1 Section for Gastroenterology, Orphanin FQ (OFQ), also known as nociceptin, is
a recently isolated endogenous peptide with a structure similar to the
endogenous opioid peptides. The present study examines the actions of
centrally administered OFQ on in vivo murine gastrointestinal and
colonic transit as well as the actions of OFQ on the isolated colon.
Intracerebroventricular injections of OFQ dose dependently inhibited
colonic propulsive activity. OFQ inhibition of colonic propulsion was
unaffected by coadministration of the competitive opioid receptor
antagonist naltrexone. A subadditive response was observed when
approximately equipotent doses of either morphine sulfate or the
transit; enteric nervous system; opioid; central nervous system
BOTANICAL ALKALOIDS SUCH AS morphine, as well as
synthetic opioid compounds, have severe constipating and antidiarrheal
activity in humans and animals. These gastrointestinal effects can
limit the use of these compounds as analgesics. The constipating
effects of opiate alkaloids result from actions on smooth muscle
activity (both tone and contractility) as well as inhibition of mucosal fluid secretion (reviewed in Ref. 6). Motility changes by opioids can
be either stimulatory or inhibitory, depending on the species and
preparation utilized; however, the net effect of opioids is to prolong
transit of luminal contents through the gastrointestinal tract. Thus
adverse gastrointestinal side effects of opioid compounds limit their
full potential as analgesics.
Three types of opioid receptors (µ, The endogenous peptide ligand for the OFQ receptor is a 17-amino-acid
peptide recently isolated from porcine hypothalamus and also rat brain.
The sequence of OFQ is most similar to the endogenous opioid peptide
dynorphin A, a Because opioid compounds act through both central and peripheral
mechanisms to produce constipating effects due to actions on both
gastrointestinal motility and mucosal secretion, we were interested in
determining what actions OFQ might have on gastrointestinal function.
Specifically, we sought to determine
1) the effects of central
administration of OFQ on in vivo colonic propulsive activity,
2) the effects of central
administration of OFQ on gastric emptying/small intestinal transit, and
3) the effects of OFQ on in vitro
colonic smooth muscle contractility.
Animals.
All procedures utilizing animals were approved by the Animal Care
Committee of the University of Wisconsin-Madison. Male ICR mice
(25-34 g) were obtained from Harlan Sprague Dawley (Madison, WI)
and were housed in groups of three to five in plastic cages. Mice were
maintained on a 12:12-h light-dark cycle with lights on beginning at
6:00 AM. Food and water were provided ad libitum up until the time of
testing, except for those animals in the gastrointestinal transit
study. Those animals were fasted for 24 h before testing.
Compounds and administration.
All substances used in this study were purchased from either Research
Biochemicals (Natick, MA) or Sigma Chemical (St. Louis, MO).
Intracerebroventricular injections were performed as described by
Laursen and Belknap (15) on mice lightly anesthetized with ether. Light
anesthesia was defined as loss of the animal's righting reflex.
Animals generally recovered from anesthesia within 3 min. All compounds
were dissolved in sterile saline and injected in a volume of 5 µl.
Colonic transit assay.
A modification of the method described by Jacoby and Lopez (12) was
utilized. Drugs were administered intracerebroventricularly 5 min
before the insertion, under light ether anesthesia, of a single 3-mm
glass bead 2 cm into the distal colon of each mouse. Bead insertion was
accomplished with a glass rod, one end of which was fire-polished so as
to be rendered atraumatic. After bead insertion, mice were placed in
individual plastic cages lined with white paper to aid visualization of
bead expulsion. The time required for expulsion of the glass bead was
determined to the nearest 0.1 min for each mouse. Mice that did not
expel the bead within 3 h were necropsied to confirm the presence of
the bead in the lumen of the large intestine. Mice for which bead
localization could not be confirmed were not included in the results;
unconfirmed bead localization occurred in <1% of the mice tested.
Intestinal transit assay.
A modification of the method originally described by Macht and
Barba-Gose (17) was utilized. Opioid agonist doses were chosen to be
approximately equipotent to the half-maximal value for OFQ. Five
minutes after intracerebroventricular injection of test compounds, 0.3 ml of an aqueous suspension of 10% charcoal in 5% gum arabic was
administered by stomach tube to conscious mice. Thirty minutes later,
mice were killed by cervical dislocation, and the gastrointestinal tract from the stomach to the cecum was removed and hung under its own
weight from the gastric end. The distance from the pylorus that the
leading edge of the charcoal meal had traveled and the entire length of
small intestine were recorded for each mouse. The quotient of the
charcoal progression distance divided by intestinal length was
calculated, yielding an index of gastrointestinal transit.
In vitro colonic contractility.
Segments of mouse colon (~1 cm in length) were obtained from proximal
(immediately distal to the cecum) and distal (~1 cm proximal to the
anus) regions of the large intestine and were prepared for recording of
isometric smooth muscle contraction. Segments were suspended in the
axis of the longitudinal muscle under 9.8 mN resting tension in heated
(37°C) organ baths containing 15 ml of a physiological salt
solution (PSS) of the following composition (in mM): 118.1 NaCl, 4.7 KCl, 2.5 CaCl2 · 2H2O,
1.2 MgSO4 · 7H2O,
1.2 KH2PO4,
25 NaHCO3, and 5 glucose. The
solution was continuously gassed with 95%
O2-5%
CO2. Tissues were allowed to
equilibrate for 1 h, with changes of PSS every 15 min. At the end of
the equilibration period but before bath addition of test compounds,
tissues were contracted with 30 µM carbachol, a concentration that
results in a maximal contractile response of this tissue.
ABSTRACT
Top
Abstract
Introduction
Methods
Results
Discussion
References
-agonist DPDPE were coadministered with OFQ. No subadditivity was
observed with coadministration of the µ-agonist DAMGO, suggesting a
functional interaction between OFQ and
-opioid central pathways
regulating colonic transit. High, but not low, doses of OFQ also
inhibited the transit of a nonabsorbable charcoal marker through the
stomach and/or small intestine. OFQ potently contracted
isolated colon preparations; contractile activity was abolished by TTX
or chlorpromazine. Our results suggest that OFQ may be an important
peptide ligand acting on a novel inhibitory neural pathway that
modulates gastrointestinal transit.
INTRODUCTION
Top
Abstract
Introduction
Methods
Results
Discussion
References
, and
) have been defined
based on the results of radioligand binding assays (16, 26), functional
experiments (18), and, finally, the molecular cloning of the receptor
cDNA sequences (3, 8, 13, 35). Opioid receptors are members of the G
protein-coupled receptor superfamily, and their activation results in
an inhibition of adenylate cyclase and a decrease in intracellular cAMP
levels. The elucidation of the opioid receptor cDNA sequences allowed investigators to search nucleic acid libraries for other opioid receptor types or subtypes, the existence of which had been suggested from pharmacological studies. Recently, a novel member of the opioid
receptor family was discovered using low-stringency hybridization techniques (10) and/or RT-PCR with degenerate primers to
conserved regions of the three opioid receptor cDNAs (22). Shortly
thereafter, this receptor's endogenous peptide ligand, termed orphanin
FQ (OFQ) (31), or, alternately, nociceptin (19), was simultaneously isolated. The cloned human OFQ receptor bears approximately the same
percent amino acid identities to the human µ-,
-, and
-opioid receptors as these three receptors do to each other. Like the opioid
receptors, stimulation of the OFQ receptor results in suppression of
adenylyl cyclase activity. Interestingly, the OFQ receptor does not
significantly bind any of the endogenous opioid peptides, and naloxone,
a competitive opioid receptor antagonist, does not antagonize the
binding of OFQ to its receptor. OFQ and its receptor are expressed
widely throughout the rat central nervous system (1, 2, 10, 14, 22) . The expression patterns of the OFQ receptor as well as the results of
pharmacological investigations suggest that OFQ might mediate a variety
of physiological processes, including hyperalgesia (19, 31), locomotion
(7), and spatial learning (33). Interestingly, mice lacking the OFQ
receptor do not display significant changes in either nociceptive
threshold or locomotor activity but do display impairment in hearing
ability (24).
-opioid receptor agonist. The amino-terminal sequence
of OFQ, Phe-Gly-Gly-Phe, differs from the canonical Tyr-Gly-Gly-Phe
tetrapeptide sequence, which begins all other mammalian opioid
peptides. Also, the carboxy-terminal portion of OFQ contains several
basic residues, a property shared by dynorphin A and
-endorphin. In
contrast to the other opioid peptides, truncation of the
carboxy-terminal end of OFQ results in loss of biological activity and
lowered affinity of OFQ for its receptor (30). These results might
explain the selectivity of OFQ for its receptor and not for other
opioid receptors, as well as the lack of binding of other opioid
peptides to the OFQ receptor.
METHODS
Top
Abstract
Introduction
Methods
Results
Discussion
References
Data analysis. Data are expressed as means ± SE or with 95% confidence intervals, as indicated in the text. In vivo data were analyzed with one-way ANOVA followed by Dunnett's multiple comparison procedure to test for significant differences among means. Concentration-response curves from in vitro experiments were analyzed with nonlinear regression techniques. P < 0.05 were chosen as evidence of statistical significance. Computer software packages utilized were Minitab for Windows, release 11.13 (Minitab, State College, PA), and Prism (GraphPad Software, San Diego, CA).
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RESULTS |
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Centrally administered OFQ inhibits colonic transit.
Intracerebroventricular injection of OFQ resulted in dose-dependent
increases in bead expulsion times (Fig.
1). There was no difference in bead
latency times between animals that were administered an
intracerebroventricular injection of vehicle (saline) and animals that
did not receive intracerebroventricular injections (10.8 ± 1.0 vs.
8.8 ± 1.5 min, respectively; P > 0.05), indicating that intracerebroventricular injection of vehicle
alone had no significant effect on bead expulsion times.
Coadministration of 2.5 nmol of naltrexone, a competitive opioid
receptor antagonist, and 5 nmol OFQ had no significant effect on the
action of 5 nmol OFQ alone (36.4 ± 3.8 min with OFQ + naltrexone
vs. 39.2 ± 4.9 min with OFQ alone;
P > 0.05). This dose of naltrexone
was sufficient to antagonize the colonic transit changes caused by an
approximately equieffective dose of morphine sulfate (Fig.
2A).
Furthermore, naltrexone by itself had no effect on bead expulsion time
(8.2 ± 1.2 min with naltrexone vs. 10.0 ± 1.0 min with saline;
Fig. 2A).
|
|
Subadditive response to coadministered morphine and OFQ. Because it has been reported that OFQ may function as an endogenous antiopioid peptide when examined in assays of cutaneous nociception (20, 21), we sought to determine if this mechanism also exists in the central control of colonic transit. Coadministration of 5 nmol OFQ and 0.15 nmol morphine sulfate resulted in bead latency that was less than predicted (Fig. 2A).
Subadditive responses observed with coadministered OFQ and
- but not µ-opioid receptor agonists.
Although morphine is often regarded as a µ-receptor-preferring
agonist, it also has activity at
- and
-opioid receptors. Because
of the potential nonselective activity of morphine at opioid receptors,
we wanted to determine if the subadditive response we observed with
morphine and OFQ might be due to morphine's µ- and/or
-receptor activity. Therefore, we conducted similar coadministration experiments with more selective opioid agonists. Coadministration of
the µ-selective agonist
[D-Ala2,N-Me-Phe4,Gly-ol5]enkephalin
(DAMGO) with 5 nmol OFQ resulted in a bead latency that approximated
the latency expected from an additive effect of the two compounds given
individually (Fig. 2B).
Coadministration of the
-selective opioid agonist
[D-Pen2,
D-Pen5]enkephalin
(DPDPE) with OFQ, however, resulted in a bead latency suggestive of a
subadditive effect (Fig. 2C). Thus
the subadditive effect observed in response to morphine and OFQ
coadministration may reflect a possible
-receptor agonistic
property of morphine. Thus, in contrast to the nonselective antiopioid
effects of OFQ in nociception, subadditive colonic responses to
coadministered OFQ and opioid compounds only occurred with the
-receptor agonist DPDPE.
Centrally administered OFQ delays stomach emptying/intestinal
transit.
Low doses (1.25 and 2.5 nmol) of OFQ did not affect the progress of the
charcoal front in the small intestine (Fig.
3). Five and ten nanomole doses of OFQ,
however, significantly decreased gastrointestinal transit (25.1 ± 5.2%, P < 0.01, and 30.8 ± 5.2%, P < 0.05, respectively)
compared with the control (saline-injected) group (52.9 ± 4.4%).
Because the charcoal suspension was introduced by gavage into the
stomach, and not by a duodenal catheter, differential activity of OFQ
on stomach emptying and/or intestinal transit could not be
elucidated.
|
OFQ contracts isolated murine colon.
OFQ concentration dependently contracted isolated segments of proximal
and distal colon suspended in the longitudinal axis (Fig.
4). No significant differences in either
the potency or the efficacy of OFQ were observed between proximal and
distal segments of colon (Fig. 5). Maximal
OFQ-evoked contractile responses of the proximal and distal segments
were 43.1% (95% confidence intervals, 39.6-46.5%) and 42.2%
(39.6-44.7%) of the maximal tissue response elicited with 30 µM
carbachol. EC50 values of OFQ were 0.48 nM (0.28-0.83 nM) and 1.02 nM (0.71-1.45 nM) in the
proximal and distal colonic segments, respectively.
|
|
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DISCUSSION |
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The results of this study show that 1) OFQ administered into the cerebral ventricles of mice inhibits colonic transit in a naltrexone-insensitive manner, 2) subadditivity of in vivo colonic responses, potentially indicative of functional antagonism between opioids and OFQ, exists between central opioid and OFQ receptor-mediated control of colonic transit, 3) centrally administered OFQ decreases gastric emptying and/or small intestinal transit and, 4) OFQ contracts isolated mouse colon through a neurogenic, nonopioid-mediated mechanism.
The actions of OFQ have been studied at the molecular, cellular, and whole animal level. The molecular (i.e., receptor) level activity of OFQ is distinct from the activity of other opioid receptor ligands such as morphine and related opioid alkaloids, the synthetic opioids, and the endogenous opioid peptides. These opioid compounds bind poorly or not at all to membranes from COS-7 cells transfected with the OFQ receptor (14). In contrast to the differences between OFQ and other opioid compounds at the receptor level, some of the actions of OFQ at the cellular level are similar to those of the other opioids. Activation of the OFQ receptor transfected in Chinese hamster ovary cells inhibits forskolin-stimulated cAMP production (19, 31). Also, OFQ stimulation of its receptor has been shown to activate inwardly rectifying potassium channels in several regions of the brain (4, 36). In addition, modulation of N-type calcium channels by OFQ has been shown (5).
Given the disparities between the actions of OFQ and other opioids at
the molecular and cellular levels, it is not surprising that the
actions of OFQ and other opioids also differ in their functional
activity. Paradoxically, OFQ has been reported to possess both
analgesic and hyperalgesic properties. For example, in the mouse
tail-flick assay of nociception, intracerebroventricular injection of
OFQ was originally reported to have hyperalgesic activity (31).
However, Rossi and co-workers (32) have shown that OFQ can display
either naloxone-sensitive analgesic activity or biphasic
hyperalgesic/analgesic activity, depending on the intensity of the
stimulus. Yet another report suggests that OFQ has no inherent
analgesic activity but possesses the ability to reverse µ-, -, and
-opioid receptor-mediated analgesia (21). Therefore, although the
similarities of the receptor sequences and some of the cellular
functions of OFQ and other opioids might suggest similar functions a
priori, the data reported so far suggest otherwise. The results of the
present study show that actions of OFQ on the murine gastrointestinal
tract are qualitatively similar to the previously reported gut actions
of opioids such as morphine and the endogenous opioid peptides (28,
29), with the important exception being the naltrexone insensitivity of effects of OFQs.
In contrast to the many reports of OFQ action in the central nervous system, few studies have investigated the role OFQ might have in gastrointestinal physiology. The message for the OFQ receptor has been shown to be widely expressed throughout the porcine gastrointestinal tract (25). Zhang and co-workers (40) have demonstrated that OFQ inhibits electrically evoked twitches of longitudinal muscle from the guinea pig ileum, a classic bioassay for opioid activity. The inhibition was naloxone insensitive. OFQ has also been shown to contract isolated strips of rat colon oriented in either the circular or longitudinal axis, with OFQ evoking greater contractions in the proximal colon (39). Preliminary reports of OFQ's actions on in vivo gastrointestinal function suggest that OFQ is stimulatory to gastrointestinal smooth muscle. OFQ given intravenously to anesthetized rats has been shown to increase intragastric pressure (11). Similarly, OFQ given intravenously to rats (state of consciousness unknown) caused colonic contractions (34). All of the aforementioned studies reveal that OFQ has actions similar to those of endogenous and exogenous opioid compounds when tested in similar assays, with the important difference being that OFQ's actions are naloxone insensitive.
Experimental animals other than the mouse have been extensively studied for the actions of opioids on gastrointestinal function. The activity of gastrointestinal smooth muscle can be described as changes in transit, tone, or phasic activity (38). In the present study, we interpret the results of the colonic bead assay as alterations in colonic transit. Similarly, the charcoal meal assay reflects changes in gastrointestinal transit that may result from drug effects on stomach emptying and/or small intestinal transit. In other species, delay of gastrointestinal transit may result from increased smooth muscle tone as well as increased phasic activity (27). Although quantitative differences in opioid effects on gut function have been observed, e.g., contraction of isolated smooth muscle strips vs. inhibition of intestinal transit, there is an overall agreement on the qualitative effect of opioids on the gut, namely, inhibition of transit. For the sake of brevity, we have mainly limited our discussion to previous reports of opioid effects on murine gut.
Using essentially the same assay of in vivo colonic propulsion employed
in the present study, Raffa et al. (29) have shown that
intracerebroventricular injection of morphine, DAMGO, and the
-receptor agonist DPDPE all inhibit colonic propulsive activity in a dose-dependent, naloxone-reversible fashion. Our finding that OFQ
also inhibited colonic transit in a naltrexone-insensitive manner was
surprising, since OFQ has been shown to exert antiopioid effects in
other tests, e.g., cutaneous nociception (20). The presence of a
subadditive response to coadministered OFQ and µ-opioid agonist DPDPE
but not to coadministered OFQ and µ-selective agonist DAMGO was also
unexpected given the results of a previous study that demonstrated the
presence of functional antagonism of antinociception elicited by µ-,
-, and
-receptor agonists by OFQ (21). Our data suggest that OFQ
might interact with a central
-opioid pathway regulating colonic
motility. The differences between the OFQ/
-opioid subadditive
response that we observed and the nonselective opioid/OFQ functional
antagonism of nociception may reflect differences in the central
pathways responsible for colonic antitransit and pain transmission or
perhaps differences in animal strain responsiveness. Coadministration
of a
-selective antagonist, such as naltrindole, with OFQ would
provide additional evidence for the involvement of
-opioid receptors
in modulating the central gastrointestinal actions of OFQ. We did not
test the effects of
-agonists or of
-agonist/OFQ coadministration
on colonic propulsion, so a potential role for morphine's
-opioid
activity cannot be excluded. This seems unlikely given the poor
efficacy of
-agonists on gastrointestinal motility in rats and mice
when given supraspinally.
Alternatively, morphine and OFQ might be acting through separate neural pathways that converge onto a third pathway that in turn affects inhibition of colonic motility. The combined stimulation of this hypothetical component by morphine and OFQ could result in saturation or desensitization of its ability to inhibit colonic motility and the appearance of a subadditive response to coadministration of morphine and OFQ. The intestinal antisecretory effect of morphine has been shown to be indirect, involving multiple neurotransmitters and their receptors, suggesting that a parallel mechanism exists in the peripheral nervous system (6). Isobolographic analysis of the effects of multiple combinations of morphine and OFQ will be necessary to definitively investigate synergistic or subadditive effects of OFQ and opioids on both gastrointestinal as well as nociceptive function.
Centrally administered OFQ also delayed gastric emptying and/or
small intestinal transit of the nonabsorbable charcoal suspension. It
has been previously shown that intracerebroventricular injection of
morphine or DADLE (an enkephalin analog with -opioid activity) delayed intestinal transit in mice (37). These results were confirmed
and extended by Porreca and colleagues (28), who also showed that
inhibition of transit was mediated by µ- and
-opioid at the level
of the spinal cord. The lack of dose dependency displayed by OFQ on
gastrointestinal transit may reflect the need for higher doses of OFQ
to achieve maximal inhibition of transit. This seems unlikely, since a
trend to decreased inhibition of transit was observed at the 10 nmol
dose of OFQ. Another explanation for the lack of dose dependency may be
that OFQ is differentially modulating separate central pathways that
control stomach emptying and intestinal propulsion.
The action of OFQ on in vitro murine colon is no less intriguing than its in vivo effects. Alkaloid opioids such as morphine as well as the endogenous opioid peptides potently contract in vitro distal colon preparations from rat (23) and mouse (9). The opioid-evoked contraction of mouse colon is abolished by TTX and naloxone, indicating that contraction occurs through opioid receptors on enteric neurons. Furthermore, the contractile responses of the murine colon to opioids are unaffected by muscarinic, adrenergic, histaminergic, or serotonergic antagonists but potently inhibited by indomethacin (9), implying the involvement of a prostaglandin-mediated pathway. In our study, prostaglandins seem not to be involved in the contractile response evoked by OFQ, since 2 µM indomethacin did not affect the colon's response to OFQ. Our results in this study, as well as the results of others (39) obtained in the rat, suggest that OFQ acts through a novel neurogenic mechanism in the colon.
In summary, we have shown that the opioid-like peptide OFQ acts in a multifactorial, naloxone-insensitive manner in the murine gastrointestinal tract, inhibiting both gastrointestinal and colonic transit in vivo, while contracting isolated colon in vitro. Thus OFQ and its receptor may represent a novel inhibitory peptidergic pathway important in the regulation of gastrointestinal transit.
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ACKNOWLEDGEMENTS |
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We thank Professor Miles L. Epstein for helpful comments on this work.
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FOOTNOTES |
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This project was supported by National Institute of Diabetes and Digestive and Kidney Diseases Research Grant DK-02470-02 awarded to E. A. Gaumnitz.
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: M. A. Osinski, Univ. of Wisconsin Medical School, Dept of Medicine-Section for Gastroenterology, 516 Clinical Science Center/H6, 600 Highland Ave., Madison, WI 53792.
Received 4 July 1998; accepted in final form 5 October 1998.
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