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The Journal of Neuroscience, March 15, 1999, 19(6):2181-2186
Role of Protein Kinase A in the Maintenance of Inflammatory
Pain
Kochuvelikakam O.
Aley and
Jon D.
Levine
Departments of Anatomy, Medicine, and Oral Surgery, Neuroscience
and Biomedical Sciences Graduate Programs, National Institutes of
Health Pain Center, University of California, San Francisco, California
94143-0440
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ABSTRACT |
Although the initiation of inflammatory pain (hyperalgesia) has
been demonstrated to require the cAMP second messenger signaling cascade, whether this mechanism and/or other mechanisms underlie the
continued maintenance of the induced hyperalgesia is unknown. We report
that injection of adenylyl cyclase inhibitors before but not after
injection of direct-acting hyperalgesic agents (prostaglandin E2 and purine and serotonin receptor agonists) resulted in
reduction in hyperalgesia, evaluated by the Randall-Selitto
paw-withdrawal test. In contrast, injection of protein kinase A (PKA)
inhibitors either before or after these hyperalgesic agents resulted in
reduced hyperalgesia, suggesting that hyperalgesia after its activation was maintained by persistent PKA activity but not by adenylyl cyclase
activity. To evaluate further the role of PKA activity in the
maintenance of hyperalgesia, we injected the catalytic subunit of PKA
(PKACS) that resulted in hyperalgesia similar in magnitude to that
induced by the direct-acting hyperalgesic agents but much longer in
duration (>48 vs 2 hr). Injection of WIPTIDE (a PKA inhibitor)
at 24 hr after PKACS reduced hyperalgesia, suggesting that PKACS
hyperalgesia is not independently maintained by steps downstream from
PKA. In summary, our results indicate that, once established,
inflammatory mediator-induced hyperalgesia is no longer maintained by
adenylyl cyclase activity but rather is dependent on ongoing PKA
activity. An understanding of the mechanism maintaining hyperalgesia
may provide important insight into targets for the treatment of
persistent pain.
Key words:
adenylyl cyclase; cAMP; hyperalgesia; pain; protein
kinase A; prostaglandin E2
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INTRODUCTION |
Tissue injury results in the
production of inflammatory mediators, several of which sensitize
primary afferent nociceptors (Martin et al., 1987 ; Schaible and
Schmidt, 1988; Davis et al., 1993; Rueff and Dray, 1993),
resulting in hyperalgesic pain (tenderness) (Collier and Schneider,
1972; Moncada et al., 1975; Ferreira et al., 1978; Ferreira, 1981).
Inflammatory mediators such as prostaglandin E2
(PGE2), adenosine, and serotonin (5-HT) act
directly on primary afferent nociceptors to decrease the activation
threshold and to increase the response to a constant intensity stimulus
(Taiwo and Levine, 1989, 1990, 1992; England et al., 1996; Gold et al., 1996a). A substantial literature suggests that PGE2-,
5-HT-, and adenosine-induced hyperalgesia, as well as hyperalgesia
induced by tissue damage, is initiated by activation of the adenylyl
cyclase (AC)-cAMP-protein kinase A (PKA) second messenger cascade
(Taiwo et al., 1989; Taiwo and Levine, 1990, 1991, 1992; Pitchford and Levine, 1991; Khasar et al., 1995; England et al., 1996; Malmberg et
al., 1997). Voltage-gated sodium currents may be modulated by PKA.
Although the majority of voltage-gated sodium currents modulated by PKA
are inhibited, it has been shown that PKA is able to enhance the
tetrodotoxin-resistant sodium current (England et al., 1996; Cardenas
et al., 1997; Gold et al., 1999), a sodium current found primarily in
nociceptors (Akopian et al., 1996; Sangameswaran et al., 1996), that is
thought to underlie inflammatory mediator-induced sensitization of
nociceptors (England et al., 1996; Gold et al., 1996a; Cardenas et al.,
1997) and hyperalgesia (Khasar et al., 1999). Thus, agents that inhibit
AC and cAMP-dependent protein kinase (PKA) prevent induction of
hyperalgesia by PGE2, CGS21680, and
8-hydroxy-2-(di-N-propylamino)tetralin
(8-OH-DPAT).
Because of the important ramifications for treatment of chronic
inflammatory pain, we investigated whether ongoing activity in the cAMP
second messenger pathway contributes to maintenance as well as
initiation of hyperalgesia and, if so, which steps in the cAMP second
messenger cascade determine duration of the hyperalgesia.
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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 12:12 hr light/dark cycle. 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 Committee of the University
of California, San Francisco.
Behavioral testing. The nociceptive flexion reflex was
quantified with a Basile Analgesymeter (Stoelting, Chicago, IL),
which applies a linearly increasing mechanical force to the dorsum of the rat's hindpaw. The mean baseline threshold was determined as the
mean of three readings before the administration of the test agent. The
mean baseline threshold, before treatments, for the rats used in these
experiments was 109.0 ± 0.45 gm (mean ± SEM;
n = 284 paws). Mechanical threshold was redetermined at
three time points (15, 20, and 25 min) after treatments. The mean of these three readings was considered to be the paw-withdrawal threshold because of drug administration, and this value was used to calculate the percentage change from the baseline threshold for each paw.
The onset of hyperalgesia was determined by assessing 1, 2, 3, 4, and 5 min after injection of a hyperalgesic agent.
Drug administration. The agents used in this study were
PGE2 (Sigma, St. Louis, MO); WIPTIDE,
8-OH-DPAT, CGS21680, and SQ22356 (Research Biochemicals, Natick, MA);
protein kinase A catalytic subunit (PKACS) and RpcAMPS (Calbiochem,
La Jolla, CA); dideoxyadenosine (ddA) (courtesy of Dr. Johnson,
State University of New York, Stony Brook, NY); and SC19220 (a generous
gift from G. D. Searle). The selection of the doses used was based
on the dose-response curves determined in this or previous studies
(Aley and Levine, 1997, 1998). The stock solution of PGE2
(1 µg/2.5 ml) was prepared in 10% ethanol, and further dilutions
were made in saline; the final concentration of ethanol was  1%.
PKACS and WIPTIDE were dissolved in saline. All drugs were administered
intradermally in a volume of 2.5 µl/paw. For test agents with
low cell membrane permeability (WIPTIDE and PKACS), coinjection
of 2 µl of distilled water, to produce hypo-osmotic shock and
facilitate cell permeability to these agents, was used (West and Huang,
1980; Burch and Axelrod, 1987; Leidenheimer and Harris, 1991). When
combinations of agents were used, they were administered from the same
syringe in such a way that the agent mentioned first reached the
intradermal site first; similarly, the distilled water preceded agents
with low cell membrane permeability. The agents were separated in the
syringe by a small air bubble to prevent their mixing in the syringe.
To enhance our ability to analyze a specific second messenger system
(that is, to ensure the greatest specificity in block of function), we
have (1) used multiple inflammatory mediators known to be direct-acting
hyperalgesic agents producing hyperalgesia by the cAMP-PKA second
messenger signaling pathway, (2) used the most specific blockers
available, (3) used more than one specific blocker of a single target
in the second messenger pathway, and (4) used blockers at multiple
sites in the same second messenger pathway.
Statistics. Data are presented as mean ± SEM;
statistical significance was determined by ANOVA followed by
Scheffe's post hoc test, and p < 0.05 was
considered statistically significant.
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RESULTS |
Injection of PGE2 (100 ng) resulted in a significant
decrease in the nociceptive threshold that reached peak magnitude by 5 min (Fig. 1A).
Injection of an adenylyl cyclase inhibitor, ddA or SQ22356,
before PGE2 reduced PGE2-induced hyperalgesia;
however, if injected 5 min after PGE2, ddA or
SQ22356 had no effect on the established PGE2 hyperalgesia
(Fig. 1C). Similarly, injection of the E-type prostaglandin
receptor antagonist SC19220 before but not 5 min after PGE2
attenuated PGE2-induced hyperalgesia (Fig. 1C).
Injection of a PKA inhibitor, WIPTIDE or RpcAMPS, before PGE2 also inhibited PGE2-induced hyperalgesia
(Fig. 1D); however, unlike the cyclase inhibitors,
WIPTIDE or RpcAMPS injected 5 min after PGE2 was also able
to inhibit PGE2 hyperalgesia. These results suggest that, 5 min after its induction, PGE2 hyperalgesia is maintained by
PKA activity and that adenylyl cyclase activity is no longer
required.
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Figure 1.
A, Latency of onset of
PGE2-induced mechanical hyperalgesia
in the hindpaw of the rat (n = 12).
B, Time course of
PGE2-induced mechanical hyperalgesia
(n = 12). C, Effect on
PGE2-induced mechanical hyperalgesia
(n = 22; p < 0.05) of the
adenylyl cyclase inhibitors ddA and SQ22356
(SQ) when administered before
[ddA/PGE2, n = 8; *p < 0.05;
SQ/PGE2, n = 6;
*p < 0.05; SC19220
(SC)/PGE2,
n = 6; *p < 0.05] or 5 min
after (PGE2/ddA,
n = 10; p > 0.05;
PGE2/SQ,
n = 8; p > 0.05)
intradermal administration of PGE2.
D, Effect of PKA inhibitors [WIPTIDE and
RpcAMPS (RpcAMP)] when
administered before (WIPTIDE/PGE2,
n = 10; *p < 0.05;
RpcAMP/PGE2, n = 6; *p < 0.05) or 5 min after
(PGE2/WIPTIDE,
n = 10; *p < 0.05;
PGE2/RpcAMP,
n = 6; *p < 0.05) intradermal
administration of PGE2. NS,
Not significant.
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To evaluate the generalizability of this role of PKA in the maintenance
of inflammatory hyperalgesia, we determined the effect of adenylyl
cyclase and PKA inhibitors on hyperalgesia induced by two other
direct-acting hyperalgesic agents, 8-OH-DPAT (5-HT1A serotonin receptor agonist) and CGS21680 (A2 adenosine
receptor agonist) (Taiwo and Levine, 1990, 1992). Injection of
8-OH-DPAT and CGS21680 resulted in a significant decrease in
nociceptive threshold (Figs. 2,
3, respectively). Hyperalgesia
induced by 8-OH-DPAT or CGS21680 was fully established by 5 min.
Injection of the adenylyl cyclase inhibitors ddA and SQ22356
immediately before 8-OH-DPAT and CGS21680 resulted in reduced
hyperalgesia; however, if injected 5 min after 8-OH-DPAT and CGS21680,
ddA and SQ22356 had no effect on established hyperalgesia. Injection of a PKA inhibitor, WIPTIDE or RpcAMPS, before 8-OH-DPAT or CGS21680 also
inhibited induction of hyperalgesia (Figs. 2, 3); injected 5 min after
8-OH-DPAT or CGS21680, WIPTIDE or RpcAMPS was still able to inhibit
hyperalgesia.
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Figure 2.
A, Latency of onset of
direct-acting serotonin agonist [8-OH-DPAT
(OHDPAT)]-induced mechanical hyperalgesia in the
hindpaw of the rat (n = 6). B, Time
course of 8-OH-DPAT-induced mechanical hyperalgesia
(n = 6). C, Effect on
8-OH-DPAT-induced mechanical hyperalgesia
(n = 6; p < 0.05) of the
adenylyl cyclase inhibitors ddA and SQ22356
(SQ) when administered before
(ddA/OHDPAT, n = 6;
*p < 0.05; SQ/OHDPAT,
n = 6; *p < 0.05) or 5 min
after (OHDPAT/ddA, n = 10;
p > 0.05; OHDPAT/SQ,
n = 6; p > 0.05) intradermal
administration of 8-OH-DPAT. D, Effect of
PKA inhibitors [WIPTIDE (WIP) and
RpcAMPS (RpcAMP)] when administered
before (WIP/OHDPAT, n = 6;
*p < 0.05; RpcAMP/OHDPAT,
n = 6; *p < 0.05) or 5 min
after (OHDPAT/WIPTIDE, n = 12;
*p < 0.05; OHDPAT/RpcvAMP,
n = 6; *p < 0.05) intradermal
injection of 8-OH-DPAT.
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Figure 3.
A, Latency of onset of
direct-acting adenosine agonist [CGS21680
(CGS)]-induced mechanical hyperalgesia in the hindpaw
of the rat (n = 6). B, Time course
of CGS21680-induced mechanical hyperalgesia (n = 6). C, Effect on CGS21680-induced mechanical
hyperalgesia (n = 6; p < 0.05)
of the adenylyl cyclase inhibitors ddA and SQ22356
(SQ) when administered before (ddA/CGS,
n = 6; *p < 0.05;
SQ/CGS, n = 6;
*p < 0.05) or 5 min after (CGS/ddA,
n = 6; p > 0.05;
CGS/SQ, n = 6; p > 0.05) intradermal injection of CGS21680. D, Effect of
PKA inhibitors [WIPTIDE (WIP) and
RpcAMPS (RpcAMP)] when administered
before (WIP/CGS, n = 6;
*p < 0.05; RpcAMP/CGS,
n = 6; *p < 0.05) or 5 min
after (CGS/WIP, n = 10;
*p < 0.05; CGS/RpcAMP,
n = 10; *p < 0.05) intradermal
injection of CGS21680.
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To determine whether "exogenous," persisting PKA activity mimics
inflammatory mediator-induced hyperalgesia, we injected the PKACS that
can be introduced to an intracellular location by a preceding
injection of distilled water to produce hypo-osmotic shock (Burch and
Axelrod, 1987; Taiwo and Levine, 1989; Khasar et al.,
1995). Injection of PKACS produced hyperalgesia similar in
magnitude to that produced by PGE2 but lasting at least 48 hr (Fig. 4). Injection of WIPTIDE before
PKACS inhibited PKACS hyperalgesia (Fig. 4). WIPTIDE was also able to
reverse PKACS hyperalgesia when injected 5 min, 6 hr, or 24 hr after
PKACS.
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Figure 4.
A, Time course of
PKACS (15 U; n = 12)-induced
hyperalgesia is shown. B, Thirty minutes after
intradermal injection of PKACS (n = 12) but not its vehicle (DMSO; n = 6), significant hyperalgesia (p < 0.05) is
induced. WIPTIDE (WIP) injected before
(WIP/PKACS, n = 6;
*p < 0.05) or 5 min [PKACS/WIP (5'
post), n = 6; *p < 0.05], 6 hr [PKACS/WIP (6 hr post), n = 6;
*p < 0.05] or 24 hr [PKACS/WIP
(24 hr post), n = 6; *p < 0.05] after PKACS inhibited
PKACS-induced hyperalgesia.
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DISCUSSION |
All steps of the cAMP second messenger cascade have been shown to
be necessary for the induction of hyperalgesia by direct-acting agents.
However, our results indicate that at 5 min after injection, hyperalgesia is maintained by PKA and is independent of upstream activity in the cAMP-PKA second messenger cascade. The fact that WIPTIDE can inhibit PKACS-induced hyperalgesia when administered at any
point during its time course suggests that the hyperalgesia is not
maintained by persistence of the changes in the cell downstream from
PKA, such as long-lasting enhancement of ion channels, such as the
tetrodotoxin-resistant sodium current, the probable downstream target
for PKA in nociceptors mediating sensitization (England et al., 1996;
Gold et al., 1996a; Cardenas et al., 1997) and hyperalgesia (Khasar et
al., 1999).
Furthermore, because administration of PKACS (essentially an excess of
PKA, devoid of its regulatory subunit) produces prolonged hyperalgesia,
with a time course consistent with that of metabolic degradation of
PKACS (Lee and Steinberg, 1996), the observed time course of
hyperalgesia after PGE2 seems to reflect the time course of
PKA activation. That PKACS hyperalgesia could be reversed by PKA
inhibitors even 24 hr after onset of hyperalgesia further suggests that
mechanisms downstream from PKA activity are not effective in the
maintenance of the observed hyperalgesia.
If cAMP levels remain persistently elevated, cells undergo changes in
their A kinase signaling system; some cells alter the rate of
degradation of PKA subunits, and some change the stability of the
messages encoding subunits (Spaulding, 1993; Dunbar and Kalinski, 1994;
Garrel et al., 1995; Spatz, 1995; Knutsen et al., 1997). Therefore,
prolonged hyperalgesia after a sustained exposure to hyperalgesic
inflammatory mediators may result from prolonged exposure to cAMP and
consequent independently persisting activity of the PKA catalytic
subunit because of changes in the ratio of catalytic to regulatory
subunits. For example, in nociceptor-like neurons in Aplysia
(Clatworthy and Walters, 1993a,b; Dulin et al., 1995; O'Leary et al.,
1995), PKA plays an important role in the facilitation that mediates
both short- and long-term sensitization (Kandel and Schwartz, 1982;
Bailey and Kandel, 1993; Byrne et al., 1993). After exposure to the
facilitating neurotransmitter serotonin, protein kinase A activity
becomes persistently elevated at basal cAMP levels, because of a
decrease in the ratio of the concentration of regulatory to catalytic
subunits (Sweatt and Kandel, 1989; Chain et al., 1995). Our
demonstration that administration of PKACS produces prolonged
hyperalgesia, compatible with its rate of metabolism, suggests that a
modification of its metabolism could contribute to chronic hyperalgesic states.
In summary, we have provided evidence for the first time that
maintenance of hyperalgesia involves a mechanism distinct from the
initiating mechanism. Understanding of the mechanisms maintaining hyperalgesia can provide rationales for novel targets for the treatment
of chronic inflammatory pain. Specifically, the results of the present
study suggest that continued exposure to inflammatory mediators may not
be needed to maintain chronic hyperalgesic pain and, therefore, that
the most effective site for therapeutic intervention may not be the
cell surface receptor in primary afferent nociceptors but the
responsible intracellular second messengers. This observation might
also underlie the development of resistance to agents that block the
production of hyperalgesic inflammatory mediators, such as the
nonsteroidal anti-inflammatory drugs, inhibitors of the synthesis of prostaglandins.
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FOOTNOTES |
Received Aug. 27, 1998; revised Dec. 17, 1998; accepted Dec. 22, 1998.
This research was supported by National Institutes of Health Grant
NS21647. We thank Drs. Philip Heller and David Reichling for many
helpful discussions during the course of these studies and for comments
on this manuscript.
Correspondence should be addressed to Dr. Jon D. Levine, National
Institutes of Health Pain Center, University of California, San
Francisco, C-522, Box 0440, 521 Parnassus Avenue, San Francisco, CA
94143-0440.
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Top
Abstract
Introduction
