Department of Pharmacology, College of Medicine, University of Iowa, Iowa City, Iowa 52242
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ABSTRACT |
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Ozaki, Noriyuki,
J. N. Sengupta, and
G. F. Gebhart.
Differential Effects of µ-, -, and
-Opioid Receptor
Agonists on Mechanosensitive Gastric Vagal Afferent Fibers in the Rat.
J. Neurophysiol. 83: 2209-2216, 2000.
Single-fiber recordings were made from the decentralized right cervical
vagus nerve (hyponodosal) of the rat. A total of 56 afferent fibers
that responded to gastric distension (GD) were studied: 6 fibers were
stimulated by phasic balloon GD, 50 by fluid GD. All fibers gave
increasing responses to increasing pressures of GD (5-60 mmHg). The
effects of µ-opioid (morphine),
-opioid (SNC80), and
-opioid
(EMD61,753, U62,066) receptor agonists were tested on responses of
afferent fibers to GD. Morphine, administered systemically over a broad
dose range (10 µg to 31 mg/kg, cumulative), had no effect on either
resting activity or responses of vagal afferent fibers to GD.
Similarly, the
-opioid receptor agonist SNC80 (0.05-3.2 mg/kg) did
not affect resting activity or responses to GD. In contrast, cumulative
intra-arterial doses of the
-opioid receptor agonist EMD61,753 or
U62,066 dose dependently attenuated afferent fiber responses to GD.
Doses producing inhibition to 50% of the control response to GD of
EMD61,753 (8.0 mg/kg) and U62,066 (8.8 mg/kg) did not differ. The
effect of U62,066 was moderately attenuated by a nonselective dose (4 mg/kg) of naloxone hydrochloride; the
-opioid receptor-selective
antagonist nor-BNI (20 mg/kg) was ineffective. These results
demonstrate that
-, but not µ- or
-opioid receptor agonists
modulate visceral sensation conveyed by vagal afferent fibers
innervating the stomach. Given that
-opioid receptor agonists
effects were only modestly antagonized by naloxone and not at all by
nor-BNI, the results point to a novel site of action.
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INTRODUCTION |
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The antinociceptive effects of opioids are
mediated through activation of opioid receptors in central and
peripheral tissues. To date, three opioid receptors (µ, , and
)
have been shown to be involved in the modulation of visceral
nociception. In a model of visceral nociception in the rat, intrathecal
administration of µ- and
-opioid receptor agonists (ORAs), but not
the
-ORA U50,488, attenuate visceromotor and cardiovascular
responses to noxious colorectal distension (Danzebrink et al.
1995
; Diop et al. 1994
; Harada et al.
1995
; Ness and Gebhart 1988
). Systemic administration of
-ORAs, however, dose dependently attenuates responses to noxious colorectal distension (Burton and Gebhart 1998
). Electrophysiological studies resolved that in addition to a supraspinal site of action,
-ORAs have direct peripheral actions as well. We found that putative
- (U50,488, U69,593, U62,066),
2- (bremazocine), and
3- (naloxone benzoylhydrazone) ORAs, a
peripherally restricted
-ORA (EMD61,753), and a mixed
/µ-ORA
(fedotozine), but not either µ- (morphine and fentanyl) or
-
[D-pen2,
D-pen3-enkephalin (DPDPE) and SNC80]
ORAs dose dependently inhibit responses of mechanosensitive pelvic
nerve afferent fibers to noxious colorectal or urinary bladder
distension in the rat (Sengupta et al. 1996
, 1999
; Su et al. 1997a
,b
). In addition,
-ORAs attenuate high-voltage-activated calcium currents in the cell
bodies of these pelvic nerve sensory fibers (Su et al.
1998
).
Many visceral pains are treated satisfactorily with currently available
opioids. There are a variety of functional bowel disorders, however,
for which opioids are not generally used to manage pain and discomfort.
Given that -ORAs have significant peripheral effects on urinary
bladder and colonic input via the pelvic nerve, the principal objective
of the present study was to examine the effects of receptor-selective
ORAs on mechanosensitive vagal afferent fibers in the stomach. Some of
these data have been presented previously in abstract form
(Ozaki et al. 1998
; Sengupta et al. 1997
).
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METHODS |
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General procedures
Experiments were performed on 53 male Sprague-Dawley rats
(Harlan, Indianapolis, IN; 400-500 g). Food, but not water was
withheld for 24 h before surgery. The animals were anesthetized
initially with an intraperitoneal injection of pentobarbital sodium
(Nembutal, Abbott Laboratories, Abbott Park, IL; 45-50 mg/kg) and
subsequently maintained with an intravenous infusion of pentobarbital
(5-10 mg · kg1 · h
1). The right femoral vein was cannulated for
infusion of fluid and anesthetic. The right femoral artery was
cannulated and connected to a pressure transducer for monitoring blood
pressure and heart rate. The mean arterial pressure was maintained at
80 mmHg with supplemental intravenous injection of 5% dextrose in
saline administered in a bolus of 1-1.5 ml as required. The trachea
was intubated to permit artificial ventilation with room air. The rat
was paralyzed with pancuronium bromide (0.2-0.3 mg/kg iv) and
mechanically ventilated with room air (~70 strokes/min, 2-2.5 ml
stroke volume). Supplemental doses of pancuronium bromide (0.2-0.3 mg
· kg
1 · h
1) were
given to maintain paralysis during the experiment. Core body
temperature was maintained at 36°C by a hot water circulating heating
pad placed under the rat and a overhead feedback-controlled heat lamp
(thermoprobe inserted into the rectum, Yellow Springs Instrument,
Yellow Springs, OH). At the end of experiments, rats were killed with
an overdose of pentobarbital. The experimental protocol was approved by
the Institutional Animal Care and Use Committee, The University of Iowa.
The abdomen was opened by a transverse epigastric incision 4-5 cm in length. To measure afferent fiber conduction velocity, a bipolar wire electrode was placed on the vagal trunk at the esophageal-gastric junction in some experiments. The right and left vagal nerves were isolated from the esophagus, and a pair of Teflon-coated, 40-gauge stainless steel wires stripped at the tips were placed around the nerve and sealed with nonreactive Wacker gel (Wacker Silicone, Adrian, MI).
For phasic balloon gastric distension (GD), a 2.0-2.5 cm long, 2-3 cm
diam flaccid, flexible latex balloon was placed surgically in the
stomach through the fundus. The balloon occupied approximately two-thirds of the proximal stomach. The pylorus was not obstructed, and
there was no blockage of gastric emptying. The outside diameter of the
balloon when inflated was greater than the intraluminal diameter of the
stomach of the rat. Therefore the pressure measured during GD reflected
actual intragastric pressure. The balloon catheter was connected to a
distension control device via a low volume pressure transducer (see
Gebhart and Sengupta 1996 for details).
For fluid GD, the stomach was intubated with flexible Tygon tubing (2.3 mm OD, 1.3 mm ID) via the mouth, esophagus, and cardia. The catheter was secured by a ligature around the esophageal-gastric junction. Another Tygon tube (3.9 mm OD, 2.4 mm ID) was introduced distally through the pylorus and was secured by a ligature placed caudal to the pyloric sphincter; the duodenum was ligated close to the pyloric ring. For GD, the oral catheter was connected to a reservoir containing saline at room temperature. Constant pressure distension was achieved using the distension control device with the distal catheter clamped. Intragastric pressure was monitored by connecting the distal catheter via a three-way stopcock to a low-volume pressure transducer. The abdomen was closed with silk sutures.
Recording of afferent nerve activity
The right vagus nerve was exposed by a ventral midline incision in the neck. The sternocleidomastoid, sternohyoid, and omohyoid muscles were removed. The skin was reflected laterally and tied to the stereotaxic frame to make a pool for warm mineral oil (37°C). The nerve was dissected away from the carotid tissue sheath, decentralized close to its entry to the nodose ganglion, and placed over a black micro-base plate. The perineural sheath was removed in the pool of warm mineral oil, the nerve was split into thin bundles, and fine filaments were teased from the bundle to obtain a single unit. Electrical activity of the single unit was recorded by placing the fiber over one arm of a bipolar silver-silver chloride electrode. A fine strand of connective tissue was placed over the other pole of the electrode for differential recording.
Action potentials were monitored continuously by analogue delay and displayed on a storage oscilloscope after low noise AC differential amplification. Action potentials were processed through a window discriminator and counted (1 s binwidth) on-line using the SPIKE2/CED 1401 data acquisition program (Cambridge Electronic Design, Cambridge, UK). Peristimulus time histograms, intragastric pressure, and blood pressure were displayed on-line continuously. Data were also recorded on tape for later analysis.
Experimental protocol
Mechanosensitive gastric muscle afferents in the vagus nerve were identified by response to a test stimulus of GD (40 mmHg, <5 s). If a fiber responded to GD, a stimulus-response function (SRF) to distending pressures of 5, 10, 20, 30, 40, and 60 mmHg, 30 or 60 s duration at 4-min intervals was determined.
To measure conduction velocity, the vagus nerve was stimulated with a
single 0.5-ms square-wave pulse at 3-8 mA, and the conduction delay
(time between stimulus artifact and evoked response) was recorded. The
conduction distance was measured postmortem. Fibers were classified on
the basis of their conduction velocities; those with conduction
velocities <2.5 m/s were considered unmyelinated C-fibers, and those
with conduction velocities >2.5 m/s were considered thinly myelinated
A-fibers.
The effects of representative µ- (morphine), - (SNC80), and
- (EMD61,753, U62,066) ORAs were tested on resting activity and
responses to 60 mmHg GD (30 or 60 s, every 4 min) of
mechanosensitive gastric afferent fibers. All drugs were administered
intra-arterially in a cumulative dose paradigm. Each dose of drug was
given 120 s before the onset of distension. Cumulative
dose-response relationships for morphine were obtained by giving
cumulative doses of 0.5, 1, 2, 4, and 8 mg/kg; doses of SNC80 were
0.05, 0.1, 0.2, 0.4, 0.8, 1.6, and 3.2 mg/kg. Cumulative doses of
EMD61,753 and U62,066 were 0.5, 1.0, 2.0, 4.0, 8.0, 16.0, and 32.0 mg/kg. Thirteen fibers that were not affected by morphine were
subsequently tested in the presence of other ORAs.
To determine whether effects of -ORAs were produced at opioid
receptors, the effects of U62,066 (8 mg/kg) alone (n = 4) and after intra-arterial administration of a non-receptor-selective dose of naloxone hydrochloride (NLXH, 4 mg/kg; n = 5)
on response to GD were examined. The effects of U62,066 (8 mg/kg) were
also tested before and after administration of NLXH in three fibers. The effects of U62,066 were studied in the presence of
nor-binaltorphimine dihydrochloride (nor-BNI), a selective
-opioid
receptor antagonist. Nor-BNI (20 mg/kg sc) was injected 24 h
before (n = 4) or 24 and 48 h before experiments
(n = 1).
At the end of the protocol for each fiber, the abdomen was opened and the mechanosensitive receptive field was located by probing the stomach with a fine, blunt glass rod.
Drugs
Morphine sulfate (MW: 668.7, Merck Chemical Division, Merck, Rahway, NJ), U62,066 (MW: 356.5, Research Biochemicals, Nattick, MA), naloxone hydrochloride (MW: 363.8, Sigma Chemical, St. Louis, MO), and nor-binaltorphimine dihydrochloride (nor-BNI; MW: 698.27, Tocris Cookson, St. Louis, MO) were dissolved in 0.9% saline. SNC80 (MW: 449.6, Tocris Cookson) was dissolved in 10% DMSO and 1% acetic acid. EMD61,753 (MW: 469.1, E. Merck, Darmstadt, Germany) was dissolved in 10% DMSO.
Data analysis
The resting activity of a fiber was counted for 60 s before GD, and the response to GD was determined as the increase in discharge during GD above its resting activity (imp/s). SRFs to graded GD were plotted for each individual fiber, and a least-squares regression line was obtained from the linear part of the SRF. The regression line then was extrapolated to the ordinate (representing distension pressure) to estimate response threshold.
All data are expressed as means ± SE. Results were analyzed using
paired or unpaired Student's t-test. The inhibitory dose 50 (ID50; dose to produce 50% inhibition of the
response to distension) and 95% confidence intervals were calculated
from the 20-80% component of the cumulative dose-response curve
(Tallarida and Murray 1987). A value of
P < 0.05 was considered statistically significant.
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RESULTS |
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Fiber sample
A total of 56 gastric afferent fibers were studied, all of which responded to GD. In the presence of the balloon in the stomach (n = 6), fibers exhibited ongoing activity (mean: 3.9 ± 2.2 imp/s; range: 0.02-14.2 imp/s). Forty-two of 45 fibers that responded to fluid GD were spontaneously active (mean: 1.5 ± 0.3 imp/s; range: 0.01-8.5 imp/s). Five of the total 56 fibers were pretreated 24 or 48 h before an experiment with nor-BNI (n = 5; mean spontaneous activity: 3.2 ± 1.4 imp/s; range: 0.2-8.5 imp/s).
Conduction velocities of 15 fibers that responded to fluid GD
were measured by electrical stimulation of the vagus nerve. All 15 fibers were unmyelinated C-fibers (mean conduction velocity: 0.6 ± 0.02 m/s, range: 0.5-0.9 m/s). In a previous study of gastric vagal
afferent fibers (Ozaki et al. 1999), we also encountered only C-fibers (n = 27, mean conduction velocity:
0.7 ± 0.06 m/s).
SRFs
Responses to graded balloon or fluid GD were studied in all
56 fibers (see Fig. 1 for examples). SRFs
of fibers in the different experimental groups, excepting five fibers
from rats pretreated with nor-BNI, are given in Fig.
2. Extrapolation of the linear portion of
individual SRFs revealed that gastric vagal afferent fibers exhibited a
range of thresholds for response to GD. The mean response threshold to
30 s balloon GD was 7.9 ± 1.6 mmHg (range: 2.0-13.8 mmHg),
to 30 s fluid GD 3.8 ± 1.2 mmHg (range: 0-16.9 mmHg), and
to 60 s fluid GD 4.4 ± 0.6 mmHg (range: 0-12.6 mmHg). This
sample of 51 fibers is very similar to a different sample of vagal
afferent fiber using the same methods to distend the stomach
(Ozaki et al. 1999).
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The mean SRFs of vagal afferent fibers to GD are presented in Fig.
2D. When responses to the more natural fluid filling of the
stomach were compared with responses to phasic balloon GD, response
magnitude generally was greater to fluid GD, particularly during the
second half of the period of distension. Although GD was delivered at a
constant pressure whether by balloon or fluid, the rate at which the
final pressure was achieved and the duration of the target pressure
differed for the two types of GD (see pressure traces in Fig. 1). The
mean SRF of vagal afferent fibers to balloon GD significantly differed
from the SRFs to fluid GD. Characteristics of this sample of gastric
vagal afferent fibers are similar to what we found in an earlier study
(Ozaki et al. 1999).
Effects of opioid receptor agonists (ORAs) on gastric mechanosensitive vagal afferent fibers
µ-ORA.
When we began these studies, we tested morphine first and anticipated
that relatively low concentrations would affect vagal afferent fiber
activity (e.g., Randich et al. 1991). We tested cumulative doses of morphine from 10-300 µg/kg (n = 11), progressing in subsequent experiments to a cumulative dose of 31 mg/kg. A total of 19 fibers were studied and spontaneous activity was
not affected by morphine.
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-ORA.
Cumulative doses of the selective
-ORA SNC80 (3.2 mg/kg) did not
alter resting activity or responses to GD of five mechanosensitive afferent fibers tested. An example is shown in Fig. 4, and the data are
summarized in Fig. 5.
-ORAS.
Cumulative doses of EMD61,753 (32 mg/kg, n = 6) and
U62,066 (16 mg/kg, n = 3) dose dependently attenuated
responses of mechanosensitive afferent fibers to GD. Representative
examples are shown in Fig. 6. The effect
of a cumulative dose (800 µl/kg) of vehicle (10% DMSO) was tested on
responses to GD (60 mmHg, 60 s) of five mechanosensitive afferent
fibers and did not alter responses to GD. The mean
ID50 values and 95% confidence intervals for
EMD61,753 and U62,066 were 8.0 (2.7-23.7) and 8.8 (1.6-48.9) mg/kg,
respectively. Figure 5 summarizes the dose-dependent effects of these
two
-ORAs on responses to GD. Neither
-ORA affected spontaneous
activity or response afterdischarge at low doses, but at doses
8.0
mg/kg spontaneous activity was decreased by EMD61,753 in three of five fibers that had spontaneous activity; U62,066 did not affect resting activity, but modestly affected afterdischarge in two of three fibers.
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DISCUSSION |
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The present results document an inhibitory effect of -ORAs on
responses of gastric vagal afferent fibers to GD. Kappa ORAs, but
neither morphine (µ-ORA) nor SNC80 (
-ORA), dose dependently attenuated responses to GD. This is consistent with previous studies of
ORA effects on pelvic nerve afferent fiber responses to urinary bladder
(Su et al. 1997a
) or colorectal distension
(Sengupta et al. 1996
, 1999
; Su et
al. 1997b
). In the present study, as in previous studies,
naloxone was able to antagonize in part the effects of the
-ORAs
tested, whereas the
-opioid receptor antagonist nor-BNI was without
effect. We interpreted this outcome to suggest that their exists in the
viscera an opioid-like receptor at which
-ORAs act to attenuate
visceral nociception, and the present results are consistent with this interpretation.
Differential effects of -ORAs in binding, physiological, and
behavioral studies suggest the existence of three
-opioid receptors (
1,
2, and
3). Benzacetamide
-ORAs (U50,488, U62,066,
EMD67,753) bind preferentially to a
1-opioid
receptor, whereas benzomorphan compounds (bremazocine and
ethylketocylazocine) bind preferentially to
2-opioid receptors (Caudle et al.
1998
; Clark et al. 1989
; Zukin et al.
1988
). Behavioral characterization of
1 and
2 receptors in
a rat model of persistent pain suggested that
1-ORAs are ineffective as analgesics when
injected intrathecally, whereas agonists that have high affinity for
2 receptors are effective intrathecally in
modulating hyperalgesia and allodynia (Ho et al. 1997
).
This is consistent with the recent report by Ness (1999)
showing that intrathecally administered U50,488, a
1-selective agonist had no effect on spinal
neurons excited by colorectal distension. Radioligand binding studies
indicate that in the spinal cord of rats, guinea pig, monkeys, and
humans
2 receptors are 10-fold more abundant
than
1 receptors (Caudle et al.
1998
). The existence of functional
2
receptors requires molecular evidence, which is presently not
available. It has been proposed that this receptor could be a
posttranslational modification of the cloned
1
receptor (Caudle et al. 1998
). Radioligand binding and
antisense studies also indicate the existence of two affinity sites of
1 receptors for
-ORAs;
1a and
1b
(Clark et al. 1989
; Lai et al. 1994
;
Pasternak et al. 1999
; Rothman et al.
1990
).
Support for presence in the viscera of a -like receptor different
from the
1-opioid receptor cloned in the CNS
is based on the following. First, the mean effective doses of the two
-ORAs studied here that attenuated responses of gastric vagal
afferent fibers to GD (8.0 mg/kg for EMD61,753; 8.8 mg/kg for U62,066) are not different from each other or different from doses of the same
and other
-ORAs that attenuated responses of pelvic nerve afferent
fibers to colorectal or urinary bladder distension to 50% of control
(Sengupta et al. 1996
; Su et al.
1997a
,b
). These results are in contrast to the >100-fold
differences reported in the literature for these same
-ORAs in
binding studies (Clark et al. 1989
; Devlin and
Shoemaker 1990
; Rothman et al. 1990
;
Zukin et al. 1988
) and various models of nociception.
Effective antinociceptive doses of
-ORAs have been reported to range
from the µg/kg to mg/kg range (e.g., Burton and Gebhart
1998
; Herrero and Headley 1993
; Hunter et
al. 1990
; Paul et al. 1990
). In unanesthetized, intact rats, where
-ORAs have access to both peripheral and central sites of action, effective doses of
-ORAs for 50% attenuation of
visceromotor or pressor responses to colorectal distension range from
10 µg/kg to 8 mg/kg (Burton and Gebhart 1998
). Second, the
-selective opioid receptor antagonist nor-BNI was without effect
in the present study. Nor-BNI can have a long latency to effect and has
a long duration of action (Spanagel et al. 1994
; Takemori et al. 1988
). Accordingly, we pretreated rats
for 48 or 24 h with nor-BNI, but did not observe any attenuation
of the effect of the
-ORAs tested. Naloxone, morever, was only
modestly effective in partly attenuating the effects of U62,066 on
responses of gastric vagal afferent fibers to GD. We have considered
previously that the
-like receptor in the viscera may be an orphan
receptor similar to opioid-receptor-like 1 (ORL1), at which the
endogenous orphanin FQ/nociceptin peptide acts (Meunier et al.
1995
; Reinscheid et al. 1995
). The ORL1 receptor
most closely resembles the
-opioid receptor, although it is distinct
from the
- and other opioid receptors (Meunier 1997
).
We tested nociceptin on responses of pelvic nerve afferent fibers to
colonic distension and observed no effect (V. Julia
and G. F. Gebhart, unpublished observations). The absence of
antagonism of effects by nor-BNI and modest antagonism by naloxone
suggests that effects were produced at a nonopioid receptor.
Benzacetamide -ORAs have been reported to exert local
anesthetic-like effects on Na+ channels
(Alzheimer and Ten Bruggencate 1990
; Pugsley and
Goldin 1999
; Zhu and Im 1992
; Zhu et al.
1992
). In vitro studies reveal that benzacetamide
-ORAs as
well as benzacetamide compounds with very poor binding affinity for
-opioid receptors produce concentration-dependent blockage of
Na+ channels (e.g., Pugsley and Goldin
1999
; Pugsley et al. 1993
). Structurally related
compounds have also been shown to possess anticonvulsant and
antiarrhythmic efficacy (Pugsley et al. 1992
, 1993
; Zhu et al. 1992
). The
-ORAs
studied here did not affect conduction velocity of pelvic nerve
afferent fibers or action potential amplitude (Sengupta et al.
1996
; Su et al. 1997a
,b
), suggesting the absence
of a local anesthetic-like effect. Moreover,
-ORA effects on mean
arterial pressure in the present experiments were modest (
10 mmHg
decrease) compared with the magnitude of the nonopioid
receptor-mediated hypotension reported in similarly barbiturate-anesthetized rats (Pugsley et al. 1992
,
1993
). Moreover, the µ-,
-, and
-ORAs tested
here produced equivalent, modest hypotensive effects. Although these
considerations suggest that a local anesthetic-like action does not
explain the current results, we cannot exclude this possibility based
on the data collected.
We were surprised that morphine, studied over a very broad dose range,
did not affect either resting activity or responses of gastric vagal
afferent fibers to GD. There is a considerable literature that suggests
that morphine (0.1-2.5 mg/kg iv) and other µ-ORAs activate vagal
afferent fibers and in so doing contribute to analgesia. For example,
Randich et al. (1991) reported that bilateral cervical
vagotomy significantly attenuated the antinociception produced by
morphine given intravenously. The effects were dose dependent, and the
role of vagal afferent fibers was greatest at the lower doses of
morphine tested (see also Randich and Gebhart 1992
).
With respect to the viscera, Kumazawa et al. (1989)
reported that morphine generally excited spermatic nerve afferent
fibers in vitro. In a study in anesthetized cats, Balkowiec et
al. (1994)
applied morphine to the receptive fields of thoracic
viscera and noted that 7 of 10 vagal afferent fibers tested increased
activity. Eastwood and Grundy (1995)
reported that
morphine, the µ-receptor-selective peptide agonist
[D-Ala2,N-Me-Phe4,Gly5-ol]-enkephalin
(DAMGO) and the
-receptor-selective agonist
[D-Ala2,Leu5]-enkephalin (DADLE), but not
U50,488, stimulated both vagal and nonvagal intestinal afferents in the
rat. Excitatory effects of opioid agonists have also been described in
vitro. Very low concentrations of µ-,
-, and
-selective opioid
agonists decrease a voltage-activated K+ current
in mouse dorsal root ganglion (DRG) neurons in culture (Fan et
al. 1993
). Furthermore, nanomolar concentrations of µ-,
-,
and
-selective agonists prolong the action potential duration in DRG
neurons (Crain and Shen 1990
; Shen and Crain
1989
, 1994a
,b
).
There have been relatively few studies of -ORA effects on single
afferent fibers (not including those from this laboratory). In a sample
of articular afferent fibers innervating the inflamed knee joint of the
cat, Russell et al. (1987)
reported that two
-ORAs
(U50,488 and ethylketocyclazocine) significantly depressed spontaneous
activity in a naloxone-reversible manner. Andreev et al.
(1994)
examined the effects of the
-ORA U69,593 on polymodal nociceptors in the saphenous nerve innervating hind paw skin of the rat
(in vitro). After ultraviolet (UV) irradiation, these nociceptors
became spontaneously active, and U69,593 applied to the receptive field
significantly decreased spontaneous activity. Binder and Walker
(1998)
also reported that EMD61,753 exhibited an
antinociceptive effect in arthritic, but not nonarthritic rats, indicating that inflammation is necessary for EMD61,753-induced analgesia. We recently reported that the potency of EMD61,753 is
significantly increased in rats with chronically inflamed colon (Sengupta et al. 1999
). We did not find in that study,
however, that either µ- or
-ORAs were effective in the presence of
chronic colonic inflammation.
In conclusion, previous studies of pelvic nerve afferent fibers
innervating the urinary bladder or colon, and in the present study of
gastric vagal afferent fibers, responses to distension of hollow organs
have reliably been shown to be dose-dependently attenuated by -ORAs
(Sengupta et al. 1996
, 1999
; Su et
al. 1997a
,b
). The effects of
-ORAs are only partially
antagonized by naloxone at high doses, but not by
1-receptor-selective antagonists like nor-BNI. We have yet to observe an effect of either µ- or
-ORAs on
responses of these same fibers.
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ACKNOWLEDGMENTS |
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We thank M. Burcham for preparation of the figures and S. Birely for secretarial assistance. N. Ozaki is an exchange scientist from the Department of Anatomy, Fukushima Medical University, Fukushima, Japan.
This work was supported by National Institute of Neurological Disorders and Stroke Grants NS-19912 and NS-35790.
Present address of J. N. Sengupta: AstraZeneca, S-431 83 Molndal, Sweden.
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FOOTNOTES |
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Address for reprint requests: G. F. Gebhart, Dept. of Pharmacology, The University of Iowa, College of Medicine, 2-471 Bowen Science Bldg., Iowa City, IA 52242.
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 13 August 1999; accepted in final form 6 January 2000.
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REFERENCES |
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