Departments of Medicine and Oral and Maxillofacial Surgery, Division of Neuroscience and Biomedical Sciences Program, National Institutes of Health Pain Center (UCSF), University of California, San Francisco, California 94143-0440
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ABSTRACT |
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Khasar, Sachia G.,
Gordon McCarter, and
Jon D. Levine.
Epinephrine produces a -adrenergic receptor-mediated mechanical
hyperalgesia and in vitro sensitization of nociceptor-like neurons in
the rat. Hyperalgesic and nociceptor sensitizing effects mediated by the
-adrenergic receptor were evaluated in the rat. Intradermal injection of epinephrine, the major endogenous ligand for
the
-adrenergic receptor, into the dorsum of the hindpaw of the
rat produced a dose-dependent mechanical hyperalgesia, quantified by
the Randall-Selitto paw-withdrawal test. Epinephrine-induced hyperalgesia was attenuated significantly by intradermal
pretreatment with propranolol, a
-adrenergic receptor antagonist,
but not by phentolamine, an
-adrenergic receptor antagonist.
Epinephrine-induced hyperalgesia developed rapidly; it was
statistically significant by 2 min after injection, reached a maximum
effect within 5 min, and lasted 2 h. Injection of a more
-adrenergic receptor-selective agonist, isoproterenol, also produced
dose-dependent hyperalgesia, which was attenuated by propranolol but
not phentolamine. Epinephrine-induced hyperalgesia was not
affected by indomethacin, an inhibitor of cyclo-oxygenase, or by
surgical sympathectomy. It was attenuated significantly by inhibitors
of the adenosine 3',5'-cyclic monophosphate signaling pathway (the
adenylyl cyclase inhibitor, SQ 22536, and the protein kinase A
inhibitors, Rp-adenosine 3',5'-cyclic monophosphate and WIPTIDE),
inhibitors of the protein kinase C signaling pathway (chelerythrine and
bisindolylmaleimide) and a µ-opioid receptor agonist DAMGO
([D-Ala2,N-Me-Phe4,Gly5-ol]-enkephalin).
Consistent with the hypothesis that epinephrine produces hyperalgesia
by a direct action on primary afferent nociceptors, it was found to
sensitize small-diameter dorsal root ganglion neurons in culture, i.e.,
to produce an increase in number of spikes and a decrease in latency to
firing during a ramped depolarizing stimulus. These effects were
blocked by propranolol. Furthermore epinephrine, like several other
direct-acting hyperalgesic agents, caused a potentiation of
tetrodotoxin-resistant sodium current, an effect that was abolished by
Rp-adenosine 3',5'-cyclic monophosphate and significantly attenuated by
bisindolylmaleimide. Isoproterenol also potentiated
tetrodotoxin-resistant sodium current. In conclusion, epinephrine
produces cutaneous mechanical hyperalgesia and sensitizes cultured
dorsal root ganglion neurons in the absence of nerve injury via an
action at a
-adrenergic receptor. These effects of epinephrine are
mediated by both the protein kinase A and protein kinase C
second-messenger pathways.
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INTRODUCTION |
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A contribution of catecholamines to both inflammatory and
neuropathic pain states has been suggested based on both clinical evidence and animal models (Jänig et al. 1996;
Raja 1998
). Although most research in the area has
evaluated the contribution of the sympathetic postganglionic neuron
(SPGN) and its major transmitter norepinephrine, these pain states also
may be associated with increased activity of the sympathoadrenal
system, leading to elevation of the plasma concentrations of
epinephrine [an endogenous
-adrenergic receptor (
-AR) agonist]
(Cryer 1980
; DeTurck and Vogel 1980
; Taylor et al. 1989
; Wortsman et al.
1984
). Although activation of
-ARs was shown, almost two
decades ago, to produce behavioral hyperalgesia (Ferreira
1980
) and epinephrine can cause anginal pain in the absence of
apparent ischemia (Eriksson et al. 1995
), further
studies of the role of
-ARs in peripheral pain and the elucidation
of mechanisms involved have been lacking. We investigated mechanisms
involved in epinephrine-induced hyperalgesia, hypothesizing that
epinephrine produces hyperalgesia by directly sensitizing primary
afferent nociceptors.
We tested this hypothesis in vivo using the behavioral model of
mechanical hyperalgesia and in vitro using cultured dorsal root
ganglion (DRG) neurons. We also tested whether epinephrine enhances
tetrodotoxin-resistant sodium currents (TTX-R
INa), which are carried by an ion channel
selectively found in primary afferent nociceptors (Akopian et
al. 1996; Sangameswaran et al. 1996
) and the
activity of which is increased by agents that act directly on primary
afferent nociceptors in vivo to produce hyperalgesia (England et
al. 1996
; Gold et al. 1996b
). Finally,
we examined the second-messenger systems that may mediate the
hyperalgesic and sensitizing effects of epinephrine.
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METHODS |
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Experimental procedures
BEHAVIORAL EXPERIMENTS. Behavioral experiments were performed on lightly restrained male Sprague-Dawley rats (250-350 g) purchased from Bantin and Kingman (Fremont, CA) and housed in the animal care facility of the University of California, San Francisco, under a 12-h light/dark cycle. Care and use of rats conformed to National Institutes of Health guidelines, and experimental protocols were approved by the University of California, San Francisco, Committee on Animal Research. The nociceptive flexion reflex was quantified by an Ugo Basile Analgesimeter (Stoelting, Chicago, IL), which applies a linearly increasing mechanical force to the dorsal surface of the rat's hind paw.
Before the rats were used for behavioral experiments, they were trained in the paw-withdrawal reflex test at 5-min intervals for 1 h each day for a period of 5 days. This training procedure reduces variability and produces a more stable baseline paw-withdrawal threshold measurement, thereby enhancing the ability to detect the effect of agents that modulate nociception (Taiwo et al. 1989SYMPATHECTOMY.
To test if epinephrine hyperalgesia is dependent on the presence of
intact sympathetic postganglionic neurons (SPGNs), rats were
sympathectomized surgically under pentobarbital anesthesia (50 mg/kg
body wt, with additional doses given to maintain areflexia during
surgery). After a lateral abdominal incision, the sympathetic chain was
reached via an extraperitoneal approach, and the lumbar sympathetic
chains, from ganglia L1 to L4, were removed
bilaterally (Baron et al. 1988; Miao et al.
1995
). This procedure results in complete sympathetic
denervation of the hind limbs (Baron et al. 1988
). Sham
surgeries were performed in a similar manner, except that the
sympathetic chains were left intact, after exposure. The dose-response
relationship for epinephrine-induced hyperalgesia was determined 7 days
after surgical sympathectomy or sham surgery.
CELL CULTURE AND ELECTROPHYSIOLOGY.
To examine the effect of epinephrine on the excitability and ionic
conductance of isolated DRG neurons, primary cultures of adult rat
lumbar DRGs (L1-L6) were prepared as
previously described (Gold et al. 1996a). Culture medium
consisted of minimal essential medium (MEM) supplemented with 10%
fetal bovine serum and 1,000 units per ml each of penicillin and
streptomycin. Neurons were plated onto glass cover slips coated with
laminin and poly-DL-ornithine and were maintained in
culture medium with nerve growth factor (NGF; GIBCO BRL, Gaithesburg,
MD) at 37°C under 3% CO2. Neurons were used within
24 h of plating before there was appreciable outgrowth of
neurites. Small-diameter neurons (20-30 µm in diameter) were studied
because they selectively express properties of nociceptors (Gold
et al. 1996a
). Bath solution continuously perfused the
recording chamber at 1-2 ml/min. Drugs were added as described in the
respective figure legends. Experiments were performed at room
temperature (21-24°C).
Materials
Drugs or reagents used in this study were from Sigma (St. Louis,
MO) unless otherwise noted: prostaglandin E2
(PGE2), epinephrine [an endogenous -adrenergic receptor
(
-AR) agonist], isoproterenol (a specific
-AR agonist),
propranolol (a specific
-AR antagonist), phentolamine (a specific
-adrenergic receptor (
-AR) antagonist, CIBA-GEIGY, Summit, NJ),
DAMGO, enkephalin (a µ-opioid receptor agonist; Research
Biochemicals, Natick, MA); SQ 22536 (an adenylyl cyclase inhibitor);
BIM (a PKC inhibitor) (both from Calbiochem, La Jolla, CA);
chelerythrine (a PKC inhibitor; L. C. Labs., Woburn, MA); Rp-cAMPS
(a PKA inhibitor; Biolog, La Jolla, CA); WIPTIDE (a PKA inhibitor;
Peninsula Labs, Belmont, CA); indomethacin sodium salt (a generous gift
from Merck Research Labs, Rahway, NJ). PGE2 (4 mg/ml) stock
solution was made by dissolving it in 10% ethanol in normal saline;
further dilutions were made by adding saline. Final concentration of
ethanol was <1%. Isoproterenol, phentolamine, propranolol,
chelerythrine, BIM, and WIPTIDE were dissolved in distilled water.
Epinephrine (4 mg/ml) was dissolved in distilled water with an
equivalent amount of ascorbic acid just before it was used and was kept
on ice in subdued lighting conditions. All other drugs were dissolved
in normal saline or bath solution.
Data are presented as means ± SE and analyzed statistically using one-factor ANOVA or repeated measures ANOVA as appropriate. Where ANOVA showed significant differences between groups, Fisher's protected least-significant difference (PLSD) post hoc test was used to determine the specific pairs of groups between which statistically significant differences occurred. P < 0.05 was the accepted level for statistical significance.
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RESULTS |
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Behavioral studies
Epinephrine (1 ng to 1 µg) produced a dose-dependent decrease in the mechanical nociceptive threshold (i.e., produced hyperalgesia; F = 90.7, P < 0.01; one-factor ANOVA) when injected intradermally into the dorsal surface of the hindpaw of the rat (mean baseline paw-withdrawal threshold for this group of rats was 107.5 ± 1.2 g; n = 31) (Fig. 1A). The intradermal injection of ascorbic acid (4 mg/ml) did not significantly affect basal paw-withdrawal threshold (data not shown). The latency to onset of epinephrine (1 µg)-induced hyperalgesia was brief (Fig. 2); it was significant 2 min after injection, reached peak effect by 5 min (Fig. 2A) and lasted ~2 h (Fig. 2B). Epinephrine-induced hyperalgesia was attenuated by treating the paws (mean baseline paw-withdrawal threshold 102.6 ± 2.2 g; n = 8) with propranolol, significantly shifting the dose-response curve to the right of that for epinephrine alone (Fig. 1A). Injection of propranolol alone did not alter basal paw-withdrawal threshold (data not shown). Pretreatment of paws with distilled water and subsequent coinjection with epinephrine during the course of the experiment also produced dose-dependent hyperalgesia (F = 40.76, n = 14; Fig. 1B). Repeated injections of distilled water alone did not produce hyperalgesia (F = 1.48, n = 4; Fig. 1A).
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Because epinephrine has affinity for both - and
-ARs, we
evaluated the contribution of the
-AR to epinephrine-induced
hyperalgesia. We tested epinephrine-induced hyperalgesia against
phentolamine, an
-AR antagonist. Earlier studies (Levine et
al. 1986
) showed that injection of phentolamine alone had no
effect on basal paw-withdrawal threshold in the normal rat. In the
current study, phentolamine did not significantly affect
epinephrine-induced hyperalgesia (Fig. 1A) The mean baseline
paw-withdrawal threshold of this group of rats was 107.0 ± 1.8 g; n = 17. A similar dose for phentolamine was
shown to significantly reverse formalin-induced decrease in paw
threshold (Levine et al. 1986
) and also inhibit
rolipram-induced prolongation of PGE2 hyperalgesia
(Ouseph et al. 1995
). All data from the groups of rats
in Fig. 1, A and B, were analyzed together. ANOVA
showed significant differences between the groups (F = 12.32; P < 0.01).
It has been shown that bradykinin (BK) and norepinephrine act on
intermediary cells to trigger prostaglandin synthesis, which then acts
on the primary afferent to sensitize it (Lembeck et al.
1976; Taiwo and Levine 1988
). We therefore
tested whether the inhibition of prostaglandin synthesis by
indomethacin would affect epinephrine-induced hyperalgesia.
Indomethacin (4 mg/kg ip, pretreatment, and 1 µg id, during the
course of the experiment), did not affect the ability of epinephrine to
produce hyperalgesia (Fig. 1B). The mean baseline
paw-withdrawal threshold of this group of rats was 109.2 ± 6 g; n = 8. Earlier studies (Levine et al.
1986
; Taiwo et al. 1990
) showed that injection
of indomethacin alone has no effect on basal paw-withdrawal threshold
in the normal rat. Because BK and norepinephrine also act indirectly
via sympathetic neurons to affect nociceptors (Levine et al.
1986
), we tested the effect of sympathectomy on
epinephrine-induced hyperalgesia. The elimination of sympathetic
innervation of the hindpaw by sympathectomy had no effect on the
hyperalgesia produced by epinephrine (Fig. 1B). The mean
baseline paw-withdrawal threshold of this group of rats was 104.2 ± 3.2 g; n = 8, for the sympathectomized and 113.6 ± 3.2 g; n = 6, for the
sham-sympathectomized group.
To further explore the contribution of the -AR to hyperalgesia, we
used the
-AR-selective agonist, isoproterenol (Ahlquist 1976
). Intradermal injection of isoproterenol (1 ng to 1 µg), like epinephrine, produced dose-dependent hyperalgesia
(F = 104.7, P < 0.01, one-factor
ANOVA; Fig. 3). The mean baseline
paw-withdrawal threshold of this group of rats was 103.1 ± 1.5 g; n = 20. Propranolol significantly
attenuated the hyperalgesia produced by isoproterenol, whereas
phentolamine had no effect. The mean baseline paw-withdrawal threshold
of the isoproterenol + propranolol group of rats was 101.3 ± 2.7 g; n = 8 and that for the isoproterenol + phentolamine group was 111.3 ± 2 g; n = 8.
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The intradermal coinjection of DAMGO (1 µg) with epinephrine (100 ng)
or intradermal pretreatment of rat paws with SQ 22536, chelerythrine,
BIM, Rp-cAMPS (all 1 µg), or WIPTIDE (100 ng) 15 min before injection
of epinephrine, significantly attenuated epinephrine-induced
hyperalgesia. The same dose of chelerythrine or BIM had no effect on
PGE2-induced hyperalgesia (Table
1). BIM (1 µg) also significantly
attenuated isoproterenol hyperalgesia and WIPTIDE (100 ng) almost
completely abolished it (Table 1). The intradermal injection of none of
these agents alone affects basal paw-withdrawal threshold [Aley
and Levine 1997, (for DAMGO) and unpublished observations].
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In vitro electrophysiological studies with cultured DRG neurons
To test the hypothesis that epinephrine-induced hyperalgesia was
mediated by a direct effect of epinephrine on the primary afferent
nociceptor, we performed whole cell patch-clamp electrophysiological experiments on dissociated DRG neurons in culture. Small-diameter (i.e., 20-30 µm) neurons were used within 12-24 h of plating as a
model for peripheral nociceptor neurons. This is based on data showing
similarities in the pharmacological repertoires of the cell body in
vitro after 12-24 h in culture and the primary afferent nociceptor
terminal in vivo (Baccaglini and Hogan 1983;
England et al. 1996
; Gold et al. 1996a
;
Pitchford and Levine 1991
).
Current-clamp recordings were performed using the perforated-patch
whole cell technique. The number of action potentials generated during
a 750-ms ramp-and-plateau depolarizing current injection (see
METHODS), as well as the latency to the first spike, were used as measures of excitability. After 5-10 min of baseline
recordings, epinephrine (1 µM) was added to the bath. Figure
4A shows voltage traces from a
typical neuron before and during exposure to 1 µM epinephrine,
whereas Fig. 4B shows the time course of changes in the
number of action potentials and the latency to the first action
potential for another cell. For 11 neurons treated with 1 µM
epinephrine, the average number of action potentials generated in
response to the current ramp-and-plateau stimulus was 1.7 ± 0.2 before the addition of epinephrine and 5.3 ± 0.9 5 min or more
after the start of drug perfusion (P < 0.01, paired
Student's t-test). The mean latency from the start of
current injection to the peak of the first spike was 278 ± 42 ms
before epinephrine and 189 ± 21 ms after the start of drug
perfusion (n = 11, P < 0.05). Of the
11 neurons tested, 9 (81%) showed an increase in spike number, and of
those, 5 (45% of neurons tested) also showed a decrease (of 50 ms)
in the spike latency. The mean resting membrane potential of these
neurons was not changed by epinephrine (
60 ± 2 mV before
epinephrine,
60 ± 2 mV after, n = 11, P > 0.05).
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Propranolol blocked the sensitization of small-diameter DRG neurons by epinephrine. When 10 µM propranolol was perfused 30 s before and with 1 µM epinephrine, there was no increase in the number of spikes (1.2 ± 0.1 before drugs vs. 1.3 ± 0.2 after, n = 7, P > 0.05) nor any decrease in the latency to the first spike (235 ± 9 vs. 233 ± 10 ms, P > 0.05).
Because hyperalgesic agents (e.g., PGE2) that
sensitize nociceptors in vitro have been shown to increase TTX-R
INa (England et al. 1996;
Gold et al. 1996b
), we performed whole cell
voltage-clamp experiments to determine whether epinephrine acted
similarly. Epinephrine (1 µM) caused a marked potentiation of TTX-R
INa (Fig. 5). The
peak current amplitude in response to a depolarizing test pulse was
increased by 37 ± 5% (n = 24, P < 0.01). Comparison of the current-voltage plots before and after drug
exposure indicate that activation of TTX-R INa
was shifted by ~10 mV in the hyperpolarized direction (Fig.
5B). This dose of epinephrine caused an increase in TTX-R
INa in 16 of 24 neurons (67%); isoproterenol
caused a similar increase in TTX-R INa (Fig.
5C). There was no potentiation of TTX-R
INa when epinephrine was applied in the presence
of 2 µM propranolol; mean normalized current was 87 ± 5% of
baseline in the third minute of exposure to epinephrine and propranolol (n = 6) (Fig. 6). The
increase in current was not attenuated by 5 µM phentolamine
(n = 5) (Fig. 6).
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In the behavioral experiments, hyperalgesia caused by epinephrine was dependent on both the PKA and PKC second-messenger systems. Therefore we examined the relative roles these two second-messenger systems play in the effect of epinephrine on TTX-R INa. When Rp-cAMPS (100 µM), a competitive inhibitor of PKA types I and II, was included in the recording pipette, the increase in TTX-R INa by epinephrine was prevented (Fig. 7).
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We also applied epinephrine in the presence of the PKC inhibitor, BIM. The mean normalized current increase in response to 1 µM epinephrine was significantly smaller when neurons were pretreated with BIM compared with control experiments with no BIM pretreatment (Fig. 8; P < 0.01, n = 11 for both conditions). Of the control cells, 8 of 11 responded to the epinephrine (defined as a >10% increase in current amplitude within 3 min) whereas only 5 of 11 did with BIM present. For those neurons that responded to epinephrine, there was a mean increase of 49% in the peak current for the controls compared with 32% with BIM present. Therefore, inhibition of PKC caused both a decrease in the number of neurons responding to epinephrine and a decrease in the mean magnitude of the response.
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DISCUSSION |
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The rapid onset of epinephrine hyperalgesia and the observation
that neither sympathectomy nor indomethacin pretreatment affected it,
is consistent with a direct action of epinephrine on sensory nerve
terminals in the skin (Taiwo and Levine 1989b, 1990
,
1992
). The efficacy of our sympathectomy or indomethacin has
been established in previous studies by observing an immediate increase
in paw temperature of 2-3°C after sympathectomy as well as the loss
of BK-induced hyperalgesia in the normal rat (Khasar et al.
1998
; Miao et al. 1996
). We have suggested
earlier that small-diameter cultured DRG neurons are a good in vitro
model for the study of nociceptors because they possess several
properties of nociceptors (Gold et al. 1996a
).
Furthermore we have shown that agents, such as PGE2, that
produce hyperalgesia by a direct action on primary afferents enhance
TTX-R INa in cultured DRG neurons (Gold
et al. 1996b
). The observed potentiation of TTX-R
INa by epinephrine may be the mechanism by which
it sensitizes nociceptors (England et al. 1996
;
Gold et al. 1996b
). The sensitivity of epinephrine- or
isoproterenol-induced hyperalgesia to propranolol but not phentolamine is consistent with a
-AR-mediated effect. These
-ARs are most likely coupled to G proteins because epinephrine-induced hyperalgesia was attenuated by DAMGO. DAMGO previously has been shown to attenuate PGE2-induced hyperalgesia by activating a pertussis
toxin-sensitive inhibitory G protein (Khasar et al.
1995b
) and to prevent the potentiation of TTX-R
INa by PGE2 (Gold and Levine
1996
); a similar mechanism may explain inhibition of
epinephrine-induced hyperalgesia. Downstream from receptor activation,
the production of cAMP as well as activation of both PKA and PKC were
necessary because their respective antagonists inhibited
epinephrine-induced hyperalgesia.
The results of the in vitro experiments on DRG neurons are consistent
with the behavioral data and definitively demonstrate a direct action
of epinephrine on primary afferent neurons. Both the sensitization of
small-diameter neurons and the potentiation of TTX-R
INa by epinephrine, like behavioral
hyperalgesia, were blocked by propranolol. The potentiation of TTX-R
INa was mimicked by isoproterenol. Taken
together, these results provide the first evidence for -ARs on DRG
neurons as well as sensory nerve terminals. Potentiation of TTX-R
INa by epinephrine was blocked by inhibition of
PKA but also significantly attenuated by inhibition of PKC. The
mechanical hyperalgesia, sensitization, and potentiation of TTX-R
INa all occurred with a similar time course of
onset after introduction of epinephrine, the effects peaking within
5 min.
Ferreira (1980) found that the methylxanthines,
caffeine, and theophylline (which, among other actions, are inhibitors
of phosphodiesterase, the enzyme that breaks down cAMP), potentiated the hyperalgesic effect of epinephrine and isoproterenol and concluded that the propranolol-sensitive hyperalgesia was mediated by the cAMP
second-messenger system. Our data, from experiments using inhibitors of
adenylyl cyclase, PKA and PKC, suggest that the
-AR-mediated
hyperalgesia is mediated by the PKC as well as the PKA second-messenger
systems because PKC as well as PKA inhibitors significantly attenuated
epinephrine hyperalgesia. PKC has been shown to play a role in
nociceptor sensitization, both in vivo and in vitro (Cesare and
McNaughton 1996
; Leng et al. 1996
). Inhibition of isoproterenol-induced hyperalgesia by BIM and WIPTIDE suggests that
-AR activation can be mediated by both the PKA and the PKC second-messenger systems. Thus
-AR activation alone is enough to
account for the hyperalgesic action of epinephrine. The in vitro
results agree with the behavioral data in that TTX-R
INa potentiation by epinephrine was blocked by
Rp-cAMPs and significantly attenuated by BIM.
Epinephrine does not play a significant role as a neurotransmitter in
the periphery or as a local inflammatory mediator under normal
circumstances. However, its release from the adrenal medulla (its main
source in the periphery) is increased by acute stress (Taylor et
al. 1989; Wortsman et al. 1984
) as is the
activity in sympathetic postganglionic neurons (Mazzeo et al.
1997
). Under conditions of acute stress, circulating levels of
epinephrine have been shown to increase dramatically in humans as well
as in rats (Cryer 1980
; DeTurck and Vogel
1980
; Taylor et al. 1989
; Wortsman et al.
1984
) and stress has been shown to induce hyperalgesia (Kawanishi et al. 1997
; Okano et al.
1997
; Vidal and Jacob 1986
). Although it remains
to be determined whether the epinephrine levels attained under these
circumstances actually contribute to primary afferent nociceptor
sensitization and hyperalgesia, increases in circulating levels of
epinephrine produced by stress have well-documented physiological
effects (Cryer 1980
; Wortsman et al.
1984
). Epinephrine is the endogenous
-AR agonist, and
-AR
antagonists can attenuate inflammation in humans with rheumatoid
arthritis (Kaplan et al. 1980
) and in adjuvant-induced
arthritis in the rat (Coderre et al. 1990
; Levine
et al. 1988
). Furthermore, it has been suggested that
epinephrine can produce cardiac pain (angina) independent of its
vasoconstrictor effects in patients with syndrome X who have normal
coronary arteries (Eriksson et al. 1995
). Certainly, effects of epinephrine and the role of
-ARs in the mediation of pain
and hyperalgesia deserve further study, both in the setting of nerve
injury as well as inflammation, in which the sympathoadrenal axis may
be activated.
In conclusion, our data suggest that epinephrine produces mechanical hyperalgesia in the rat and sensitizes cultured DRG neurons. These effects of epinephrine appear to be mediated by at least two second-messenger systems, cAMP/PKA and PKC.
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ACKNOWLEDGMENTS |
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We are grateful to Dr. Frederick Miao for performing surgical sympathectomies.
This study was supported by National Institute of Neurological Disorders and Stroke Grants NS-21647 and NS-21445 and The Peninsula Foundation.
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FOOTNOTES |
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Address for reprint requests: J. D. Levine, NIH Pain Center, Box 0440, C-522, University of California, San Francisco, CA 94143-0440.
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. Section 1734 solely to indicate this fact.
Received 30 April 1998; accepted in final form 20 November 1998.
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REFERENCES |
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