Department of Physiology and Cell Biology, College of Medicine and Public Health, Ohio State University, Columbus, Ohio 43210
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ABSTRACT |
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Actions of nociceptin on electrical and synaptic behavior of morphologically and neurochemically identified neurons in the guinea pig duodenal myenteric plexus were studied with conventional techniques. Nociceptin hyperpolarized the membrane potential in 104 of 121 AH-type and 28 of 51 S-type neurons with an EC50 of 11.9 ± 1.2 nM. Increased K+ conductance accounted for the hyperpolarizing responses that were blocked by pertussis toxin and unaffected by naloxone. The selective opioid receptor-like (ORL)1 receptor antagonist [Phe1-psi(CH2-NH)-Gly2]nociceptin(1-13)-NH2 suppressed the nociceptin-evoked responses while behaving like a partial agonist. The nonselective ORL1 antagonist naloxone benzoylhydrazone competitively suppressed nociceptin actions with a pA2 value of 5.8. Nociceptin acted at presynaptic inhibitory receptors to suppress fast excitatory nicotinic postsynaptic potentials in 25 of 30 neurons (EC50 = 22.5 ± 4.4 nM) and slow synaptic excitation in 38 of 45 neurons (EC50 = 15.1 ± 1.6 nM). Presynaptic inhibitory action of nociceptin was unaffected by naloxone and was antagonized by [Phe1-psi(CH2-NH)-Gly2]nociceptin(1-13)-NH2 or naloxone benzoylhydrazone. The results suggest that nociceptin acts both pre- and postsynaptically by activating an ORL1 receptor that is distinct from typical naloxone-sensitive opioid receptors.
autonomic nervous system; enteric nervous system; intestine; orphanin FQ; opioid receptor-like1 receptor
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INTRODUCTION |
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THE HEPTADECAPEPTIDE
NOCICEPTIN (20), also known as orphanin FQ
(29), is a recently discovered neuropeptide that has been identified as the endogenous ligand for the "orphan" opioid
receptor-like (ORL)1 receptor (3, 4, 11, 21, 33,
35). Despite evidence for certain structural analogies between
nociceptin and opioids as well as between the ORL1 receptor
and opioid receptors, nociceptin selectively binds to the
ORL1 receptor but not to µ-, -, or
-opioid receptor
subtypes, and opioid peptides do not bind to the ORL1
receptor (20, 21, 29). Like other opioid receptors, the
ORL1 receptor is coupled to G proteins (20,
29) that, when activated, result in inhibition of
forskolin-stimulated adenylyl cyclase activity (20, 29),
suppression of Ca2+ channels (7, 16),
activation of inward rectifying K+ channels (6, 31,
32), and modulation of neurotransmitter release (10, 17,
28, 34).
Both nociceptin and ORL1 receptors are widely expressed in discrete areas of the central nervous system and are thought to serve a number of functional roles including processing of nociceptive stimuli, control of neuroendocrine functions, and regulation of blood pressure and water balance (8). The presence of ORL1 receptors has also been reported in several peripheral organs including the intestine, vas deferens, and spleen, and biological effects of nociceptin have been shown at these sites (21, 27, 33). Nociceptin evokes TTX-sensitive contractions in the isolated colon of rats and mice, which suggests that enteric neurons are involved (26, 30, 38). Nociceptin suppresses the electrically stimulated contractions of the guinea pig ileum (39) and suppresses acetylcholine release in response to electrical field stimulation in rat stomach and small intestine (38).
Several reports describe the occurrence of nociceptin-like immunoreactivity in the enteric nervous system of the rat and guinea pig (2, 38). It is localized to cell bodies and dense fiber networks in the myenteric plexuses of the duodenum, ileum, and colon. Aside from this, the physiological role of nociceptin in the enteric nervous system is unknown. The aim of the present study was to examine the effects of nociceptin on electrical and synaptic behavior of myenteric neurons in the guinea pig duodenum. A preliminary report of the results has appeared in abstract form (18).
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MATERIALS AND METHODS |
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Adult male Hartley strain guinea pigs (400-600 g) were stunned by a blow to the head and exsanguinated from the cervical vessels according to procedures approved by the Ohio State University Laboratory Animal Care and Use Committee. A 2- to 5-cm segment of duodenum was removed proximal to the pyloric region. Preparations of the myenteric plexus to be used for electrophysiological recording were microdissected as described earlier (37). The preparation was mounted in a 2.0-ml recording chamber that was superfused at a rate of 10-15 ml/min with Krebs solution warmed to 37°C and gassed with 95% O2-5% CO2 to buffer pH to 7.3-7.4. The composition of the Krebs solution was (in mM) 120.9 NaCl, 5.9 KCl, 1.2 MgCl2, 1.2 NaH2PO4, 14.4 NaHCO3, 2.5 CaCl2, and 11.5 glucose. The Krebs solution contained nifedipine (1 µM) and scopolamine (1 µM) to prevent smooth muscle movements from dislodging the intracellular electrode.
The myenteric ganglia were visualized with differential interference
contrast optics and epilumination. Ganglia selected for study
were immobilized with 100-µm-diameter L-shaped stainless steel wires
placed on either side of the ganglion. Transmembrane electrical
potentials were recorded with conventional intracellular microelectrodes filled with 2% biocytin in 2 M KCl containing 0.05 M
Tris buffer (pH 7.4). Resistances of the electrodes were 80-120
M. The same electrodes were used to inject the neuronal tracer
biocytin by the passage of hyperpolarizing current into the impaled
neurons. The preamplifier (M767, World Precision Instruments, Sarasota,
FL) was equipped with a bridge circuit for intraneuronal current
injection. Fast and slow excitatory postsynaptic potentials (EPSPs)
were evoked by electrical shocks (0.1-20 Hz) applied focally to
interganglionic connectives with 20-µm-diameter Teflon-insulated Pt
wire electrodes connected through stimulus-isolation units (Grass SIN5)
to Grass S48 stimulators. Chart records were made on Astro-Med thermal
recorders. The amplitude of the spikes in some of the recordings was
blunted by the low-frequency response of the recorder. All data were
recorded on videotape for later analysis.
At the end of each recording session, the marker dye biocytin was injected into the impaled neurons from the recording electrodes by the passage of hyperpolarizing current (0.5 nA for 10-30 min). The anal end of the preparations was marked, and the tissue was transferred to a disposable chamber filled with fixative that contained 4% formaldehyde plus 15% of a saturated solution of picric acid and was kept at 4°C overnight. The preparations were cleared in three changes of dimethyl sulfoxide and three 10-min washes with PBS, reacted with avidin coupled to horseradish peroxidase, carried through a diaminobenzidine color-developing reaction, and dehydrated in alcohol. They were then mounted in Canada balsam and examined microscopically.
Neurochemical coding of the neurons that responded to nociceptin was determined by first reacting the preparations with streptavidin coupled to fluorescein to reveal biocytin fluorescence. They were then processed for immunohistochemical demonstration of calbindin, calretinin, or nitric oxide synthase (NOS) immunoreactivity. For calbindin localization, mouse anti-calbindin antiserum at a dilution of 1:2,000 was used; for calretinin, goat anti-calretinin at 1:1,500; and for NOS, rabbit anti-NOS at 1:500. The preparations were then incubated with secondary antibodies labeled with Texas red. Fluorescent labeling was examined under a Nikon Eclipse E600 fluorescent microscope that was equipped with appropriate filters and a SPOT-2 chilled color and B/W digital camera (Diagnostic Instruments, Sterling Heights, MI).
The actions of nociceptin and related pharmacological agents were studied by either pressure microejection or application in the superfusion solution. Micropipettes (10-µm diameter) manipulated with the tip close to the impaled neurons were used to microeject the substances. Pressure pulses of nitrogen with predetermined force and duration were applied to the micropipettes through electronically controlled solenoid valves.
The pharmacological agents used in this study and their sources were as follows. Nociceptin (orphanin FQ), naloxone, acetylcholine, substance P, 5-hydroxytryptamine (5-HT), TTX, pertussis toxin (PTX), bestatin, DL-thiorphan, and barium chloride (BaCl2) were obtained from Sigma (St. Louis, MO). [Phe1-psi(CH2-NH)-Gly2]nociceptin(1-13)-NH2 (NC-NH2), nocistatin, and naloxone benzoylhydrazone (NBH) were from RBI (Natick, MA). Nociceptin(1-7) was from Tocris Cookson (Ballwin, MO). Fluorescein streptavidin was from Vector (Burlingame, CA). Calbindin, calretinin, and NOS antiserum were from Chemicon (Temecula, CA).
Data are expressed as means ± SE; n values refer to the number of neurons. The concentration-response curves for drug-induced responses were constructed with the following least-squares fitting routine: V = Vmax/[1 + (EC50/C)nH], where V is the observed response, Vmax is maximum response, EC50 is the concentration that induces the half-maximal response, C is the concentration, and nH is the apparent Hill coefficient. Antagonist potency was assessed by constructing Schild plots for three different concentrations of the antagonist and the calculation of pA2 values (1).
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RESULTS |
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Results were obtained from 172 myenteric neurons with impalements
lasting from 20 min to 8 h. All neurons had resting membrane potentials greater than 45 mV. The neurons were classified into AH
and S types according to the criteria described previously by Hirst et
al. (15) and Wood (36). Of all the neurons
examined, 121 were identified as AH type and 51 as S type.
Nociceptin-induced hyperpolarization.
Application of nociceptin either by addition to the superfusion
solution or by pressure microejection hyperpolarized the membrane potential, decreased the input resistance, and suppressed excitability in 104 of 121 AH-type and 28 of 51 S-type neurons. The average maximal
membrane hyperpolarization during application of 300 nM nociceptin was
19.8 ± 4.5 mV (n = 11). The input resistance with this concentration of nociceptin was reduced by 34.5 ± 9.9%
(n = 8). Suppression of excitability was reflected by
the failure of depolarizing current pulses to evoke action potentials
(data not shown), blockade of anodal-break excitation at the offset of
intraneuronally injected hyperpolarizing current pulses (Figs. 1A and
2B), and
inhibition of the ongoing discharge of action potentials in
spontaneously active neurons (Figs. 2A and 4A). These effects began within 10-30 s after entry of nociceptin into the tissue chamber and developed gradually over a period of 1-2 min. Recovery of membrane potential and input resistance to control levels required 7-15 min after washout. In 43.3% (13 of 30) of the neurons, subsequent applications of nociceptin at the same concentration evoked weaker responses, presumably because of receptor desensitization phenomena. In neurons without apparent desensitization, the effects of nociceptin were concentration dependent, with an EC50 of 11.9 ± 1.2 nM (Fig. 1B). The
inhibitory effects of 100 nM nociceptin were unaffected by the addition
of 300 nM TTX. The mean hyperpolarizing response was 15.0 ± 3.0 mV in controls (n = 6) and 14.5 ± 3.1 mV in TTX
(n = 6), indicating a direct action of nociceptin
rather than activation of neurons synaptically connected with the
impaled ganglion cell.
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Mediation of nociceptin responses by ORL1 receptors.
To determine whether the responses evoked by nociceptin were mediated
by the ORL1 receptor or by one of the classic opioid receptors, the nonselective opioid receptor antagonist naloxone, the
selective ORL1 receptor antagonist NC-NH2, and
the nonselective ORL1 receptor antagonist NBH were used.
Bath application of nociceptin (30 nM) elicited a membrane
hyperpolarization of 10.4 ± 3.3 mV (n = 5; Fig.
2A) that was unaltered by the addition of 10 µM naloxone (10.0 ± 2.8 mV; n = 5; Fig. 2A). On
the other hand, the hyperpolarization evoked by 1 µM
[Met]enkephalin in the same neurons was suppressed significantly by
10 µM naloxone (8.8 ± 2.0 vs. 1.6 ± 0.7 mV;
n = 5; P < 0.05; Fig. 2A).
The putative ORL1 antagonist NC-NH2 (1 µM)
suppressed the hyperpolarization evoked by 30 nM nociceptin by 60%
when coapplied with nociceptin in the superfusion solution (13.1 ± 1.1 vs. 5.2 ± 0.8 mV; n = 5; P < 0.05; Fig. 2B). Application of the putative
ORL1 antagonist (1 µM) alone produced a small hyperpolarizing response in 12 of 17 cells (Fig. 2B). The
3-receptor agonist NBH has been reported to exert
antagonist actions at ORL1 receptors (9, 23).
Figure 4A shows
concentration-dependent suppression of the effects of
nociceptin (30 nM) by NBH. The concentration-response curve for
nociceptin was shifted in a rightward direction by NBH (Fig.
4B). Schild analysis confirmed that the antagonism was
competitive with a pA2 value of 5.8 (Fig. 4C).
NBH (1, 3, or 10 µM) did not change the membrane potential when
applied alone.
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Evidence for increased K+
conductance.
Plots of current-voltage relations revealed decreased input resistance
during the hyperpolarizing action of nociceptin that was reflected by a
decreased slope relative to control values. The current-voltage curves
obtained in the presence and absence of nociceptin intersected at
membrane potentials between 80 and
105 mV, with an average of
90.5 ± 1.2 mV (n = 7; Fig.
5A). This suggested
that the reversal potential for the conductance change was near the
estimated K+ equilibrium potential (36). This
suggestion was reinforced by observations that manual current clamp of
the membrane potential to progressively greater levels of
hyperpolarization was accompanied by a progressive decrease in the
amplitude of the hyperpolarizing response to nociceptin (Fig.
5C). Current clamp to membrane potentials more positive than
the resting potential resulted in an increase in the amplitude of the
hyperpolarizing responses to nociceptin (Fig. 5C). The
hyperpolarizing responses were nullified when the membrane potential
was clamped between
90 and
105 mV. The ionic nature of the
nociceptin effects was investigated further by the application of 300 µM BaCl2 to nonspecifically block K+
channels. Nociceptin (100 nM) did not hyperpolarize the neurons in the
presence of 300 µM BaCl2 (n = 5; Fig.
5C). This was consistent with the hypothesis that increased
K+ conductance was involved in the hyperpolarizing action.
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Effects of protease inhibitors nociceptin(1-7) and nocistatin. To exclude the possibility that the inhibitory actions of nociceptin were due to products resulting from proteolytic degradation of the peptide, the protease inhibitors bestatin (20 µM) and DL-thiorphan (2 µM) were applied together with nociceptin (100 nM). The inhibitory effects of nociceptin were unaffected by the presence of the protease inhibitors (n = 5). Application of 10 µM nociceptin(1-7), a major metabolite that is derived from the NH2-terminal region of nociceptin, had no effect on the membrane potential and did not interfere with the actions of nociceptin (100 nM). These findings suggest that the inhibitory effects observed for nociceptin were a result of the actions of the intact peptide.
Nocistatin is another novel heptadecapeptide derived from the same precursor as nociceptin (24, 25). Application of nocistatin (10 µM) did not change the membrane potential in any of the myenteric neurons tested (n = 6), nor did it affect the inhibitory actions of nociceptin.Nociceptin-evoked presynaptic inhibition.
Focal electrical stimulation applied to interganglionic connectives
evoked fast EPSPs characteristic of well-documented nicotinic EPSPs
known to occur in enteric neurons (36). Nociceptin
(1-300 nM) suppressed, in a concentration-dependent manner, the
stimulus-evoked fast EPSPs in most of the neurons examined (25 of 30),
with an EC50 of 22.5 ± 4.4 nM (Figs.
6 and 7).
Suppression of the fast EPSPs by nociceptin was unaffected by naloxone
but was abolished by the selective ORL1 receptor antagonist
NC-NH2 and the nonselective ORL1 receptor
antagonist NBH (Fig. 6A). NC-NH2 (1 µM)
suppressed fast EPSPs by 17.0 ± 1.0% in 9 of 12 neurons. This
was suggestive of partial agonist activity. Nociceptin did not reduce
the depolarizing responses evoked by exogenously applied acetylcholine
(control, 15.0 ± 1.5 mV vs. nociceptin, 14.7 ± 1.6 mV;
n = 6; P > 0.05; Fig. 6B).
In four myenteric neurons, nociceptin suppressed the fast EPSPs without
producing any effects on the membrane potential. This and the failure
to suppress responses to applied acetylcholine suggested that the site
of action of nociceptin was at presynaptic inhibitory ORL1
receptors on the nicotinic nerve terminals and that suppression of the
fast EPSPs resulted from inhibition of acetylcholine release from the
terminals.
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DISCUSSION |
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We found that nociceptin, an endogenous ORL1 receptor ligand, evoked concentration-dependent and reversible hyperpolarization of the membrane potential in myenteric neurons of the guinea pig duodenum. The hyperpolarizing responses were associated with decreased input resistance and suppression of excitability that appeared to reflect increased K+ conductance. Persistence of the inhibitory effect after blockade of synaptic transmission by TTX was indicative of a direct action at receptors on the neuronal cell bodies. We also found that nociceptin has a presynaptic inhibitory action on fast nicotinic excitatory synaptic transmission and noncholinergic slow excitatory synaptic transmission in the duodenal myenteric plexus.
Three lines of evidence suggest that the nociceptin-induced membrane
hyperpolarization was mediated by ORL1 receptors. First, the responses to nociceptin were reversibly blocked by the selective ORL1 receptor antagonist NC-NH2
(14), whereas naloxone, a prototypical antagonist to the
µ-, -, and
-subtypes of opioid receptors, was ineffective even
at high concentrations. NC-NH2 alone had direct membrane
hyperpolarizing effects similar to those of nociceptin, suggesting that
this peptidergic antagonist might be a partial agonist. Second, NBH, a
putative nonselective ORL1 receptor antagonist, also
blocked the effect of nociceptin. This naloxone derivative was first
described as an agonist at
3- and as an antagonist at
both µ- and
-receptors (13). It has been recently
recognized as an ORL1 receptor antagonist in rat vas
deferens (9, 23) and in mouse brain (34).
Third, the concentration-response relationships for nociceptin (i.e.,
EC50 = 11.9 nM) were comparable to those reported
earlier for various types of cellular responses to nociceptin, including increase in K+ conductance in dorsal raphe nuclei
(EC50 = 22 nM; Ref. 31) and the locus
coeruleus (EC50 = 90 nM; Ref. 6),
reduction of Ca2+ currents (EC50 = 42 nM;
Ref. 7), and inhibition of adenylate cyclase in CHO cells
expressing cloned ORL1 receptors (EC50 = 1 nM; Refs. 20, 29). Furthermore, the mRNA for the
ORL1 receptor (27, 33) and immunoreactivity
against nociceptin peptide (2, 38) were found to be
expressed in the myenteric plexus. Therefore, it seems reasonable to
postulate a functional role for the ORL1 receptor-nociceptin peptide system in the enteric nervous system.
Recent studies on other neuronal types have indicated that nociceptin acts to increase K+ conductance via G protein coupling to the ORL1 receptor (6, 31, 32). In the present study, the membrane hyperpolarization and decreased input resistance in response to nociceptin suggested an increase in K+ conductance. Findings that the hyperpolarizing action was suppressed by Ba2+ and that the reversal potential was near the estimated K+ equilibrium potential support this suggestion (36). Nociceptin has been reported to act by opening K+ channels in other neuronal types (6, 31, 32), and this appears to be the case also for enteric neurons. In this respect, the action of nociceptin is reminiscent of the hyperpolarizing action of opioid peptides on enteric neurons (22).
The hypothesis that the nociceptin receptors were G protein coupled was based on the primary structure of the ORL1 receptor, which displays the seven membrane-spanning domains of typical G protein-coupled receptors (3, 11, 21, 35). Nociceptin is known to suppress forskolin-stimulated cAMP accumulation in transfected cells (20, 29) and to increase inwardly rectifying K+ conductance in amygdaloid neurons (19) via PTX-sensitive G proteins. In the present study, incubation with PTX prevented responses to nociceptin, indicative of coupling of the ORL1 receptor to the Gi/Go class of G proteins.
Both AH- and S-type neurons were hyperpolarized by nociceptin. Nevertheless, responses to nociceptin were quantitatively different for the two types of neurons, with the greatest proportion of responses occurring in AH neurons. Most nociceptin-responsive AH neurons had Dogiel type II morphology, whereas the nociceptin-responsive S-type neurons had either filamentous or Dogiel type I morphology. The available evidence suggests that S-type neurons with Dogiel type I morphology and NOS immunoreactivity are inhibitory motor neurons that project to circular muscle layers (5), whereas the AH neurons with Dogiel type II morphology are interneurons responsible for excitatory drive and coordination of the discharge of motor neurons to intestinal effector systems (12, 36). The intestinal circular muscle coat is under tonic influence stemming from the firing of inhibitory motor neurons, with cell bodies located in the myenteric plexus (36). AH interneurons are thought to be synaptically coupled into networks that supply excitatory drive to the inhibitory motor neurons. By suppressing firing in AH-type interneurons and/or inhibitory motor neurons, nociceptin removes inhibition from the muscle and unmasks myogenic contractile activity (36). This may be the neural basis for the elevated contractile activity of the intestinal musculature that has been reported as another action of nociceptin (26, 30, 38). Enteric neuronal involvement in nociceptin-evoked contractile responses is further suggested by susceptibility to blockade by TTX (26, 38).
Nociceptin behaved like opiates and opioid peptides (36) in its action to suppress stimulus-evoked nicotinic fast EPSPs. This appeared to be a direct action at presynaptic inhibitory receptors on cholinergic nerve terminals because nociceptin did not suppress the depolarizing action of exogenously applied acetylcholine, and the suppression of fast nicotinic EPSPs occurred in neurons without any nociceptin-induced hyperpolarization.
Nociceptin also suppressed slow EPSPs. Stimulus-evoked slow EPSPs were assumed to reflect the release of excitatory neurotransmitters from the terminals of noncholinergic neurons because muscarinic receptors were blocked by the presence of 1 µM scopolamine in the bathing solution. Substance P and 5-HT are among the putative mediators of slow EPSPs in the enteric nervous system and evoke slow EPSP-like responses when applied experimentally to enteric neurons (36). Nociceptin did not reduce the slow EPSP-like responses to exogenously applied substance P or 5-HT. This implicates presynaptic inhibition of neurotransmitter release as the likely explanation for the inhibitory action on slow synaptic excitation. Suppression of both fast and slow EPSPs by nociceptin was blocked by NC-NH2 or NBH but not by naloxone. The finding that the membrane hyperpolarization evoked by nociceptin was also reversed by NC-NH2 and NBH suggests that ORL1 receptors mediate both the pre- and postsynaptic inhibitory actions of nociceptin.
In summary, we found two distinct actions of nociceptin on guinea pig myenteric neurons. One action was direct membrane hyperpolarization and suppression of neuronal excitability at the level of the ganglion cell somas. The second action was presynaptic inhibition of neurotransmitter release at fast and slow excitatory synapses. These actions involve activation of G protein-coupled ORL1 receptors that are distinct from naloxone-sensitive opioid receptors. The widespread pre- and postsynaptic actions of nociceptin that were observed in this study suggest that this peptidergic system could play an important role as a neuromodulator in the enteric nervous system.
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ACKNOWLEDGEMENTS |
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This study was supported by National Institute of Diabetes and Digestive and Kidney Diseases Grants RO1-DDK-37238 and DDK-46941.
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FOOTNOTES |
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Address for reprint requests and other correspondence: J. D. Wood, Dept. of Physiology and Cell Biology, Ohio State Univ., 302 Hamilton Hall, 1645 Neil Ave., Columbus, OH 43210-1218 (E-mail: wood.13{at}osu.edu).
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Received 8 September 2000; accepted in final form 13 February 2001.
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