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NEUROPHARMACOLOGY
Department of Molecular Pharmacology and Neuroscience, Nagasaki University School of Pharmaceutical Sciences, Nagasaki, Japan (M.I., T.K., H.U.); and University of Hawaii, Maui Community College, Kahului, Hawaii (R.G.A.)
Received for publication
January 21, 2003
Accepted
March 27, 2003.
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Abstract |
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 Top Abstract Materials and MethodsResultsDiscussionReferences |
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s
(i.t.) and with KT-5720 (i.pl.), a cyclic AMP-dependent protein kinase
inhibitor, but not with pertussis toxin. The nociception was neither
attenuated by neonatal capsaicin nor by i.t. injection with CP-99994, but it
was attenuated by i.t. injection with MK-801. These results suggest that
nocistatin and C-peptide derived from prepro-N/OFQ stimulate distinct
nociceptive fibers through different in vivo signaling mechanisms.
; Reinscheid et al.,
1995), is generated from a larger precursor protein, prepro-N/OFQ
(Saito et al., 1995;
Mollereau et al., 1996;
Nothacker et al., 1996). N/OFQ
has been seen as active at multiple sites of nociceptive transmission, ranging
from peripheral nociceptors (Inoue et al.,
1998) to nociceptive centers in the brain
(Morgan et al., 1997).
Pharmacologically, the actions of N/OFQ are complex and seem to be
contradictory; intracerebroventricular or intrathecal (i.t.) administration of
this peptide exerts pronociceptive (or hyperalgesia) and/or analgesia (for
reviews, see Calo, 2000; Mogil and
Pasternak, 2001). We also previously reported that N/OFQ (i.t.)
exerts nocifensive actions in a femtomolar dose range through a substance P
release from primary substance P fibers, whereas analgesic actions in a
nanomolar dose range come through an inhibition of substance P actions on the
second-order neuron in the spinal cord
(Inoue et al., 1999). These
findings suggest that the opposing actions of N/OFQ may depend on the dose
administered.
However, nocistatin, another peptide derived from the same precursor
protein, has been shown to be an anti-N/OFQ peptide that diminished
N/OFQ-induced allodynia and hyperalgesia
(Okuda-Ashitaka et al., 1998).
In addition, several lines of evidence suggest that nocistatin is a
biologically active peptide involved in nociception at the spinal level
(Xu et al., 1999;
Okuda-Ashitaka and Ito, 2000;
Zeilhofer et al., 2000).
Prepro-N/OFQ (160–187), which is the C-terminal peptide derived from the
same prohormone (C-peptide), has been identified in the brain and the spinal
cord (Allen et al., 2001;
Mathis et al., 2001). Because
administration of this peptide into brain regions produces antinociception or
pronociceptive actions (Mathis et al.,
2001; Rossi et al.,
2002), this peptide is also a biologically active peptide,
probably activating a membrane receptor that has yet to be identified. Little
is known, however, of the in vivo signal transduction of these peptides
derived from the N/OFQ precursor in pain control.
Recently, we developed a new technique in mice to study the mechanism of
pronociceptive actions induced by intraplantar injection of various algogenics
(Inoue et al., 1998;
Ueda 1999). We called it
algogenic-induced nociceptive flexion (ANF) test. This test has been proved to
be advantageous in the point of sensitivity, compared with the known test
measuring biting and licking behaviors, which we called algogenic-induced
biting and licking test (Inoue et al.,
2003b). The ANF test was about 10,000 times more sensitive to
produce nociception by various algogenics than the algogenic-induced biting
and licking test (Inoue et al.,
2003b). Because constant nociceptive flexor responses upon
repeated challenges of algogenics are observed, the ANF test is useful to
characterize the dose-response relationship and in vivo signaling of
nociception (Inoue et al.,
1998; Ueda 1999).
Furthermore, we found very little increase in plasma corticosterone levels
after the ANF test in the absence and presence of bradykinin stimulation (40%
of control level), which is equivalent to those in mild nociception tests such
as Hargreaves thermal and paw pressure mechanical tests
(Inoue et al., 2003b).
Considering the fact that significant increase in plasma corticosterone levels
was observed after both formalin and tail-flick tests (150% of control level),
the ANF test is unlikely accompanied with heavy stress. Using this ANF test,
we have studied pharmacological mechanisms of pronociceptive and
antinociceptive actions of N/OFQ and N/OFQ (13–17), an N/OFQ C-terminal
fragment, and revealed that these peptides stimulate Gi/o,
phospholipase C and substance P release from nociceptor endings (Inoue et al.,
1998,
1999,
2001). Here, we report the
pharmacological mechanisms underlying nocistatin- or C-peptide-induced
pronociceptive actions using the ANF test.
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Materials and Methods |
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TopAbstractMaterials and MethodsResultsDiscussionReferences |
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Drugs. The following drugs were used: N/OFQ (Sawady Technology, Tokyo, Japan), nocistatin (Peptide Institute, Osaka, Japan), capsaicin (Nacalai Tesque, Kyoto, Japan), MK-801 (Sigma/RBI, Natick, MA), pertussis toxin (Funakoshi, Tokyo, Japan), and KT-5720 and calphostin C (Wako Pure Chemicals, Tokyo, Japan). Prepro-N/OFQ 160–187 (C-peptide) was synthesized at Phoenix Pharmaceuticals Inc. (Belmont, CA). CP-99994 was generously provided by Pfizer Pharmaceuticals (Sandwich, Kent, UK). 1-[(3R,4R)-1-Cyclooctylmethyl-3-hydroxymethyl-4-piperidyl]-3-ethyl-1,3-dihydro-2H-benzimidazole-2-one (J-113397) was generously provided by Banyu (Tokyo, Japan). All drugs except KT-5720, calphostin C, and capsaicin were dissolved in physiological saline. KT-5720 and calphostin C were dissolved in 30% dimethyl sulfoxide, capsaicin in 10% ethanol, and 10% Tween 80 in physiological saline.
Treatment of Antisense Oligodeoxynucleotide (AS-ODN). The AS-ODN
(5'-AGT CAC CCA TTA GTG ACG CC-3') and its missense
oligodeoxynucleotide/MS-ODN (5'-AGC TAC CAC TAT GTG CAG CC-3') for
Gs were synthesized by Sawady (Tokyo, Japan), freshly
dissolved in physiological saline, and used for i.t. injection in a volume of
2 µl on the 1st, 3rd, and 5th days. On the 6th day, mice were used to
assess the nocistatin- or C-peptide-induced nociception.
Western Blot Analysis. To confirm the effect of AS-ODN for
Gs, SDS-polyacrylamide gel electrophoresis using 12%
polyacrylamide gel, and immunoblot analysis were performed as described
previously (Yoshida and Ueda,
1999). After three times treatments of AS-ODN on the 1st, 3rd, and
5th days, we isolated dorsal root ganglion on the 6th day. Ten micrograms of
protein extracted from the dorsal root ganglion was used. To get equal
transfer efficiency, we applied all samples to the same gel and carried out
the immunoblot transfer using the same membrane. Visualization of
immunoreactive bands was performed by use of an enhanced chemiluminescent
substrate for detection of horseradish peroxidase, Super Signaling Substrate
(Pierce Chemical, Rockford, IL). The intensities of the immunoreactive bands
were analyzed by NIH Image for Macintosh after scanning exposed films.
ANF Test. Experiments were performed, as described previously
(Inoue et al., 1998;
Ueda, 1999). Briefly, mice
were held in a cloth sling with their four limbs hanging free through holes.
The sling was suspended on a metal bar. All limbs were tied with strings, and
three were fixed to the floor, whereas the other one was connected to an
isotonic transducer and recorder. A polyethylene cannula (0.61 mm in outer
diameter) filled with drug solution was connected to microsyringe and then
carefully inserted into the undersurface of the right hind paw. We used light,
soft polyethylene cannulae to ensure that they did not fall off the paw during
the experiments. As the intensity of flexor responses differs from mouse to
mouse, we used the biggest response among spontaneous and nonspecific flexor
responses occurring immediately after cannulation as the maximal reflex.
Algogenic substance injection was given intraplantarly (i.pl.) every 5 min
unless otherwise stated. Algogenic substance-induced nociceptive activity was
expressed as the ratio of the maximal reflex in each mouse, and in the
dose-response experiments, increasing doses of compound were given every 5-min
interval. Averages of responses by twice-repeated challenges per each dose
were evaluated. In some experiments, nocistatin (or C-peptide)-induced
nociceptive activity was expressed as the ratio of the response observed over
the average of twice-repeated control nocistatin (or C-peptide)-induced
responses obtained at the beginning of the experiments. Test drugs affecting
nocistatin (or C-peptide) responses were given through another cannula
immediately after the second control response was measured. Intrathecal
pretreatment with neurokinin 1 or NMDA receptor antagonist was performed 20
min before the nocistatin (or C-peptide) challenge.
Statistical Analysis. The data were analyzed using Student's t test. For the experiments with repeated injection of drugs in escalating doses, the data were analyzed with repeated measures analyses of variance and appropriate post-comparisons with Scheffé test for the experiments with repeated injection of drugs in escalating doses and for the time-course experiments. The criterion of significance was set at p < 0.05. All results were expressed as the mean ± S.E.M.
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Results |
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TopAbstractMaterials and MethodsResultsDiscussionReferences |
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Lack of Blockade Nocistatin- and C-Peptide-Induced Nociception by NOP
Antagonist. Although nocistatin or C-peptide (i.pl.) induced
dose-dependent nociceptive flexor responses in a range of 0.01 to 10 or to 1
pmol (i.pl.), respectively, in the ANF tests, these responses were not
affected by J-113397, a nonpeptidic NOP antagonist
(Ozaki et al., 2000;
Ueda et al., 2000a) at a dose
of 10 pmol, which had been pretreated 20 min before administration of
nocistatin or C-peptide through another adjacent cannule
(Fig. 1, B and C). However, the
N/OFQ (1 fmol, i.pl.)-induced response was completely abolished by this
antagonist at a dose as low as 10 fmol
(Fig. 1D), as reported
previously (Ueda et al.,
2000a). This finding is consistent with the previous report that
the spinal response by nocistatin is retained in mice lacking the genomic NOP
(Ahmadi et al., 2001).
In Vivo Signal Transduction of Nocistatin-Induced Pronociceptive
Responses. Nocistatin (i.pl.)-induced nociceptive responses were
completely abolished by the i.pl. injection of 10 ng of pertussis toxin in
between nocistatin challenges (Fig.
2A). The AS-ODN for Gs was pretreated to reduce
its protein expression in sensory neurons. As shown in
Fig. 2B, nocistatin-induced
nociceptive responses were not affected, but the Gs
expression in the dorsal root ganglion was markedly reduced by this
pretreatment (Fig. 2C). The
nocistatin responses were markedly inhibited by 3 nmol of U-73122, a
phospholipase C inhibitor (Fig.
2D), but not by 3 nmol of U-73343, its inactive isomer (data not
shown). In addition, these responses were also markedly blocked by 1 pmol of
CP-99994, a substance P (neurokinin 1) receptor antagonist, as shown in
Fig. 2E.
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In Vivo Signal Transduction of C-Peptide-Induced Pronociceptive
Responses. On the other hand, the C-peptide (i.pl.)-induced pronociceptive
responses were not affected by pertussis toxin
(Fig. 3A), whereas they were
abolished by the pretreatment with AS-ODN for Gs, but not
with MS-ODN (Fig. 3B). The
responses were abolished by KT-5720, a cyclic AMP-dependent protein kinase
(PKA) inhibitor, but not by U-73122 nor calphostin C, a protein kinase C
inhibitor (Fig. 3, C and D),
which effectively blocked acute morphine (i.pl.) analgesic tolerance
(Inoue and Ueda, 2000).
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Characterization of Nociceptive Fibers Stimulated by Nocistatin and
C-Peptide. In neonatal capsaicin-treated mice, which degenerates polymodal
C-fibers (Inoue et al., 1999),
nocistatin (i.pl.)-induced nociceptive responses at doses of 0.01 to 10 pmol
were markedly inhibited, as shown in Fig.
4A. The i.t. treatment with CP-99994 (1 nmol) 20 min before the
ANF test also abolished the nocistatin responses
(Fig. 4B). However, the
pretreatment with MK-801, an NMDA receptor antagonist (1 nmol i.t.) did not
affect these responses (Fig.
4B). The C-peptide-induced nociception was not affected by the
neonatal pretreatment with capsaicin or by CP-99994 (i.t.), whereas it was
completely abolished by MK-801 (i.t.), as shown in
Fig. 4, C and D.
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Discussion |
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TopAbstractMaterials and MethodsResultsDiscussionReferences |
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). A
family of opioid peptides is a representative case
(Noda et al., 1982). All
opioid peptides derived from their three distinct precursors have affinities
to either of three distinct types of receptors
(Goldstein, 1987). However, all
these receptors are coupled to pertussis toxin-sensitive G proteins
(Gi/o). N/OFQ has been discovered as the endogenous peptide ligand
for opioid receptor-like Gi/o-coupled NOP
(Meunier et al., 1995;
Reinscheid et al., 1995). The
amino acid sequence of N/OFQ is also similar to dynorphin A (1–17). All
these facts suggest that opioid peptide precursors and prepro-N/OFQ might be
derived from the same ancestor protein
(Darland, 1998). However, the
present findings demonstrated that prepro-N/OFQ-derived peptides have distinct
features in their cellular signalings.
We found four peptides derived from preproN/OFQ caused significant
dose-dependent nociceptive flexor responses in the ANF test
(Fig. 1A). Because the
responses caused by the third dose (1 fmol) of N/OFQ were equivalent to those
by the initial dose (1 fmol) (Fig. 1, A and
D), the dose orderly effects likely result from increasing dose,
but not repeated injection of algogenic substance. Similar discussion is also
true with nocistatin and C-peptide (Figs.
1, A–C,
2B,
3B, and
4, A–D). Because the
nociceptive flexor responses evaluated by percentage of maximal reflex are
constant upon repeated challenges and reproducible from mice to mice, we
attenuated to characterize the in vivo signalings of pronociceptive actions of
these peptides. Throughout a series of experiments using this test, we have
proposed at least three different types of nociceptive fibers stimulated by
various algogenics. The nociceptor type classification in these studies was
defined by the pharmacological characteristics, such as susceptibility to
neonatal capsaicin pretreatment, which is known to degenerates C-fibers
(Inoue et al., 1999), and to
the i.t. injection of substance P (neurokinin 1) or glutamate (NMDA) receptor
antagonists. In this paradigm, bradykinin, substance P, and histamine through
Gq/11-coupled receptors or N/OFQ, kyotorphin, and morphine through
Gi/o-coupled receptors stimulate neonatal capsaicin-sensitive
polymodal C fibers, which use substance P and neurokinin 1 receptor for
primary afferent pain transmission in the spinal cord (we call it type I),
whereas ATP and P2X3 agonist through P2X3 receptor
stimulate the capsaicin-sensitive fibers, which use glutamate and NMDA
receptor for the pain transmission (we call it type II). On the other hand,
prostaglandin I2-agonist stimulates the capsaicin-insensitive
fibers, which use glutamate and NMDA receptor for the pain transmission (we
call it type III).
The type I and II fibers in our definition likely correspond to those
defined by Snider and McMahon
(1998), with (class I)
polymodal C-fiber containing substance P and possessing sensitivity to nerve
growth factor, and (class II) polymodal C-fiber expressing
P2X3-type ATP receptor and possessing sensitivity to glia-derived
neurotrophic factor, although details on the similarity remain to be
determined. The type III fibers in our studies, on the other hand, apparently
differ from these two types of fibers in the point of insusceptibility to
neonatal capsaicin. Recently, we have found that type I-responses disappeared,
type II ones without changes, whereas prostaglandin I2
agonist-induced type III ones markedly potentiated after the partial sciatic
nerve injury (Rashid et al.,
2003). The potentiation of prostaglandin I2
agonist-induced responses was abolished by local application with capsaicin
cream, which desensitizes the nociceptor endings through capsaicin receptor
(TRPV1). In addition to these, immunoreactive TRPV1 was newly expressed in
N52-positive A-fiber neurons after the injury. Although more detailed studies
to characterize type III fibers should be necessary, these results suggest
that type III responses are likely through A-fibers and also have distinct
characteristics from the other two types of algogenic-induced responses,
particularly after the nerve injury.
Using this system, here we attempted to characterize the in vivo signaling
of nociceptive flexor responses induced by N/OFQ, nocistatin, and C-peptide.
Nocistatin-induced responses were completely abolished by the i.pl. injection
of 10 ng of pertussis toxin in between nocistatin challenges
(Fig. 2A). The blockade was
observed as early as 10 min after application of the pertussis toxin. Such a
rapid blockade has also been observed in other cases with N/OFQ, kyotorphin,
and morphine (Inoue et al.,
1998; Ueda and Inoue
2000; Ono et al.,
2002). These findings strongly suggest that nocistatin stimulates
an unidentified but putative Gi/o-coupled receptor, as well as
N/OFQ (Inoue et al., 1998). For
a comparison with N/OFQ (Inoue et al.,
1998), various inhibitors were tested to clarify in vivo signaling
of nocistatin responses. We found that this peptide shares common
post-receptor mechanisms through Gi/o, phospholipase C and
substance P release from nociceptor endings with N/OFQ
(Fig. 5). Although nocistatin
has been reported as an endogenous peptide to inhibit N/OFQ-induced allodynia
and hyperalgesia (Okuda-Ashitaka et al.,
1998; Okuda-Ashitaka and Ito,
2000); however, it remains to be determined what mechanisms are
involved in the blockade of N/OFQ-actions by nocistatin. It might be possible
that nocistatin counteracts the N/OFQ actions in vivo through different
synaptic pathways. Details of the different in vivo pain-regulatory roles of
both of these peptides need to be elucidated.
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On the other hand, C-peptide was found to use different mechanisms from
N/OFQ and nocistatin. The C-peptide-induced nociceptive responses were
insensitive to J-113397 and pertussis toxin. The most striking evidence was
that the responses were abolished by pretreatments with AS-ODN for
Gs and KT-5720. It should be further noted that they were
insensitive to neonatal pretreatment with capsaicin, but were blocked by the
intrathecal injection of MK-801, but not of CP-99994
(Fig. 5). These characteristics
are quite similar to the mechanisms for the nociceptive responses induced by
prostaglandin I2 agonist (Ueda
et al., 2000b), whose receptor (IP receptor) is coupled to
Gs (Namba et al.,
1994) through type III nociceptive fibers
(Inoue et al., 2003a;
Rashid et al., 2003).
In a previous study, we reported that N/OFQ (13–17), a fragment
peptide of N/OFQ, also induced nociceptive responses in ANF tests
(Inoue et al., 2001), with its
potency being 100 times higher than N/OFQ. The in vivo signaling of these
actions through Gi/o and phospholipase C mechanisms is identical to
those with N/OFQ and nocistatin. However, it remains to be seen whether these
three peptides have distinct roles in pain regulation. In preliminary studies,
they did not show significant stimulatory actions on [35S]guanosine
5'-O-(3-thio)triphosphate binding in the membrane preparations
from dorsal root ganglion, whereas only N/OFQ did in a preparation from spinal
cord. These observations may possibly be explained by a lower abundance in the
expression of corresponding receptors in dorsal root ganglion, or by their
selective translation in nerve endings. The latter possibility may be related
to a report that Eph A2 receptor is selectively translated in nerve endings,
but not in somatic regions (Brittis et al.,
2002).
In conclusion, the present study suggests that nocistatin and C-peptide as well as N/OFQ and N/OFQ (13–17), derived from the same prohormone, induced nociceptive flexor responses in ANF tests. It is also suggested that nocistatin, N/OFQ, and N/OFQ (13–17) share common signaling through Gi/o, phospholipase C and substance P release from capsaicin-sensitive type I C-fibers, whereas C-peptide uses the mechanisms through Gs and PKA in capsaicin-insensitive type III fibers.
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Acknowledgements |
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Footnotes |
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ABBREVIATIONS: N/OFQ, nociceptin/orphanin FQ; NOP, nociceptin/orphanin FQ receptor; ANF, algogenic-induced nociceptive flexion; AS-ODN, antisense oligodeoxynucleotide; MS-ODN, missense oligodeoxynucleotide; i.pl., intraplantar; NMDA, N-methyl-D-aspartate; PKA, protein kinase A; CP-99994, (+)-(2S,3S)-3-(2-methoxybenzylamino)-2-phenylpiperidine; MK-801, (–)-5-methyl-10,11-dihydro-5H-dibenzo[a.d]cyclohepten-5.10-imine maleate; KT5720, [9R,10S,12S]-2,3,9,10,11,12-hexahydro-10-hydroxy-9-methyl-1-oxo-9,12-epoxy-1H-diindolo[1,2,3-fg:3,2,1-kl]pyrrolo[3,4-l][1,6]benzodiazocine-10-carboxylic acid hexyl ester.
Address correspondence to: Dr. Hiroshi Ueda, Division of Molecular Pharmacology and Neuroscience, Nagasaki University Graduate School of Biomedical Sciences, 1-14 Bunkyo-machi, Nagasaki 852-8521, Japan. E-mail: ueda{at}net.nagasaki-u.ac.jp
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), N/OFQ (
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J-113397. J-113397 (10 pmol; 
