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The Journal of Neuroscience, June 15, 2000, 20(12):4680-4685
Chronic Hypersensitivity For Inflammatory Nociceptor
Sensitization Mediated by the  Isozyme of Protein Kinase
C
K. O.
Aley1,
Robert O.
Messing2,
Daria
Mochly-Rosen3, and
Jon D.
Levine1
1 National Institutes of Health Pain Center, University
of California, San Francisco, San Francisco, California 94143-0440, 2 Ernest Gallo Clinic and Research Center, University of
California, Emeryville, California 94608, and 3 Molecular
Pharmacology, Stanford University, Stanford, California 94305
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ABSTRACT |
We have identified a mechanism, mediated by the  isozyme of
protein kinase C (PKC) in peripheral neurons, which may have a role
in chronic inflammatory pain. Acute inflammation, produced by
carrageenan injection in the rat hindpaw, produced mechanical hyperalgesia that resolved by 72 hr. However, for up to 3 weeks after
carrageenan, injection of the inflammatory mediators prostaglandin E2 or 5-hydroxytryptamine or of an adenosine A2
agonist into the same site induced a markedly prolonged hyperalgesia
(>24 hr compared with 5 hr or less in control rats not pretreated with
carrageenan). A nonselective inhibitor of several PKC isozymes and a
selective PKC inhibitor antagonized this prolonged hyperalgesic
response equally. Acute carrageenan hyperalgesia could be inhibited by PKA or PKG antagonists. However, these antagonists did not inhibit development of the hypersensitivity to inflammatory mediators. Our
findings indicate that different second messenger pathways underlie
acute and prolonged inflammatory pain.
Key words:
carrageenan; chronic pain; inflammation; prostaglandin
E2; protein kinase C; second messenger
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INTRODUCTION |
In studying mechanisms underlying
pain, researchers have been successful in elucidating bases of acute
inflammatory pain (for review, see Cesare and McNaughton, 1997 ; Levine
and Reichling, 1999). Although chronic inflammatory pain syndromes
(e.g., arthritis, gastritis, colitis, dermatitis, and post-traumatic
and repetitive strain injuries) result in enormous morbidity and
societal cost, they remain poorly understood. Specifically, it is not
known whether novel mechanisms different from those of acute
inflammatory pain are involved, which is a critical point for the
design of rational therapies.
Because chronic inflammatory pain states can follow an episode of acute
inflammation (Lockwood, 1989; MacIntyre et al., 1995; Melhorn, 1998),
we investigated whether acute inflammation can induce a long-lasting
increase in the sensitivity to inflammatory hyperalgesic mediators.
Such an increased sensitivity could underlie the development of a
chronic pain syndrome and could be used to identify second messenger
systems that contribute to chronic inflammatory states. In these
experiments, we studied rats previously treated with the inflammatory
agent carrageenan, at a dose that produces only short-lived
inflammation and hyperalgesia (Guilbaud et al., 1989; Dawson et al.,
1991). We found that this treatment resulted in a long-lasting increase
in subsequent sensitivity to hyperalgesic inflammatory mediators. We
also evaluated the initiation, duration, and mechanisms, including
contributing second messengers, underlying this long-lasting
hypersensitivity to proinflammatory mediators.
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MATERIALS AND METHODS |
Animals. Experiments were performed on male Sprague
Dawley rats (200-250 gm; Bantin-Kingman, Fremont, CA). Animals were
housed in groups of two under a 12 hr light/dark cycle (lights on at 7:00 A.M.). Food and water were available ad libitum.
All behavioral testing was done between 10:00 A.M. and 4:00 P.M.
Experiments were performed under approval of the Institutional Animal
Care and Use Committee of the University of California, San Francisco.
Behavioral testing. The nociceptive flexion reflex
(Randall-Selitto paw-withdrawal test) was quantified with a Basile
Analgesymeter (Stoelting, Chicago, IL), which applies a linearly
increasing mechanical force to the dorsum of the rat's hindpaw. Three
readings were taken at 5 min intervals, and their mean was considered
the baseline threshold. Groups that were compared with to determine effect of drug administration had similar baseline thresholds. Mechanical threshold was redetermined at various time points after drug
administration. These time points were determined based on the latency
and duration of action of each drug used in the study. The mean of
three readings (taken at intervals of 5 min, the last reading
corresponding to the time specified [always taken at least at 30 min
and 4 hr for prostaglandin E2
(PGE2)] after drug treatment) was used to
calculate the percentage change from the baseline threshold. To
determine the carrageenan dose to be used in the study, the effect of
different doses (0.1-2%) were evalvated studied. The time at which
each drug had a maximal effect also was considered in timing the
measurement of the paw-withdrawal threshold (maximum effect for
carrageenan at 4 hr and for the other drugs at 30 min). To study the
onset of carrageenan-induced changes in response to hyperalgesic
inflammatory mediators, we injected rats with PGE2 at various times (0.5-96 hr) after
injection of carrageenan.
Drug administration. The drugs used in this study were as
follows: PGE2 (direct-acting hyperalgesic
inflammatory mediator),  carrageenan (inflammatory agent),
NG-methyl-L-arginine
(L-NMA) (nitric oxide synthase inhibitor), 2-[(2-bis - [carboxymethyl] amino-5-methylphenoxy)
methyl]-6-methoxy-8-bis [carboxymethy] aminoquinoline (Quin-2)
(calcium chelator), 3,4,5-trimethoxybenzoic acid 8-(diethylamino) octyl
ester (TMB-8) (inhibitor of intracellular Ca2+ transport), and 5-hydroxytryptamine
(5-HT, serotonin) (all from Sigma, St. Louis, MO); Walsh inhibitor
peptide (WIPTIDE) [protein kinase A (PKA) inhibitor 5-22 amide;
Peninsula Laboratories, Belmont CA]; and
{1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one} (ODQ) (guanylyl cyclase inhibitor), an inhibitor of protein kinase G (PKG) (peptide with sequence, H-Arg-Lys-Arg-Ala-Arg-Lys-Glu-PH) that corresponds to a
nonphosphorylatable analog (Ser32 to
Ala32) of histone
H2B (residues 29-35), bisindolylmalemide 1 HCl
(Bis) [protein kinase C (PKC) inhibitor] (all from
Calbiochem-Novabiochem, La Jolla, CA);
(+)-5-methyl-10,11-dihydro-5H-dibenzo [a,d] cyclohepten-5,10-imine maleate (MK-801) (NMDA receptor antagonist) and carboxyethyl
phenethylamino-5'-N-ethylcarboxamido adenosine HCl
(CGS-21680) (an adenosine A2 agonist)
(both from Research Biochemicals, Natick, MA). HDAPIGYD (pseudo
RACK ( R), a PKC agonist (Dorn et al., 1999) and
PKCV1-2 peptide, H2N-EAVSLKPT-COOH, a PKC
inhibitor (Gray et al., 1997) were synthesized by SynPep (Dublin, CA).
The selection of the drug doses used in this study was based on
dose-response curves determined during this as well as previous
studies (Aley et al., 1995, 1998; Khasar et al., 1999a). The stock
solution of PGE2 (1 µg/2.5 µl) was prepared in 10% ethanol, and additional dilutions were made in saline; the
final concentration of ethanol was  1%. All other drugs were dissolved in saline except ODQ, which was dissolved in DMSO and diluted
with saline (final concentration of DMSO was 10%). All drugs were
administered intradermally in a volume of 5 µl/paw. For test agents
with low cell membrane permeability (i.e., WIPTIDE, PKC inhibitor, and
R), 2 µl of distilled water was injected first, in the same
syringe as the test agent, to produce hypo-osmotic shock and thus
transiently permeabilize the cell membrane (Keeney and Linn, 1990;
Lepers et al., 1990; Schulz, 1990). When drug combinations were used,
they were administered at 5 min intervals with the drug mentioned
first, the antagonist, administered first. All of the drugs except
carrageenan were administered using a 30 gauge hypodermic needle.
Because of its high viscosity, carrageenan was injected using a 27 gauge needle. All drugs were administered either to control rats or on
days 5 or 21 after carrageenan. After injection of hyperalgesic
inflammatory mediators, readings of nociceptive threshold were always
taken at 30 min and 4 hr and sometimes at other time points to
determine the time course.
Statistical analysis. Data are presented as mean ± SEM; means were compared by ANOVA. Differences between pairs of
means were analyzed by Scheffe's post hoc test and were
considered significant at p < 0.05.
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RESULTS |
Carrageenan induces a long-term prolongation of inflammatory
mediator-induced hyperalgesia
We hypothesized that a low dose of an inflammatory agent such as
carrageenan would produce a short-term (several days) hyperalgesia from
which the animal would fully recover, but might also induce a
long-lasting heightened hyperalgesic response to inflammatory mediators. By measuring the carrageenan dose-response relationship (Fig. 1A; see Materials
and Methods), we determined that 5 µl of 1% carrageenan (w/v in
physiological saline) resulted in swelling, erythema, and reduced
paw-withdrawal threshold to mechanical pressure beginning 30-60 min
after injection, reaching a maximum between 2-4 hr, and resolving
within 72 hr (Fig. 1A,B).
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Figure 1.
A, Dose (0.1-2%)-response curve
of carrageenan (Carr; n = 12)
induced mechanical hyperalgesia measured at 4 hr in the hindpaw of the
normal rat. The Randall-Selitto paw-withdrawal test is an established
method to assess heightened nociception in animals in which this
subjective experience of pain cannot be directly determined. Measures
using this technique have been shown to correlate with pain-like
behaviors in animals. B, Time course of hyperalgesia
induced by carrageenan 1% (5 µl, n = 24) in
normal rats.
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Intradermal injection of the inflammatory mediators
PGE2, 5-HT, or the A2
adenosine receptor agonist CGS-21680, at the same site into which
carrageenan had been injected 5 d earlier, resulted in a prolonged
mechanical hyperalgesia lasting >24 hr (Fig.
2A). This ability of
carrageenan to prolong hyperalgesia induced by inflammatory mediators
persisted for at least 3 weeks after carrageenan administration (Fig.
2B). In comparison, in control rats exposed to
vehicle without carrageenan, PGE2, CGS-21680, and
5-HT produced transient hyperalgesia lasting <4 hr (Fig.
2C).
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Figure 2.
A, PGE2 (100 ng,
n = 24), 5-HT (1 µg, n = 6),
and CGS-21680 (100 ng, n = 6)-induced mechanical
hyperalgesia at 30 min, 4 hr, and 24 hr after injection in rats treated
5 d previously with carrageenan. B, Mechanical
hyperalgesia induced by PGE2 (n = 12),
5-HT (n = 6), and CGS-21680 (n = 6) at 30 min, 4 hr, and 24 hr after injection in rats treated 21 d previously with carrageenan. C, Time course of
PGE2-, 5-HT-, and CGS-21680-induced mechanical hyperalgesia
in rats 5 d after vehicle used for carrageenan
(n = 12 each).
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Novel mechanism of prolonged
PGE2-induced hyperalgesia
We next examined the second messengers that mediate the ability of
carrageenan to prolong hyperalgesia induced by inflammatory mediators.
To examine this issue, we evaluated PGE2-induced
hyperalgesia and used inhibitors of second messenger pathways important
in peripheral nociception. In control animals, previous treatment with
the PKA inhibitor (WIPTIDE) or the nitric oxide synthase inhibitor
(L-NMA) attenuated PGE2-induced
mechanical hyperalgesia, whereas Bis (PKC inhibitor) or
PKCV1-2 (PKC inhibitor) was without effect
(Fig. 3A). PKGI (PKG
inhibitor), ODQ (guanylyl cyclase inhibitor), TMB-8 and Quin-2 (calcium
antagonists), and MK-801 (NMDA receptor antagonist) were also without
effect (data not shown). In rats treated with carrageenan 5 d
previously, WIPTIDE or L-NMA inhibited the early
phase of PGE2-stimulated hyperalgesia 30 min
after injection of PGE2. This was similar to what
was observed in control animals not pretreated with carrageenan (Fig.
3A). In contrast, neither WIPTIDE nor
L-NMA inhibited the late phase (4 hr after
injection) of PGE2-induced hyperalgesia observed
in carrageenan pretreated rats (Fig. 3B). Bis and the PKC
inhibitor did not reduce early PGE2-stimulated
hyperalgesia in control or carrageenan pretreated rats (Fig.
3A). However, these agents inhibited the late phase of
PGE2 hyperalgesia seen in carrageenan pretreated rats (Fig. 3B). The PKC inhibitor also inhibited the late
phases of 5-HT and CGS-21680 hyperalgesia in carrageenan pretreated
rats (data not shown). TMB-8 and Quin-2 or MK-801 had no effect on PGE2-induced hyperalgesia in carrageenan
pretreated or control rats (data not shown).
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Figure 3.
A, Effect of PKA inhibitor WIPTIDE
(WIP/E2; 1 µg/100 ng, n = 24),
nitric oxide synthase inhibitor
NG-methyl-L-arginine
(L-NMA/E2; 1 µg/100 ng, n = 12),
PKC inhibitor bisindolylmalemide 1 hydrochloride
(Bis/E2; 1 µg/100 ng, n = 12),
PKC inhibitor (PKCV1-2/E2; 1 µg/100 ng,
n = 12), administered 5 min before
PGE2, on PGE2
(E2)-induced mechanical hyperalgesia measured at 30 min
after PGE2 injection in control rats and in rats treated
5 d previously with carrageenan. B, Effect of PKA
inhibitor WIP/E2 (n = 24), nitric
oxide synthase inhibitor L-NMA/E2 (n = 12), PKC inhibitor Bis/E2 (n = 12), PKC inhibitor PKCV1-2/E2)
(n = 12), administered 5 min before
PGE2, on PGE2
(E2)-induced mechanical hyperalgesia measured at 4 hr
after PGE2 injection in control rats and in rats treated
5 d previously with carrageenan.
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We next investigated whether similar second messenger systems mediate
acute carrageenan-induced hyperalgesia and the ability of carrageenan
to prolong PGE2 hyperalgesia. Carrageenan-induced hyperalgesia was attenuated by an inhibitor of PKA or PKG (Fig. 4A). However, when
PGE2 was administered after injection of WIPTIDE plus carrageenan or the PKG inhibitor plus carrageenan (Fig.
4B,C), a prolonged hyperalgesic
response to PGE2 was still observed beginning 48 hr after carrageenan injection (Fig.
4B,C).
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Figure 4.
A, Effect of PKA inhibitor WIPTIDE
(WIP/Carr; n = 24) and PKG inhibitor
(PKGI/Carr; n = 8) on
carrageenan-induced mechanical hyperalgesia in the rat hindpaw. Agents
were administered 5 min before carrageenan. All readings were taken 4 hr after carrageenan. B, C, Effect of
PGE2 injected at different times (30 min to 96 hr) in
different groups of rats after injection of carrageenan plus WIPTIDE
(B) or PKGI (C). All
readings were taken 4 hr after prostaglandin E2 injection.
n = 6 each group.
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Administration of a PKC agonist is sufficient to induce the
prolonged hyperalgesic response to PGE2
Because the long-term prolongation of PGE2
hyperalgesia was inhibited by PKC inhibitors, we evaluated whether
specific activation of PKC could, like carrageenan, result in a
similar long-term prolongation of PGE2
hyperalgesia. To perform these studies, we used the PKC peptide
agonist R (Dorn et al., 1999).
Intradermal injection of the PKC agonist R into the hindpaw of
the rat produced a dose-dependent mechanical hyperalgesia (Fig.
5A), inhibitable by a
nonselective PKC inhibitor (Bis) and a PKC selective inhibitor
(PKCV1-2), but not by inhibitors of other
second messenger pathways implicated in hyperalgesia (WIPTIDE, PKGI,
ODQ, L-NMA, Quin-2, TMB-8, or MK801) (Fig.
5D). R-induced hyperalgesia lasted for ~72 hr (Fig.
5C). After recovery from R-induced hyperalgesia, on
the fifth day after administration of R, the response to
PGE2 was markedly prolonged (lasting >24 hr)
(Fig. 5B), similar to that observed after recovery from
carrageenan hyperalgesia. As after carrageenan, Bis and PKC
inhibitor, but not WIPTIDE, PKGI, ODQ, L-NMA,
Quin-2, TMB-8, and MK801, attenuated the prolonged hyperalgesia induced
by PGE2 (Fig. 5E). Instead, as found
in carrageenan-pretreated rats, WIPTIDE inhibited only the early (30 min after injection) phase of PGE2 hyperalgesia in R-pretreated rats.
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Figure 5.
A, Dose-response curve
of R (0.1-10,000 ng, n = 8)-induced
mechanical hyperalgesia measured at 30 min in the hindpaw of the rat.
B, PGE2-induced hyperalgesia at 30 min, 4 hr, and 24 hr in rats treated 5 d previously with R (1 µg,
n = 6). C, Time course of R (1 µg/paw, n = 12)-induced hyperalgesia (1 µg).
D, Role of second messengers important in
R-induced hyperalgesia. PKA inhibitor WIPTIDE
(WIP/ R; both 1 µg, n = 24), the nitric oxide synthase
inhibitor NG-methyl-L-arginine
(L-NMA/R; both 1 µg,
n = 12), the PKC inhibitor bisindolylmalemide 1 hydrochloride (Bis/R; both 1 µg, n = 12), the PKC inhibitor
(PKCV1-2/R; both 1 µg,
n = 12), the PKG inhibitor
(PKGI/R; both 1 µg,
n = 8), the guanylyl cyclase inhibitor ODQ
(ODQ/R; both 1 µg,
n = 6), the calcium transport antagonist
3,4,5-trimethoxybezoic acid 8-(diethylamino) octyl ester
(TMB/R; both 1 µg,
n = 6), the calcium chelator
(2-[(2-bis-[carboxymethyl] amino-5-methylphenoxy)
methyl]-6-methoxy-8-bis[carboxymethy]
aminoquinoline (Quin/R; both 1 µg, n = 6), or the NMDA receptor antagonist
MK-801 (MK801/R; both 1 µg,
n = 8) 5 min before injection of R (1 µg).
All readings were taken 30 min after injection of R.
E, Role of second messengers in PGE2-induced
hyperalgesia in rats pretreated with R. Rats were administered
the PKA inhibitor WIPTIDE (E2/WIP; 100 ng/1 µg,
n = 6), the nitric oxide synthase inhibitor
L-NMA
(E2/L-NMA; 100 ng/1 µg,
n = 6), the PKC inhibitor Bis
(E2/Bis; 100 ng/1 µg, n = 10), the
PKC inhibitor (E2/PKCV1-2; 100 ng/1 µg, n = 6), the calcium antagonists Quin-2
and TMB-8 (E2/Quin and E2/TMB; both 100 ng/1 µg, both n = 6), or the NMDA receptor
antagonist MK-801 (E2/MK801; 100 ng/1 µg,
n = 10) 5 min before injection of PGE2
(E2) (100 ng) on the fifth day after receiving R
(1 µg). All readings were taken 4 hr after injection of
PGE2.
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DISCUSSION |
Although many mechanisms have been demonstrated to contribute to
acute inflammatory pain, very little is known of the cellular changes
underlying chronic inflammatory pain states. Recently, it has been
suggested that sensitization and sprouting may be important mechanisms
by which the CNS contributes to chronic inflammatory pain (Woolf
and Doubell, 1994; Baranauskas and Nistri, 1998). We now demonstrate a
novel peripheral pronociceptive mechanism initiated by acute
inflammation, involving a PKC-dependent prolongation of hyperalgesic
responses to inflammatory mediators lasting several weeks after
resolution of the initial acute inflammation. This prolonged response
to inflammatory mediators constitutes a dramatic unprecedented plastic
change in primary afferent nociceptor function, most striking in the
marked, sixfold or greater increase in duration of hyperalgesia after a
single injection of PGE2 and in the persistence of this change for a 3 week period or more. In addition, this plastic
change in the primary afferent nociceptor is not accompanied by a
residual baseline hyperalgesia or by histopathological evidence of
ongoing inflammation (Guilbaud et al., 1989; Dawson et al., 1991).
Because in the dermis, the site of injection of all the test agents we
used, PKC is present exclusively in nerve processes (Khasar et al.,
1999a), this plastic change appears to occur in the primary afferent nociceptor.
Carrageenan, which we used to induce the initial inflammation, is a
classic agent for the induction of experimental inflammation and
inflammatory pain and is considered relevant to clinically important
inflammatory pain states (Di Rosa, 1972; Dawson et al., 1991; Gilroy et
al., 1999). In addition, the mediators for which we demonstrated the
development of a prolonged response [PGE2, 5HT,
and purines (CGS-21680)] are known to be present at increased concentration at sites of inflammation (Foon et al., 1976; Driver et
al., 1993; Villena et al., 1999) and are known to produce hyperalgesia by a direct action on primary afferent nociceptors (Taiwo and Levine,
1990, 1992; Gold et al., 1996). Therefore, the hyper-responsive state
we describe, dependent on PKC, is very likely active in peripheral
nociceptors in chronic inflammatory pain. Such an exaggerated response
to inflammatory mediators may explain the inordinate and lasting
responses observed in patients with chronic inflammatory pain syndromes
after minor stimuli (Lockwood, 1989; MacIntyre et al., 1995; Melhorn,
1998).
In our model, mild acute carrageenan hyperalgesia could be blocked
without inhibiting subsequent enhanced responsiveness to PGE2. This demonstrated that enhanced
responsiveness to PGE2 was not dependent on the
preceding acute hyperalgesia. This finding allowed us to determine that
enhanced responsiveness to PGE2 was present as
early as 48 hr after injection of carrageenan. These observations
suggest that development of a propensity for persistent chronic
inflammatory pain may occur after a period of only minimal hyperalgesia, providing an explanation for instances in which chronic
inflammatory pain develops without an episode of preceding overt acute inflammation.
Pronociceptive plastic changes in CNS circuitry are well established
(Woolf and Doubell, 1994; Mannion et al., 1996; Baranauskas and Nistri,
1998). The search for such changes in the periphery, however, has
received little attention, although there are recent reports of altered
gene expression in primary afferent neurons stimulated by NGF and
electrical activity (Gilchrist et al., 1991; McCarson and Krause, 1994;
Nahin and Byers, 1994; Black et al., 1997; Itoh et al., 1997; Tonra and
Mendell, 1998; Fjell et al., 1999; Woolf and Costigan, 1999). The time
of onset of ~48 hr for the development of long-term prolongation of
hyperalgesic responses to inflammatory mediators is compatible with
gene expression followed by transport or newly synthesized protein to
peripheral terminals.
Although our data do not exclude actions by other isozymes of PKC, that
the epsilon isozyme alone, of PKC, is responsible is supported by the
observations that the prolonged response to inflammatory mediators was
totally prevented by injection of a specific PKC inhibitor and that
the injection of a PKC agonist alone resulted in a similar prolonged
hyperalgesic response. PKC is known also to contribute to acute
nociception, specifically to acute hyperalgesia produced by epinephrine
(Khasar et al., 1999a,b), which may be present at increased levels
during inflammation (Cunha et al., 1991; Mikhailov and Rusanova, 1993).
That there is a different function of PKC in prolonged hyperalgesia
compared with acute nociception is suggested by the chronic (>24 hr)
nature of the resultant hyperalgesia and the apparent novel coupling of
PKC to the PGE2 receptor, a phenomenon not
seen in acute hyperalgesia produced by PGE2
(Levine and Reichling, 1999).
In summary, we have established, for the first time, a plastic
pronociceptive mechanism, most likely in nociceptors, that is dependent
on PKC and may have a role in chronic inflammatory pain states. The
dependence on a mechanism not found with acute hyperalgesia and its
presence after even mild inflammation has important clinical
implications. Our experimental paradigm provides a model for the
investigation of other cellular mechanisms that may contribute to
chronic inflammatory pain. It should be possible, using this model, to
obtain valuable information for the rational development of targeted
therapies for both active disease and remission of chronic inflammatory
pain states, such as arthritis, bronchitis, asthma, dermatitis,
inflammatory bowel disease, and repetitive strain injuries, which
contribute greatly to morbidity worldwide. Finally, because the
targeted pronociceptive mechanism is peripheral, at the site of pain,
it may be possible to administer analgesic therapies locally with
minimal or no systemic side effects.
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FOOTNOTES |
Received Oct. 28, 1999; revised Feb. 18, 2000; accepted March 27, 2000.
This work was funded by National Institutes of Health Grant NS21647. We
acknowledge many helpful discussions with Drs. David Reichling, Philip
Heller, and Paul Green.
Correspondence should be addressed to Dr. K. O. Aley, National
Institutes of Health Pain Center, University of California, San
Francisco, Box 0440, San Francisco, CA 94143-0440. E-mail: aley{at}itsa.ucsf.edu.
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TOP
ABSTRACT
INTRODUCTION
