Division of Gastroenterology and Hepatology, Medical College of Wisconsin, Milwaukee, Wisconsin 53226
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ABSTRACT |
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Spinal afferents innervating the
gastrointestinal tract are the major pathways for visceral nociception.
Many centrally acting analgesic drugs attenuate responses of visceral
primary afferent fibers by acting at the peripheral site. -Amino
butyric acid (GABA), a major inhibitory neurotransmitter, acts via
metobotropic GABAB and ionotropic
GABAA/GABAC receptors. The aim of this study was to test the peripheral effect of selective GABAB
receptor agonist baclofen on responses of the pelvic nerve afferent
fibers innervating the colon of the rat. Distension-sensitive pelvic nerve afferent fibers were recorded from the S1 sacral
dorsal root in anesthetized rats. The effect of baclofen (1-300
µmol/kg) was tested on responses of these fibers to colorectal
distension (CRD; 60 mmHg, 30 s). A total of 21 pelvic nerve
afferent fibers was recorded. Mechanosensitive properties of four
fibers were also recorded before and after bilateral transections of
T12-S3 ventral roots (VR). Effect of baclofen
was tested on 15 fibers (7 in intact rats, 4 in rats with transected
VR, and 4 in rats pretreated with CGP 54626). In nine fibers (5/7 in
intact and 4/4 in VR transected rats), baclofen produced dose-dependent
inhibition of response to CRD. Pretreatment with selective
GABAB receptor antagonist CGP 54626 (1 µmol/kg) reversed
the inhibitory effect of baclofen. Results suggest a peripheral role of
GABAB receptors in the inhibition of mechanotransduction
property of distension-sensitive pelvic nerve afferent fibers.
baclofen; visceral pain; spinal cord; sacral nerve; ventral roots
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INTRODUCTION |
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-AMINO
BUTYRIC ACID (GABA), a major inhibitory neurotransmitter, plays
an important role in antinociception. This effect is largely mediated
by GABAB receptors ubiquitously present in the brain and
spinal cord (13, 15, 17, 27, 31, 62, 63). The
GABAB receptor is a unique G protein-coupled receptor that
requires dimerization of two subunits (GABAB1,
GABAB2) to form a functional receptor (22, 26,
61). It is thought that GABAB1 subunit is essential
for binding with the ligand, whereas GABAB2 subunit is
necessary for the expression of the functional receptor on the cell
surface. A number of splice variants of the GABAB1 subunit
(GABA1a, GABA1b, GABA1c,
GABA1d) have been identified in the rat and human, which
are differentially expressed in different tissues (20, 24, 26,
42). For example, GABAB1 subunit is ubiquitously
present in the neurons of CNS and nonneuronal tissues, whereas
GABAB2 subunit is present only in the neurons of the brain
and spinal cord (12). Recent reports indicate that GABAB receptors play a major role in transient lower
esophageal sphincter relaxation (TLESR). Systemic application of
GABAB receptor agonist baclofen decreases the number of
TLESR and prevents gastroesophageal acid reflux (7-9, 27,
29). This effect of baclofen occurs partly by attenuating the
mechanotransduction property of the vagal afferent fibers innervating
the esophagus and the proximal stomach (38, 40, 52).
Baclofen produces antinociception in the rat model of visceral pain (1, 19). Abelli et al. (1) demonstrated that in conscious rats subcutaneous injection of baclofen prevents the behavioral responses of pain produced by instilling xylene into the urinary bladder. Similarly, intrathecal injection of baclofen increases the threshold for visceromotor response (VMR) to colorectal distension (CRD) in a dose-dependent fashion (19). Expression of c-fos in the lumbosacral spinal cord to mustard oil-induced inflammation of the colon can be markedly reduced by intraperitoneal injection of baclofen (30). This effect of baclofen occurs primarily via the activation of presynaptic GABAB receptors that regulate the release of substance P (SP) from the primary afferent terminals in the spinal cord (4, 31, 33, 44). In addition, baclofen reduces the c-fos expression and internalization of neurokinin (NK)1 receptor in lamina I neurons even when SP is exogenously administered, suggesting a direct postsynaptic site of action on the dorsal horn neurons.
Recent studies have documented that baclofen and other GABAB receptor agonists have a peripheral site of action. Baclofen dose dependently attenuates responses of vagal mucosal and muscle tension-sensitive afferent fibers innervating the esophagus and proximal stomach (38, 40, 52). Results strongly suggest the presence of functional GABAB receptors at the receptive terminals of the vagal afferent fibers. Retrograde labeling of the vagal afferents from the proximal stomach and subsequent immunocytochemical reaction for GABAB receptors have confirmed the presence of GABAB receptors in the cell bodies of the nodose ganglion (3, 52). Like in the vagus nerve, GABAB receptor subunits and their mRNAs are also present in the dorsal root ganglion (18, 34, 43, 59). Therefore, it is conceivable that functional GABAB receptors may be present at the receptive terminals of the spinal primary afferent fibers, and selective agonist for the GABAB receptor may attenuate responses of these afferent fibers. Therefore, the aim of the present study was to evaluate the effect of GABAB receptor agonist baclofen on responses of mechanosensitive pelvic nerve afferent fibers innervating the colon of the rat. Preliminary data of this work were presented in abstract form at the annual meeting of American Gastroenterology Association (49).
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MATERIALS AND METHODS |
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Animals
Male Long-Evans rats (Taconic, New York) weighing 400-450 g were used in this study. Food, but not water, was withheld 12 h before the experiment. All procedures were approved by The Institutional Animal Care and Use Committee of the Medical College of Wisconsin.General Procedures
Rats were anesthetized initially with pentobarbital sodium (40-45 mg/kg ip) and maintained with supplemental doses of 5-10 mg · kgElectrophysiological Study
Surgical procedures. The lower abdomen was exposed by a 3- to 4-cm-long incision laterally at the left flank. The urinary bladder was emptied and catheterized (PE-100) through the dome of the bladder. The left testis, vas deferens, and seminal vesicle were tied and removed. The prostate lobe was reflected laterally to access the major pelvic ganglion and pelvic nerve. A pair of Teflon-coated stainless steel wires stripped at the tips was wrapped around the pelvic nerve. The exposed parts of the wires were covered with nonreactive silicon gel (Wacker). The abdomen was closed in layers with silk sutures. The sciatic nerve was approached through the ischiatic notch and transected. The left lateral tail nerve was approached at the root of the tail and transected to reduce the number of somatic afferent input to S1 dorsal root.
The lumbosacral spinal cord was exposed by laminectomy (T13-S2), and the rat was suspended from thoracic vertebral and ischial spinal clamps. The dorsal skin was reflected laterally and tied to make a pool for mineral oil. Dura was carefully removed, and the spinal cord was covered with warm (37°C) mineral oil.CRD. CRD was employed as the visceral stimulus. A flaccid, flexible latex balloon (6- to 7-cm length, 2- to 3-cm diameter; made from a condom) was inserted into the descending colon and positioned such that the end of the balloon was 1 cm into the rectum. The balloon was secured in place by taping the balloon catheter to the base of the tail. The outer diameter of the balloon when inflated was greater than the intraluminal diameter of the rat colon. Therefore, the pressure measured during distension indicated actual intracolonic pressure. The balloon catheter was connected to a computer-controlled barostatic distension device (2). Isobaric distension was achieved by opening a solenoid valve to a constant-pressure air reservoir and was altered by changing the pressure in the reservoir.
Recording of afferent nerve action potentials. The S1 dorsal root was identified and decentralized at its entry to the spinal cord. Recordings were made from the distal cut end of the central processes of primary afferent fibers. A length of nerve fiber was draped over a black microbase plate immersed in warm (37°C) mineral oil. The dorsal rootlet was split into thin bundles, and a fine filament was isolated from the bundle to obtain a single unit. Electrical activity of single units was recorded monopolarly by placing a teased fiber over one arm of a bipolar platinum electrode; a fine strand of connective tissue was placed across the other pole of the electrode. Action potentials were monitored continuously by analog delay and displayed on a storage oscilloscope after initial amplification through a low-noise AC differential amplifier. Action potentials were processed through a window discriminator, and the frequency of firing was analyzed (1-s binwidth) on line using the spike2 (version-3.21)/CED 1401 data acquisition program. Peristimulus time histograms (PSTHs), colonic distending pressures, and blood pressure were displayed on line.
Experimental Protocol
Pelvic nerve input to the S1 dorsal root was identified first by electrical stimulation of the pelvic nerve (a single 0.5-ms square-wave pulse at 5-8 mA). 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 AThe effect of baclofen (GABAB agonist) was tested on the responses of distension-sensitive pelvic nerve afferent fibers to nociceptive CRD (60 mmHg, 30 s). The interstimulus time interval was 3 min. Baclofen was injected intra-arterially 90 s before distension. A cumulative dose-response function was constructed by giving 1, 3, 10, 30, and 300 µmol/kg baclofen. To test whether the inhibitory effect of baclofen was mediated via spinal motor neurons, the effect of baclofen was tested in rats with bilateral VR transected (T12-S3).
To examine the GABAB receptor-mediated effect of baclofen, cumulative doses of baclofen were injected into rats pretreated with the GABAB receptor-selective antagonist CGP 54626 (1 µmol/kg iv). CGP 54626 was injected after recording two reproducible responses to CRD (60 mmHg). Response of the fiber to another distension was recorded after CGP 54626 injection to test the effect of CGP 54626. This was followed by a cumulative dose-response function of baclofen. Because the inhibitory effect of baclofen lasted >120 min, the dose-response function of baclofen could not be tested before transection VR or before CGP 54626 application.
Data Analysis
Resting activity of a fiber was counted for 60 s and the firing frequency was represented as impulses/s. To determine the actual response of the fiber to CRD the resting firing frequency was subtracted from the firing frequency during the CRD. SRF-to-graded CRD was plotted for individual fiber, and a least squares regression line was obtained from the linear part of the SRF. The regression line was then extrapolated to the ordinate (representing distension pressure), and the intercept point was considered as estimated response threshold. The effect of baclofen was determined by measuring the firing frequencies of the fiber to CRD (30 s) subtracted from the baseline activity.All data were expressed as means ± SE. Results were compared statistically using Student's t-test or repeated-measures ANOVA. Doses to produce 50% inhibition of response (ID50) were calculated from the 20-80% regression by fitting the data of the cumulative dose-response curve to logarithmic best fit line (58). The following equation was derived from this line: y = y0 + a · ln (x), where a is slope. Setting the y value to 50 and using the y0 and a coefficients from the logarithmic best fit line accomplished the x variable in the equation. A value of P < 0.05 was considered statistically significant.
Drugs
Baclofen (213.7 mol wt; Sigma) was dissolved in saline, and the pH was set to 7.00 by adding a few drops of acetic acid. CGP 54626 (444.7 mol wt; Tocris Cookson) was dissolved in polyethylene glycol. ![]() |
RESULTS |
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Sample
A total of 21 pelvic nerve afferent fibers was identified in the S1 sacral dorsal root that responded to CRD. Seven of these were unmyelinated C-fibers (mean: 1.85 ± 0.12 m/s, range: 1.55-2.50 m/s) and 14 were thinly myelinated AResponses to CRD
SRFs of 21 fibers were tested to graded isobaric CRD (5-100 mmHg). All fibers exhibited a linear increasing response to graded distension. Figure 1 illustrates the example of intensity-dependent response of a pelvic nerve afferent fiber to graded CRD. These fibers typically exhibited a slowly adapting response to a 30-s period of CRD. At greater intensities (
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Figure 2A shows the individual
SRFs of 17 pelvic nerve afferent fibers with intact VR. Figure
2B shows the mean SRF of these fibers. The threshold for
response of each fiber was estimated by extrapolating the linear
regression line to the x-axis. The estimated mean threshold
for response of these fibers was 4.7 ± 1.14 mmHg (range:
0-18 mmHg).
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To examine the influence of tonic effect of the spinal motorneurons
innervating the colon, SRF was repeated after bilateral transection of
VR (n = 4). Figure 3
shows examples of responses of a fiber before and after transection of
the VRs. Figure 2C shows individual SRFs of four fibers
before and after VR transection. Mean SRF plots of these fibers before
and after VR transection were very similar (Fig. 2D). Slopes
of the mean SRFs were quite identical (0.95 and 0.97), suggesting that
VR transection did not affect the mechanosensitive properties of these
fibers to isobaric distension. The mean estimated thresholds for
response before and after ventral root transection were 2.02 ± 0.70 (range: 0-3.06 mmHg) and 3.41 ± 0.33 mmHg (range:
0-3.77 mmHg), respectively.
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Effect of GABAB Receptor Agonist
The effect of selective GABAB agonist baclofen on responses to distension were tested on afferent fiber recorded in intact (n = 7) and bilateral VR transected rats (n = 4). Of seven fibers tested with baclofen in intact rats, responses of five (71%) to CRD (60 mmHg, 30s) were dose dependently inhibited. Baclofen also progressively inhibited the ongoing resting activity of these fibers. Figure 4 illustrates an example of the effect of incrementing doses (1-300 µmol/kg) of baclofen on responses of a distension-sensitive pelvic nerve afferent fiber from an intact rat. The mean maximum response to a 300 µmol/kg cumulative dose of baclofen was 8.24 ± 8.24% (n = 5) of the control response. The mean calculated ID50 of baclofen that produced responses to 60-mmHg CRD was 9.84 ± 3.18 µmol/kg. In the majority of cases, the inhibitory effect of baclofen lasted >120 min.
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To examine whether the effect of baclofen was due to inhibition of
tonically active spinal motorneurons innervating the descending colon,
baclofen was tested on four fibers after bilateral transection of VR
(T12-S3).D Like in intact
rats, baclofen produced dose-dependent inhibition of response of the
fibers to CRD in rats with VR transected (Fig.
5). The mean maximum response to a
cumulative dose of 300 µmol/kg was 20.38 ± 2.35%
(n = 4) of the control response. The mean calculated
ID50 of baclofen that produced responses to 60-mmHg CRD was
11.62 ± 2.35 µmol/kg, which was not significantly
(P > 0.05) different from the VR intact rats (see Fig.
7).
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Effect of Selective Antagonist CGP 54626
To determine whether the inhibitory effect of baclofen was produced by activation of GABAB receptors, baclofen was tested on responses of four fibers in four rats pretreated with the selective GABAB receptor antagonist CGP 54626 (1 µmol/kg iv). Because the inhibitory effect of baclofen was long lasting (>120 min), a control dose response of baclofen before the effect of CGP 54626 was not performed. The reversal by CGP 54626 was compared with that of the fibers tested only to baclofen. CGP 54626 was injected 4-5 min before cumulative injection of baclofen (1-100 µmol/kg). Figure 6 shows an example of reversal of the inhibitory effect of baclofen by the antagonist. CGP 54626 produced a brief increase in firing but no attenuation of response to CRD. The inhibitory effect of baclofen was markedly reversed by CGP 54626. The mean maximum of response at a cumulative dose of 300 µmol/kg of baclofen was 71.36 ± 17.85% (n = 4), suggesting a significantly less inhibition of response by baclofen in the presence of CGP 54626 (Fig. 7).
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DISCUSSION |
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Results show that distension-sensitive pelvic nerve afferent fibers exhibit a linear increasing response to graded CRD. All fibers exhibit a slowly adapting response to phasic distension. The present study also shows that the threshold for response and the slope of the SRF of these afferent fibers do not change after bilateral VR transection. Previous studies (46, 47, 50) have documented that in Sprague-Dawley rats, ~25-30% of pelvic nerve afferent fibers supplying the descending colon and the urinary bladder have high thresholds (>30 mmHg) for response. In the present study in Long-Evans rats, however, all fibers exhibited low thresholds (<5 mmHg) for response. This difference in results could be a strain-related phenomenon. A comparative study (36) has indicated that the mechanical stimulation of the plantar skin by von Frey filaments has significantly lowered baseline responses in Long-Evans rats compared with Sprague-Dawley and Wistar rats. This strain has the highest percentage of rats that develops mechanical allodynia to spinal cord injury. Results suggest that sensory thresholds of Long-Evans rats are relatively lower than other strains of rats.
The present study documents that selective GABAB receptor agonist baclofen dose dependently (1-300 µmol/kg) attenuates responses of distension-sensitive afferent fibers in the pelvic nerve. The effect appears to be a direct peripheral site of action of the drug at the sensory nerve terminals. It is quite unlikely that inhibition of response by baclofen is associated with changes in compliance of the lumen by relaxing the smooth muscle and/or by inhibiting the tonic control of the spinal motorneurons for two reasons: 1) the effect of baclofen was tested to isobaric (a constant pressure) distension, and 2) the effect remains unchanged when tested on fibers in bilateral VR transected rats. Reversal of inhibitory response by selective GABAB receptor antagonist CGP 54626 indicates that the action of baclofen is mediated via GABAB receptors. Results also indicate there is no correlation between the effect of baclofen and conduction velocity of the nerve fiber.
Effect of Baclofen in Visceral Pain
There are reports that baclofen has an effect on visceral pain. In the conscious, freely moving rat model of visceral pain induced by instilling xylene into the urinary bladder, subcutaneous injection of baclofen reduces the behavioral (licking of lower abdomen or perineal region, hind paws in hyperextension) responses (1). Similarly, visceral pain produced by noxious CRD is dose dependently reduced by intrathecal administration of baclofen into the lumbosacral segment of the spinal cord (19). Systemic application of Baclofen markedly reduces the c-fos expression in the lumbosacral spinal cord in capsaicin-induced irritation of the urinary bladder or mustard oil-induced inflammation of the colon (5, 30). The antinociception and reduction of c-fos expression by baclofen are thought to be principally due to the reduction of SP release from the presynaptic terminals in the spinal cord (44). The present study, however, documents that the antinociceptive effect of baclofen may also be, in part, due to direct effects on the mechanotransduction properties of visceral afferent fibers. This result is inconsistent with those of Blackshaw and colleagues (38, 40, 52), who reported a peripheral inhibitory effect of baclofen on responses of vagal afferent fibers innervating the esophagus and proximal stomach.Peripheral Site of Action
It is known that systemic applications of many of the centrally acting drugs exert inhibitory effects by acting at the peripheral sites. For example,Our results show that selective GABAB receptor antagonist CGP 54626 can reverse the inhibitory effect of baclofen at the peripheral site of the pelvic nerve afferent fibers, confirming a GABAB receptor-mediated effect of baclofen. This is consistent with the previous reports in the vagal afferent fibers (10, 38, 40, 52). The exact mechanisms by which GABAB receptors attenuate responses of the mechanosensitive pelvic nerve afferent fibers are yet to be studied. Three possible mechanisms can be discerned for GABAB-mediated action: 1) a reduction of neurotransmitter (e.g., SP, CGRP) release from the primary afferent nerve terminals that in turn may excite the fibers, 2) inhibition of Ca2+-channel couple to the GABAB receptor, and 3) activation of G protein couple inwardly rectifying K+ channels (GIRK). Although there is no direct evidence of release of SP and/or CGRP from the receptive terminals to mechanical distension, this possibility cannot be excluded. Electrophysiological studies (23) have shown that NK3 receptor antagonist SR 142,801 can attenuate mechanotransduction properties of the pelvic nerve afferent fibers innervating the colon but not the urinary bladder. Therefore, SP and/or NKB may be involved in excitation of spinal afferents to mechanical distension. However, evidence is strongest that regulations of Ca2+ and K+ channels coupled to GABAB receptors are the principal mechanisms by which baclofen attenuates responses of these afferent fibers. There is ample evidence that baclofen inhibits N- and P/Q-type Ca2+ channels in the sensory neurons and activates the GIRK (11, 15, 60).
In conclusion, the present study provides direct evidence that GABAB receptor agonist baclofen can modulate visceral nociception by attenuating responses of pelvic nerve afferent fibers at the peripheral site. Like KORA, antinociceptive effect of baclofen occurs at multiple sites and, more importantly, at the level of the spinal cord. Use of baclofen for visceral pain may be associated with a number of undesirable effects (e.g., sedation, tolerance, respiratory depression, constipation, etc.). However, recent identifications of GABAB receptor subunits (GABAB1, GABAB2), their splice variants, and specific location in the tissues are encouraging. This may lead to the design of subtype-targeted drugs for more effective therapy.
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ACKNOWLEDGEMENTS |
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We thank Dr. Cheryl Stucky, Dept. Cell Biology, Medical College of Wisconsin for comments and suggestions.
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FOOTNOTES |
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The work was supported by Medical College of Wisconsin New Faculty Grant awarded to J. N. Sengupta.
Address for reprint requests and other correspondence: J. N. Sengupta, Medical College of Wisconsin, MaccFund Research Center, Third Floor, 8701 Watertown Plank Road, Milwaukee, WI 53226 (E-mail: sengupta{at}mcw.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.
10.1152/ajpgi.00124.2002
Received 1 April 2002; accepted in final form 27 August 2002.
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