Departments of Physiology and Medicine, Medical College of Virginia, Virginia Commonwealth University, Richmond, Virginia 23298-0551
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ABSTRACT |
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The circuit of myenteric interneurons that
regulate excitatory input to longitudinal colonic muscle was identified
using dispersed ganglia and longitudinal muscle strips with adherent
myenteric plexus from rat distal colon. The preparations enabled
measurement of neurotransmitter release from interneurons
and/or excitatory motoneurons innervating longitudinal muscle.
1,1-Dimethyl-4-phenylpiperizinium (DMPP) and somatostatin were used to
activate myenteric neurons in dispersed ganglia and muscle strips,
respectively. DMPP-stimulated vasoactive intestinal peptide (VIP)
release in dispersed ganglia was inhibited by
[Met]enkephalin and bicuculline and augmented by naloxone
and GABA, implying that inhibitory opioid and stimulatory GABA neurons
regulate the activity of VIP interneurons. In muscle strips, VIP
stimulated basal and augmented somatostatin-induced substance P (SP)
release; the somatostatin-induced increase in SP release was inhibited
by VIP-(1028) and
NG-nitro-L-arginine, implying that
excitatory VIP neurons regulate tachykinin motoneurons innervating
longitudinal muscle. Somatostatin inhibited [Met]enkephalin
and stimulated VIP release; basal and somatostatin-stimulated VIP
release were inhibited by [Met]enkephalin and bicuculline
and augmented by naloxone and GABA, implying that inhibitory pathways
linking somatostatin, opioid, and GABA neurons regulate VIP
interneurons, which in turn regulate tachykinin and probably
cholinergic motoneurons.
peristaltic reflex; myenteric plexus; neurotransmitter release; enteric nervous system; neuropeptides
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INTRODUCTION |
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MOTOR INNERVATION of intestinal longitudinal muscle consists largely of excitatory neurons, particularly in smaller mammals (4, 5, 7, 8, 24, 27, 30). In the intestine and colon virtually all motoneurons innervating longitudinal muscle contain acetylcholine; about 50% of these contain also the tachykinins, substance P (SP), and neurokinin A (4, 5, 7). Inhibitory neurotransmitters such as vasoactive intestinal peptide (VIP) are present in <3% of motoneurons (4, 5, 8, 24). In contrast, intestinal circular muscle is densely innervated with excitatory cholinergic/tachykinin neurons and inhibitory motoneurons expressing or coexpressing VIP, pituitary adenylate cyclase-activating polypeptide (PACAP), and nitric oxide synthase (NOS) (7, 8, 18, 24, 26, 27, 32).
Consistent with the topography of motoneurons, contraction or relaxation of tone in longitudinal muscle is regulated by the level of activity of excitatory motoneurons, which in turn is regulated by a variety of interneurons. Previous studies have shown that VIP, PACAP, and NO, which can cause direct relaxation of longitudinal smooth muscle cells (17), cause contraction when applied to innervated longitudinal muscle strips; the contraction is blocked additively by muscarinic and tachykinin antagonists and abolished by tetrodotoxin (1, 2, 6, 20-23). Furthermore, both VIP and PACAP stimulate the release of acetylcholine and tachykinins (6, 22, 34, 35). The pattern suggests that excitatory VIP/PACAP/NOS interneurons in the myenteric plexus regulate the activity of cholinergic/tachykinin neurons innervating intestinal longitudinal muscle.
The VIP/PACAP/NOS myenteric interneurons are distinct from VIP/PACAP/NOS motoneurons innervating circular muscle. Previous studies on the colonic peristaltic reflex have shown that the latter are regulated by an integrated circuit of somatostatin, opioid, and GABA neurons (11). During peristaltic activity an increase in the activity of somatostatin and GABA neurons leads to a decrease in the activity of opioid neurons. The resultant decrease in [Met]enkephalin release relieves the restraint exerted by opioid neurons on VIP/PACAP/NOS motoneurons (3, 16), thereby increasing VIP, PACAP, and NO release and inducing circular muscle relaxation (10, 14, 15).
We postulated that the same circuit of somatostatin, GABA, and opioid interneurons may also regulate VIP/PACAP/NOS interneurons, coupled to excitatory motoneurons innervating longitudinal muscle. The activity of interneurons in this circuit should lead to reciprocal contraction of longitudinal muscle during peristaltic activity.
The operation of this circuit, depicted in Fig. 1, was tested in the present study by direct measurement of neurotransmitter release from longitudinal muscle strips with adherent myenteric plexus. The preparation excludes release of neurotransmitters from motoneurons innervating circular muscle. According to the model circuit, somatostatin, opioid, and VIP/PACAP/NOS interneurons are coupled in series to each other and to cholinergic/tachykinin motoneurons innervating longitudinal muscle. An increase in somatostatin release would induce a decrease in [Met]enkephalin release, which in turn would induce an increase in VIP, PACAP, and NO release. The increase in VIP, PACAP, and NO release activates motoneurons leading to release of acetylcholine and tachykinins and inducing longitudinal muscle contraction.
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METHODS |
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Preparation of colonic longitudinal muscle strips with adherent myenteric plexus. Segments of distal colon were obtained from adult rats and placed in Krebs-bicarbonate medium containing (in mM) 118 NaCl, 4.8 KCl, 1.2 KH2PO4, 1.2 MgSO4, 2.5 CaCl2, 25 NaHCO3, and 11 glucose for 15 min. The segments were flushed with the same medium to remove intraluminal contents and threaded onto glass rods, and the mesenteric attachment was stroked tangentially with cotton to separate the longitudinal muscle and adherent myenteric plexus from the circular muscle. The muscle sheet was cut into strips (30 mm × 10 mm; mean wet wt ± SD, 23.4 ± 8.8 mg), which were used for measurement of neurotransmitter release.
In some experiments several strips were used to prepare dispersed myenteric ganglia as described previously (13, 34). The strips were minced and incubated for 45 min at 37°C in 30 ml of Krebs-bicarbonate medium containing 2 mg/ml collagenase (type II) and 2 mg/ml protease (type IX) and triturated at 15-min intervals. The suspension was then filtered through 500 µm Nitex mesh, and the filtrate was centrifuged for 5 min at 150 rpm. The supernatant was discarded, and the pellet containing the ganglia was washed twice in 30 ml of fresh Krebs-bicarbonate medium. The final pellet was resuspended in 20 ml of fresh Krebs-bicarbonate medium, and the ganglia were individually harvested with a 50-µl pipette (total yield ~800-1,000 ganglia). Each experimental sample contained 100 ganglia per milliliter.Measurement of neurotransmitter release from myenteric
plexus-longitudinal muscle strips.
Muscle strips were suspended in 1 ml of Krebs-bicarbonate
medium maintained at 37°C and containing 0.1% bovine serum
albumin, amastatin (10 µM), and phosphoramidon (1 µM). Somatostatin
was added to the bathing medium for 5 min in the presence or absence of
neurotransmitter agonists (NO, [Met]enkephalin, VIP) or
antagonists [VIP-(1028), naloxone, bicuculline, and
NG-nitro-L-arginine
(L-NNA) (10, 11, 16, 28,
31)]. The medium was collected and frozen at
80°C for
subsequent radioimmunoassay of [Met]enkephalin, VIP, or SP.
Radioimmunoassay of [Met]enkephalin, VIP, and SP.
[Met]enkephalin was measured as described previously
(11) using antibody 18100 at a final dilution of 1:5,000. The limit of
detection of the assay was 68 fmol/ml of original sample, and the
IC50 was 272 fmol/ml. The
concentration of [Met]enkephalin in the samples ranged from
112 to 234 fmol/ml. The antibody reacts fully with
[Met]enkephalin and minimally (<3%) with
[Leu]enkephalin but does not cross-react with dynorphin-13,
SP, VIP, or VIP-(1028).
Data analysis. Neurotransmitter release was expressed as femtomoles per 100 mg tissue per minute. Values are means ± SE of n experiments; each experiment was done in tissue obtained from a different animal. Statistical significance was evaluated using Student's t-test for paired or unpaired values.
Materials.
Somatostatin and VIP-(1028) were obtained from Bachem (Torrance, CA);
somatostatin, [Met]enkephalin, SP, VIP,
125I-SP,
125I-VIP, SP antibody RAS-7451,
and VIP antibody RAS-7161 were from Peninsula Labs (Belmont, CA);
125I-labeled
[Met]enkephalin and [Met]enkephalin antibody
18100 were from Incstar (Stillwater, MN). Naloxone, bicuculline,
L-NNA, GABA, DMPP, and all other
chemicals were obtained from Sigma Chemical (St. Louis, MO). Nitric
oxide was prepared from NO gas (MG Industries, Valley Forge, PA).
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RESULTS |
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Effect of opioid and GABA agonists and antagonists on basal and
somatostatin-stimulated VIP release from myenteric plexus-longitudinal
muscle strips.
Somatostatin was used to stimulate or inhibit the release of various
neurotransmitters (11). Somatostatin (1 µM) increased basal VIP
release (45.6 ± 4.4 fmol · 100 mg1 · min
1)
by 74.5 ± 4.8% (P < 0.001) but
decreased basal [Met]enkephalin release (116.5 ± 12.6 fmol · 100 mg
1 · min
1)
by 52.3 ± 6.9% (P < 0.01; Fig.
2 and Table
1).
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Effect of opioid and GABA agonists and antagonists on basal and
somatostatin-stimulated VIP release from dispersed myenteric ganglia.
Parallel studies in dispersed myenteric ganglia confirmed the sustained
inhibitory influence of [Met]enkephalin and stimulatory influence of GABA on VIP release from interneurons. DMPP (100 µM)
increased VIP release by 12.8 ± 1.4 fmol · 100 ganglia1 · min
1
or 164 ± 14% above a basal level of 7.7 ± 0.9 fmol · 100 ganglia
1 · min
1
(n = 4, P < 0.01; Fig.
3). DMPP-stimulated VIP release was
abolished by [Met]enkephalin (0.9 ± 0.4 fmol · 100 ganglia
1 · min
1)
but augmented 109 ± 10% by naloxone to 26.2 ± 2.4 fmol · 100 ganglia
1 · min
1
above basal level (n = 4, P < 0.01; Fig. 3). DMPP-stimulated VIP release was augmented 54.7 ± 8.9% by GABA to 19.8 ± 1.9 fmol · 100 ganglia
1 · min
1
above basal level (n = 4, P < 0.02) and inhibited 45 ± 10% by bicuculline to 7.4 ± 1.0 fmol · 100 ganglia
1 · min
1
above basal level (n = 4, P < 0.01; Fig. 3).
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Effect of opioid and GABA agonists and antagonists on basal and
somatostatin-stimulated SP release from myenteric plexus-longitudinal
muscle strips.
Somatostatin (1 µM) increased basal SP release (24.9 ± 2.7 fmol · 100 mg1 · min
1)
by 90.9 ± 15.7% (P < 0.001;
Table 1). [Met]enkephalin (1 µM) decreased basal SP
release by 7.8 ± 0.4% (P < 0.01) and somatostatin-stimulated SP release from 90.9 ± 15.7 to
37.3 ± 7.6% above basal level (P < 0.001; Table 1 and Fig. 4). In
contrast, naloxone (10 µM) increased basal SP release by 69.1 ± 14.4% (P < 0.01) and
somatostatin-stimulated SP release to 234.1 ± 21.3% above basal
level (P < 0.001; Table 1 and Fig.
4). GABA (1 mM) increased basal SP release by 103.9 ± 14.5%
(P < 0.005) and
somatostatin-stimulated SP release to 185.3 ± 15.7% above basal
level (P < 0.005; Table 1 and Fig. 4). In contrast, bicuculline (20 µM) decreased basal SP release by 22 ± 2% (P < 0.01) and
somatostatin-stimulated SP release to 46.4 ± 5.1% above basal
level (P < 0.01; Table 1 and Fig.
4). As for VIP release, the pattern of inhibition of basal and
somatostatin-stimulated SP release by [Met]enkephalin and
bicuculline and stimulation by GABA and naloxone was consistent with
the postulates of the model depicted in Fig. 1. The fact that naloxone
augmented basal and somatostatin-stimulated SP release implied that
endogenous release of [Met]enkephalin exerts a continuous
restraint on SP release either directly or indirectly via inhibition of
the release of VIP from VIP interneurons. Similarly, the fact that
bicuculline inhibited basal and somatostatin-stimulated SP release
implied that endogenous release of GABA exerts a sustained stimulatory influence on SP release either directly or indirectly via stimulation of the release of VIP from VIP interneurons.
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Effect of VIP, a VIP antagonist, NO, and a NOS inhibitor on basal
and somatostatin-stimulated SP release from myenteric
plexus-longitudinal muscle strips.
VIP (1 µM) increased basal SP release by 59 ± 11% and augmented
somatostatin-stimulated SP release from 90.9 ± 15.7 to 174.8 ± 9.5% above basal level (P < 0.01;
Table 1 and Fig. 5). In contrast, VIP-(1028) had no significant effect on basal SP release but decreased somatostatin-stimulated SP release to 30.0 ± 9.9% above basal level (P < 0.01; Table 1 and
Fig. 5). Exogenous NO, like VIP, increased basal SP release by 65 ± 9% (P < 0.01) and augmented somatostatin-stimulated SP release to 248.6 ± 23.1% above basal level (P < 0.01; Table 1 and Fig.
5). The NOS inhibitor, L-NNA (100 µM) had no significant effect on basal SP release but decreased somatostatin-stimulated SP release to 26.3 ± 4.1% above basal level (P < 0.01; Table 1 and Fig.
5).
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DISCUSSION |
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We have previously shown that a modulatory circuit consisting of somatostatin, opioid, and GABA neurons regulates the activity of inhibitory VIP/PACAP/NOS motoneurons innervating the circular muscle layer of the rat colon (11). The present study shows that a similar circuit regulates also the activity of excitatory VIP/PACAP/NOS interneurons, which in turn regulate the activity of excitatory tachykinin neurons innervating the longitudinal muscle layer. The study was made possible by the use of longitudinal muscle strips with adherent myenteric plexus, thereby precluding release of neurotransmitters from neural projections to the circular muscle layer. The results were corroborated by studies in dispersed ganglia isolated from the myenteric plexus of the rat colon.
Evidence for the operation of the neuronal circuit (Fig. 1) regulating longitudinal muscle function is based on the use of selective antagonists to block the effect of neurotransmitters released at specific synapses. The evidence for the interplay of neurons in this circuit may be summarized as follows.
Somatostatin inhibited [Met]enkephalin release but stimulated VIP and SP release; the stimulation of VIP release resulted from elimination of the restraint exerted by opioid neurons on excitatory VIP interneurons. The serial coupling of two inhibitory pathways involving somatostatin and opioid neurons resulted in activation of excitatory VIP interneurons, which in turn activated tachykinin motoneurons.
[Met]enkephalin inhibited basal and somatostatin-stimulated VIP and SP release, whereas naloxone had the opposite effect. The stimulatory influence of naloxone implied that opioid neurons exert a continuous restraint on VIP interneurons and SP motoneurons (9, 19). The continuous restraint exerted on VIP interneurons was corroborated by studies in dispersed myenteric ganglia, where naloxone was shown to augment DMPP-stimulated VIP release. The results in isolated myenteric ganglia are consistent with immunocytochemical evidence for the existence of VIP interneurons in the myenteric plexus (7, 8, 24, 25) and imply that opioid neurons can project to or influence the activity of VIP interneurons.
VIP and NO stimulated basal SP release and augmented
somatostatin-stimulated SP release. The VIP antagonist VIP-(1028) and the NOS inhibitor L-NNA
inhibited somatostatin-stimulated SP release. The inhibitory influence
of VIP-(10
28) and L-NNA
implied that VIP/NOS interneurons stimulate the activity of tachykinin
motoneurons.
GABA increased basal VIP and SP release and augmented somatostatin-stimulated VIP and SP release, whereas the GABAA receptor antagonist bicuculline had the opposite effect. The inhibitory influence of bicuculline implied that GABA neurons exert a sustained stimulatory influence on VIP and SP release. This conclusion was corroborated by studies in dispersed myenteric ganglia, where GABA augmented and bicuculline inhibited DMPP-stimulated VIP release. The results obtained in myenteric ganglia imply that GABA neurons project to and can influence the activity of VIP interneurons. Previous studies (11) in whole segments of rat colon had shown that GABA and opioid neurons are coupled via reciprocal inhibitory pathways, such that a decrease in opioid neuronal activity leads to an increase in GABA neuronal activity.
The excitatory VIP/NOS interneurons also express PACAP in rat intestine (18). It is therefore likely that PACAP is released together with VIP and NO to activate tachykinin motoneurons; the latter also releases acetylcholine and is more suitably viewed as cholinergic/tachykinin motoneurons (4, 5, 7). Studies in myenteric plexus-longitudinal muscle preparations from guinea pig intestine confirm the ability of VIP, PACAP, and NO to stimulate acetylcholine and SP release and induce muscle contraction that can be additively blocked by atropine and tachykinin antagonists (1, 2, 6, 19-23).
The fact that some opioid neurons also project into longitudinal smooth muscle raises the possibility that opioid neurons may also exert a continuous presynaptic restraint on cholinergic/tachykinin motoneurons (8, 9, 19, 24). Elimination of this restraint by somatostatin or presynaptically by naloxone should also lead to activation of cholinergic/tachykinin motoneurons. Thus two pathways involving somatostatin and opioid neurons could lead eventually to activation of cholinergic/tachykinin motoneurons innervating longitudinal muscle: one pathway involves serial coupling of somatostatin, opioid, and VIP/PACAP/NOS interneurons as depicted in Fig. 1; the other pathway represents direct presynaptic regulation of cholinergic/tachykinin motoneurons by opioid nerve terminals in longitudinal muscle.
The stimulatory influence of GABA neurons on VIP/NOS interneurons demonstrated in the present study parallels the stimulatory effect previously demonstrated in whole rat colonic segments (11). As shown in Fig. 1, elimination of the inhibitory restraint exerted by opioid neurons on excitatory GABA neurons leads to an increase in VIP release and thus to an increase in SP release. It is possible, however, that SP release could result also from an excitatory presynaptic effect of GABA on cholinergic/tachykinin motoneurons. Here again, two pathways may mediate the excitatory effects of GABA on cholinergic/tachykinin motoneurons innervating longitudinal muscle: one pathway involves serial coupling of somatostatin, opioid, GABA, and VIP neurons as depicted in Fig. 1, for which corroborative evidence exists based on studies in isolated ganglia; the other pathway represents direct presynaptic regulation of cholinergic/tachykinin motoneurons by GABA acting via bicuculline-sensitive GABAA receptors located on cholinergic/tachykinin nerve terminals (28, 31). The operation of the latter pathway depends on whether GABA neurons can be shown to project into the longitudinal muscle layer.
As previously shown (11) the circuit consisting of somatostatin, GABA, and opioid neurons coupled to inhibitory VIP/PACAP/NOS motoneurons innervating circular muscle determines relaxation of circular muscle during the descending phase of the peristaltic reflex. The same circuit appears to regulate also the activity of excitatory VIP/PACAP/NOS interneurons coupled to excitatory cholinergic/tachykinin motoneurons innervating longitudinal muscle. This should result in reciprocal contraction of longitudinal muscle (12, 29, 33). Recent studies (12), in effect, provide strong evidence that relaxation of circular muscle is accompanied by contraction of longitudinal muscle during the descending phase of the peristaltic reflex; the pathway mediating longitudinal muscle contraction consists of an integrated circuit of somatostatin, opioid, GABA, and VIP/PACAP/NOS interneurons serially coupled to cholinergic/tachykinin motoneurons.
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ACKNOWLEDGEMENTS |
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This work was supported by the National Institute of Diabetes and Digestive and Kidney Diseases Grant DK-34153.
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FOOTNOTES |
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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. §1734 solely to indicate this fact.
Address for reprint requests: J. R. Grider, Depts. of Physiology and Medicine, Box 980551, Medical College of Virginia, Virginia Commonwealth Univ., Richmond, VA 23298-0551.
Received 4 May 1998; accepted in final form 27 July 1998.
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