuation of serum concentration in the presence of hepatic inducing or neutral drugs. However, optimal clinical benefi t in some patients may require twice daily dosing when metabolism is rapid.

Brain Research, Mar 1, 1982

Opiate alkaloid and opioid peptide actions on spontaneous neuronal activity and postsynaptic amin... more Opiate alkaloid and opioid peptide actions on spontaneous neuronal activity and postsynaptic amino acid responsiveness were assessed using intracellular recording techniques applied to murine spinal cord neurons in primary dissociated cell culture. Application of opiates was by superfusion and amino acids by iontophoresis. Glycine and GABA but not glutamate responses were antagonized by the opiate alkaloids. Since opiate effects on glycine and GABA responses were not naloxonereversible, only weakly stereospecific, and not produced by the opioid peptide [D-Ala2]-Met-enkephalinamide, it is unlikely that these effects were mediated by opiate recep:ors. Opiate depression of glycine inhibition was correlated with the induction of paroxysmal depolarizations in cultured spinal cord neurons, suggesting that antagonism of inhibitory amino acid transmission may underlie the convulsant actions of high concentrations of the opiate alkaloids.

Neuroscience Letters, Dec 1, 1983

We suggest that both mu-and delta-opiate receptors on dorsal root ganglion neuron somata are coup... more We suggest that both mu-and delta-opiate receptors on dorsal root ganglion neuron somata are coupled to voltage-and/or calcium-dependent potassium channels since opioid peptide decreases of calciumdependent action potential duration were: (1) not associated with a change of resting membrane potential or conductance; (2) accompanied by an increase in action potential after-hyperpolarization, and (3) blocked by intracellular injection of the potassium channel blocker cesium [18]. In contrast, norepinephrine [4l and cadmium [9], which have been reported to act on voltage-dependent calcium rather than potassium channels, shortened action potential duration and decreased afterhyperpolarization amplitude, an action not blocked by intracellular iontophoresis of cesium.

The Journal of Physiology, Aug 1, 1986