 |
 Previous Article | Next Article 
The Journal of Neuroscience, August 15, 1999, 19(16):7175-7181
Pain-Induced Analgesia Mediated by Mesolimbic Reward Circuits
Robert W.
Gear1, 2,
K.
O.
Aley2, and
Jon D.
Levine2, 3, 4, 5, 6
1 Center for Orofacial Pain, Departments of
2 Oral and Maxillofacial Surgery, 3 Anatomy,
and 4 Medicine, 5 Division of Neuroscience,
and 6 National Institutes of Health Pain Center (UCSF),
University of California, San Francisco, California 94143
 |
ABSTRACT |
We tested the hypothesis that noxious stimuli induce pain
modulation by activation of supraspinal structures. We found that intense noxious stimuli (i.e., subdermal injection of capsaicin or paw
immersion in hot water) induced profound attenuation of the jaw-opening
reflex in the anesthetized rat; forepaw subdermal capsaicin also
elevated the mechanical hindpaw-withdrawal threshold in the awake rat.
These antinociceptive effects were blocked by previous injection of
either a dopamine antagonist (flupentixol) or an opioid antagonist
(naloxone) into the nucleus accumbens. Additional experiments in
anesthetized animals showed that the antinociceptive effect of noxious
stimulation by either capsaicin ( 100 µg) or hindpaw immersion in
hot water (45°C for 4 min) correlated with the intensity of the
stimulus. The maximal antinociceptive effect of capsaicin was similar
in magnitude to that of a high dose of morphine (10 mg/kg) injected
subcutaneously. Injection of the GABAA-receptor agonist
muscimol, but not naloxone, into the rostroventral medulla, a
major component of descending pain modulation systems, blocked
capsaicin-induced antinociception. Although it is widely thought that
painful stimuli may induce analgesia by activating forebrain
structures, this is the first demonstration that such a mechanism
exists. Furthermore, this mechanism can be engaged by naturalistic
stimuli in awake animals. These observations imply that painful stimuli
might under certain conditions be rewarding.
Key words:
antinociception; capsaicin; nociception; noxious stimuli; nucleus accumbens; rostroventral medulla; opioids; dopamine; thermal
stimulation; GABA; rats
| |
INTRODUCTION |
The nucleus accumbens, which is
known to be an important component of the mesolimbic dopaminergic
reward system and has been implicated in substance abuse, also plays a
role in pain modulation. However, although microinjection of opioid
directly into nucleus accumbens has been shown to induce
antinociception (Dill and Costa, 1977 ; Yu and Han, 1989; Tseng and
Wang, 1992) and microinjection of the opioid antagonist naloxone into
nucleus accumbens has been shown to attenuate the antinociceptive
effect of systemically administered morphine (Dill and Costa, 1977;
Daghero et al., 1987), the physiological mechanisms underlying the role
of nucleus accumbens in nociception are poorly understood. We recently
demonstrated that nucleus accumbens opioidergic mechanisms participate
in a novel ascending nociceptive control circuit (Gear and Levine, 1995); that is, intra-accumbens microinjection of naloxone blocks the
antinociceptive effect of pharmacological interventions made at the
level of the spinal cord. Because this circuit could be activated by
spinal interventions, we hypothesized that peripheral sensory input,
such as noxious stimulation, might be a mechanism by which the
ascending nociceptive control is physiologically activated. Therefore,
in the present study, we tested the hypothesis that activation of
nociceptors in the paw would produce heterosegmental antinociception
via the circuitry in nucleus accumbens mediating the ascending
nociceptive control. Because nucleus accumbens dopaminergic mechanisms may play a role in pain modulation (Altier and Stewart, 1993), we also tested their involvement in noxious stimulus-induced antinociception.
The descending pathway for antinociception mediated by the nucleus
accumbens might include the well known periaqueductal gray (PAG)-rostroventral medulla (RVM)-spinal cord pain modulation system.
Pain modulation circuits in the PAG project to the RVM, which contains
both opioidergic and GABAergic circuitry also important in pain
modulation (Fields et al., 1991). The RVM, in turn, sends projections
to the spinal cord dorsal horn (Fields et al., 1977; Fields and
Basbaum, 1978; Cho and Basbaum, 1991) that attenuate nociceptive
signals originating in the periphery. The widely held expectation that
noxious stimuli can induce analgesia by activating forebrain structures
(Basbaum and Fields, 1978) has eluded demonstration, even after more
than two decades of research. Therefore, we also tested the hypothesis
that the RVM contributes to noxious stimulus-induced antinociception.
| |
MATERIALS AND METHODS |
Experiments were performed on 280-380 gm male Sprague Dawley
rats (Bantin and Kingman, Fremont, CA). These animals were maintained in the University of California, San Francisco (UCSF), animal care
facility in accordance with applicable university policies. Experimental protocols were approved by the UCSF Committee on Animal
Research. Antinociception in awake animals was measured as elevation of
threshold for withdrawal of the hindpaw from an increasing mechanical
stimulus. Antinociception in anesthetized animals was measured as
attenuation of the nociceptive jaw-opening reflex (Mason et al., 1985;
Gear and Levine, 1995) (Fig. 1).
View larger version (18K):
[in this window]
[in a new window]
|
Figure 1.
Example of jaw-opening reflex EMG tracing before
and after administration of morphine. The top trace
demonstrates two components, A and B,
which show EMG amplitudes of 1.0 and 2.9 mV, respectively. Based on the
short latency, component A results from activation of
fast-conducting (presumably non-nociceptive) afferents; the latency of
component B is compatible with the conduction velocity
of A -nociceptors (calculated conduction velocity of ~16-20
m/sec). The bottom trace, recorded from the same animal
30 min after systemic administration of morphine (10 mg/kg, i.p.),
shows attenuation of component B but no change in
component A, compatible with the findings of others that
opioids do not attenuate non-nociceptive responses. The data in this
study were always taken from that part of the EMG signal exhibiting a
latency similar to that of component B.
|
|
Anesthesia. In some experiments, animals were anesthetized
by intraperitoneal injection of 0.9 gm/kg urethane and 45 mg/kg  -chloralose (both from Sigma, St. Louis, MO).
Urethane--chloralose was chosen for anesthesia because this
anesthetic protocol provides a stable jaw-opening reflex
electromyographic (EMG) signal over the time period required to
complete the experiments (Gear and Levine, 1995).
Electrode implantation. To evoke the jaw-opening reflex, a
bipolar stimulating electrode, fabricated from two insulated copper wires (36 AWG), each with 0.2 mm of insulation removed from the tip, one tip extending 2 mm beyond the other, was inserted into the
pulp of a mandibular incisor to a depth of 22 mm from the incisal edge
of the tooth to the tip of the longest wire and cemented into place
with dental composite resin (Citrix; Golden Gate Dental Supply Inc.,
South San Francisco, CA). A bipolar recording electrode, consisting of
two wires of the same material as the stimulating electrode with 4 mm
of insulation removed, was inserted into the digastric muscle
ipsilateral to the implanted tooth to a depth sufficient to completely
submerge the uninsulated end of the wire.
Jaw-opening reflex. At the beginning of each experiment,
stimulation current was set at three times the threshold current. Changes in nociception were measured as changes in jaw-opening reflex
EMG signal amplitude (Gear and Levine, 1995) (Fig. 1). Each data
point consisted of the average peak-to-peak amplitude of 12 consecutive
jaw-opening reflex EMG signals evoked by stimulating the tooth pulp
with 0.2 msec square wave pulses at a frequency of 0.33 Hz. Baseline
amplitude was defined as the average of the last three data points,
recorded at 5 min intervals, before an experimental intervention.
Effects of experimental interventions are expressed as the mean ± SEM percentage change from the baseline for each experimental group.
Repeated measures ANOVA with the Scheffé post hoc test
or the Student-Newman-Keuls test were used to compare groups for
significant differences (p  0.05).
Paw-withdrawal test. Awake rats were gently restrained
(Taiwo et al., 1989), allowing mechanical stimulation to the hindpaws (Randall-Selitto Analgesimeter; Ugo Basile). Thresholds for withdrawal were measured for both hindpaws immediately before the administration of capsaicin and again 20, 25, and 30 min afterward. Baseline scores
were calculated as the average of the precapsaicin thresholds for the
two hindpaws. Postcapsaicin thresholds were also averaged to obtain a
single score for each animal. Effects of experimental interventions are
expressed as the mean ± SEM percentage change (in grams) from the
baseline for each experimental group.
Cannula placement. For nucleus accumbens, RVM, and
PAG injections, 25 gauge (23 gauge in awake animals) stainless
steel guide cannulas were stereotactically positioned and
cemented with orthodontic resin (L.D. Caulk Co., Milford, DE) to allow
injections via insertion of a 33 gauge (30 gauge in awake animals)
stainless steel injection cannula, which extended beyond the guide
cannulas 4 mm, connected to a 2 µl syringe (Hamilton, Reno, NV).
Supraspinal injection volumes were 0.3 µl in all experiments. These
injections were performed over a period of 90 sec, and the injection
cannulas were left in place an additional 30 sec after injection. The
stereotaxic instrument was set to the following coordinates for onsite
injections: nucleus accumbens (from bregma), 1.2 mm rostral, 7.5 mm
ventral, and ±1.8 mm lateral; RVM (from intra-aural line), 2.3 mm
caudal,  0.6 mm ventral, and ±1 mm lateral from the midline for
bilateral injections or midline for single injections. Injection sites
were verified by histological examination (50 µm sections stained
with cresyl violet acetate) and were plotted on coronal sections
adapted from the atlas of Paxinos and Watson (1986).
Drugs. Capsaicin (Sigma, St. Louis, MO) was dissolved in
Tween 80 (50%) and ethanol (50%) to an initial concentration of 50 µg/µl and was diluted with PBS as necessary to obtain the
desired dose for each experiment. Subdermal capsaicin injection volume was 50 µl in all experiments. Naloxone methiodide, a quaternary form
of naloxone, flupentixol, a nonselective dopamine receptor antagonist,
and muscimol, a GABAA-receptor agonist (Research
Biochemicals, Natick, MA) were dissolved in PBS. Bupivacaine (0.5%;
Abbott Laboratories, North Chicago, IL) was administered in two
adjacent 50 µl injections to block primary afferent activity in the
area of capsaicin injection. Morphine (Elkins-Sinn Inc., Cherry Hill,
NJ), diluted as necessary with 0.9% saline, was injected
subcutaneously in the midback; injection volumes were 1 ml/kg body
weight. [D-Ala2,
N-Me-Phe4,Gly5-ol]-enkephalin
(DAMGO) (Sigma) was dissolved in 0.9% saline.
Statistics. Repeated measures ANOVA with the Scheffé
post hoc test or the Student-Newman-Keuls test was used as
appropriate to compare groups for significant differences
(p 0.05).
| |
RESULTS |
Heterosegmental noxious stimulus-induced antinociception was
demonstrated by the ability of capsaicin, injected into the plantar surface of a hindpaw, to dose-dependently attenuate the jaw-opening reflex (Fig. 2A,B). The
maximal antinociceptive effect of capsaicin was produced by doses 250
µg, which attenuated the jaw-opening reflex >60% (Fig.
2B). To compare the potency of capsaicin-induced antinociception with that of a standard opioid analgesic, attenuation of the jaw-opening reflex by systemically administered morphine was
evaluated in separate groups of animals (Fig. 2A).
The maximal antinociceptive effect of capsaicin was similar to that of
a high dose of morphine (10 mg/kg).
View larger version (30K):
[in this window]
[in a new window]
|
Figure 2.
The antinociceptive effect of noxious stimulation.
A, Effect of capsaicin or morphine on the jaw-opening
reflex EMG plotted over time. Note that the 25 µg dose ( )
(n = 6) did not significantly affect the
jaw-opening reflex, whereas the 250 µg dose of capsaicin ( )
(n = 6) attenuated the jaw-opening reflex >60%.
This high dose of capsaicin induced significantly greater
antinociception than the 5 mg/kg dose of morphine ( )
(n = 7) but was not significantly different from
the maximal antinociceptive effect of 10 mg/kg morphine ( )
(n = 6); the slower onset of morphine
antinociception was presumably caused by the subcutaneous route
of administration. The stability of the jaw-opening reflex over time is
indicated by lack of significant change from baseline of the group
receiving capsaicin vehicle ( ) (n = 6).
B, Average attenuation of the jaw-opening reflex over 1 hr induced by various doses of capsaicin (including the two doses
plotted in A). Number of animals of each group is
indicated next to each data point. C, The effect of the
local anesthetic bupivacaine on capsaicin-induced antinociception.
Bupivacaine was administered either 15 min before (A,
 ) (n = 6) or 10 min after (B,
) (n = 6) capsaicin (250 µg) to the same site.
For comparison, the effect of the same dose of capsaicin administered
as a single agent is replotted from A ().
D, The effect on the jaw-opening reflex of immersion of
both hindpaws into water at various temperatures for 4 min. The last
baseline jaw-opening reflex was recorded immediately before immersion;
the first postimmersion recording was 15 min after removal of the paws
from the bath. 40°C, (n = 4); 45°C, (n = 6); 50°C, (n = 5).
In this and subsequent figures, the data are plotted as mean ± SEM.
|
|
The antinociceptive effect of capsaicin was blocked by injection of the
local anesthetic bupivacaine into the hindpaw 15 min before the
administration of capsaicin into the same location (Fig.
2C), indicating lack of a systemic effect by capsaicin. The
same dose of bupivacaine injected into the contralateral paw had no
effect on antinociception (data not shown). Administration of
bupivacaine 10 min subsequent to capsaicin did not reverse antinociception (Fig. 2C), indicating that the prolonged
antinociceptive effect does not depend on ongoing afferent input.
Bilateral hindpaw immersion in a hot water bath for 4 min at various
temperatures (40, 45, and 50°C) revealed a temperature-dependent
attenuation of the jaw-opening reflex (Fig. 2D),
indicating that heterosegmental antinociception can be induced by
thermal, as well as chemical, noxious stimuli.
Administration of either naloxone methiodide (1 µg bilaterally), or
flupentixol (3 µg bilaterally) into the nucleus accumbens 15 min
before intraplantar capsaicin injection blocked antinociception (Fig.
3A; see Fig. 5A for
injection sites). Antinociception induced by a noxious thermal stimulus
was also blocked by either naloxone methiodide or flupentixol (same
doses) administered into the nucleus accumbens 15 min before
stimulation (Fig. 3B). Injections of the same doses of
either naloxone methiodide or flupentixol near by but not in nucleus
accumbens did not block capsaicin-induced antinociception (Fig.
3C). Also, when administered in the absence of noxious
stimulation, neither nucleus accumbens injection of naloxone methiodide
nor flupentixol affected the jaw-opening reflex (Fig.
3C).
View larger version (25K):
[in this window]
[in a new window]
|
Figure 3.
The effect a dopamine or opioid antagonist on
noxious stimulus-induced antinociception. All pretreatments were given
15 min before the onset of noxious stimulation. A,
Naloxone methiodide (opioid antagonist, ) (n = 5) or flupentixol (dopamine antagonist, ) (n = 6) was injected into nucleus accumbens before injection of capsaicin
(250 µg) in the hindpaw. The effect of capsaicin injection without
pretreatment (same dose, ) is replotted from Figure
2A. B, Naloxone methiodide ()
(n = 6) or flupentixol () (n = 5) was injected into nucleus accumbens before thermal stimulation
(both hindpaws immersed in water, 50°C, 4 min). The effect of thermal
stimulation without pretreatment (same stimulus intensity, ) is
replotted from Figure 2C. C, The effect
of either flupentixol (flup alone)
(n = 6) or naloxone methiodide (nlx
alone) (n = 6) injected into nucleus
accumbens as a single agent; the effect on capsaicin-induced
antinociception of previous injection of either flupentixol
(flup offsite) (n = 6) or
naloxone methiodide (nlx offsite) (n = 6) administered to sites adjacent to nucleus accumbens.
D, The effect of capsaicin administered to the forepaw
on hindpaw-withdrawal threshold in awake animals when administered
either alone (cap alone) (n = 6) or
in the presence of previous administration of flupentixol (+ NAc
flup) (n = 5) or naloxone methiodide (+ NAc nlx) (n = 5). Capsaicin vehicle
with no supraspinal treatment was also administered (cap
veh) (n = 4). Antinociception is indicated
by increased threshold for withdrawal.
|
|
To confirm these results in awake animals using a different nociceptive
assay, the effect on the paw-withdrawal reflex of capsaicin (125 µg)
injected into a forepaw was determined. Thirty minutes after capsaicin
injection, the paw-withdrawal threshold was elevated 64%, and this
effect was blocked by previous administration of either naloxone or
flupentixol into the nucleus accumbens (Fig. 3D; see Fig.
5A for injection sites).
The involvement of a descending pain modulation system in noxious
stimulation-induced antinociception was assessed by injecting either
the GABAA-receptor agonist muscimol (10 ng,
single midline injection) or naloxone methiodide (1 µg bilaterally)
into the RVM 10 or 15 min, respectively, before the administration of
capsaicin to the hindpaw. Muscimol, but not naloxone methiodide,
blocked attenuation of the jaw-opening reflex (Figs.
4,
5B, injection sites),
indicating that RVM GABAergic, but not opioidergic, circuits mediate
noxious stimulus-induced antinociception. Muscimol injected into the
RVM did not itself significantly affect the jaw-opening reflex (Figs.
4, 5B, injection sites). However, compatible with the
findings of others (Kiefel et al., 1993; Roychowdhury and Fields,
1996), a similar injection of naloxone into the RVM did block
antinociception by intra-PAG injection of the µ-opioid DAMGO (60 ng)
(Figs. 4, 5B, injection sites). These results indicate that
a descending pain modulation system at the level of the RVM mediates
noxious stimulus-induced antinociception, but that circuits descending
from the PAG to the RVM that are mediated by endogenous opioids in the
RVM do not appear to be involved.
View larger version (17K):
[in this window]
[in a new window]
|
Figure 4.
The effect of either naloxone methiodide or
muscimol administered to the RVM on attenuation of the jaw-opening
reflex induced by either intraplantar capsaicin or intra-PAG DAMGO.
Each bar represents the average of four recordings taken at
15 min intervals for 1 hr. Left to right,
Intraplantar capsaicin administered as a single agent (cap
alone) (data from Fig. 3A), intra-RVM naloxone
methiodide administered 15 min before intraplantar capsaicin
(+RVM nlx) (n = 6), intra-RVM
muscimol administered 10 min before intraplantar capsaicin (+RVM
musc) (n = 6), intra-RVM muscimol
administered without noxious stimulation (RVM musc
alone) (n = 4), intra-PAG DAMGO
administered as a single agent (PAG dgo alone)
(n = 6), and intra-RVM naloxone methiodide
administered 15 min before intra-PAG DAMGO (+RVM nlx)
(n = 6).
|
|
View larger version (20K):
[in this window]
[in a new window]
|
Figure 5.
Supraspinal injection sites. One side is depicted
for each bilateral injection on drawings adapted from the atlas of
Paxinos and Watson (1986). A, Nucleus accumbens
injection sites, left (flup),
flupentixol injection sites; right (nlx),
naloxone methiodide injection sites.  ,  , Onsite injection before
capsaicin administration in anesthetized or awake animals,
respectively; , onsite injection before hindpaw immersion in 50°C
water bath anesthetized or awake animals, respectively (sites for
naloxone methiodide in anesthetized animals not shown); , off-site
injection before intraplantar capsaicin administration; , injection
given in the absence of noxious stimulation. B,
Rostroventral medulla injection sites. , Naloxone methiodide before
intraplantar capsaicin administration; , naloxone methiodide given
before intra-PAG DAMGO administration; , muscimol (single
injections) given before intraplantar capsaicin administration;  ,
without noxious stimulation.
|
|
| |
DISCUSSION |
The results of this study demonstrate that activation of primary
afferent neurons by noxious stimulation in the form of either capsaicin
administration or paw immersion in hot water induces heterosegmental
antinociception in both awake and anesthetized animals. The potency of
this noxious stimulus-induced antinociception is indicated by its
ability to produce attenuation of the jaw-opening reflex to a degree
similar to that of high-dose (10 mg/kg) systemically administered morphine.
Relatively intense nociceptor stimulation is required to induce this
form of antinociception because the response of the jaw-opening reflex
to low-dose (25 µg) capsaicin was not significantly different from
the response to vehicle; at least 100 µg was needed for a statistically significant antinociceptive effect. In comparison, capsaicin-induced secondary hyperalgesia, which is also dependent on
activation of nociceptors, has been demonstrated in the rat with doses
as low as 1 µg (Gilchrist et al., 1996). The observation that local
anesthetic prevented capsaicin-induced antinociception but did not
reverse this effect suggests that noxious stimulation-induced antinociception is initiated by primary afferent activity but is
sustained by other mechanisms.
The blockade of noxious stimulus-induced antinociception by
intra-accumbens naloxone is similar to our previous findings that this
same treatment also blocked heterosegmental antinociception induced by
a number of different spinal interventions, including intrathecally
administered DAMGO (Gear and Levine, 1995), leading us to suggest that
the same ascending nociceptive control pathway mediates the
antinociceptive effects of noxious stimuli. This suggestion is further
supported by the observation that intra-accumbens flupentixol also
blocks both noxious stimulus-induced antinociception and the
antinociceptive effect of spinal intrathecal DAMGO (R. W. Gear and J. D. Levine, unpublished data).
Importantly, the applicability of these findings to the awake state was
confirmed in the current study using a different nociceptive assay, the
paw-withdrawal reflex. Injection of capsaicin into a forepaw induced
heterosegmental antinociception, as indicated by increased thresholds
for withdrawal from a mechanical stimulus applied to the two hindpaws.
Furthermore, this effect was blocked by intra-accumbens injection of
the same doses of either flupentixol or naloxone used in the
experiments performed under anesthesia. Thus, the proposed ascending
nociceptive control circuit appears to be active in awake as well as
anesthetized animals.
Because the nociceptive assays used in the current study rely on
trigeminal or spinal reflexes, by implication there must be a
descending efferent circuit from the nucleus accumbens that projects
either directly or via intermediate synaptic relays to these trigeminal
and spinal nociceptive reflexes. Although direct projections from
nucleus accumbens to the medial rostroventral medulla have not been
reported, nucleus accumbens sends projections to many areas of the
brain [e.g., the hypothalamus (Groenewegen and Russchen, 1984)],
which, in turn, send projections to the brainstem (Sim and Joseph,
1991). Intra-RVM naloxone blocked the antinociceptive effect of
intra-PAG DAMGO but failed to attenuate capsaicin-induced
antinociception, suggesting that antinociceptive circuits arising in
the PAG that are mediated by RVM endogenous opioids (Kiefel et al.,
1993; Roychowdhury and Fields, 1996) do not mediate noxious
stimulation-induced antinociception. However, intra-RVM administration
of the GABAA-receptor agonist muscimol blocked
noxious stimulus-induced antinociception, suggesting that heterosegmental antinociception results from nonopioid inhibition of
tonic GABAergic neurotransmission in the RVM. Because RVM
GABAA-receptor agonists induce hyperalgesia if
given in sufficiently high doses (Drower and Hammond, 1988; Heinricher
and Kaplan, 1991), we injected muscimol in the absence of noxious
stimulation as a control. This treatment did not enhance the
jaw-opening reflex significantly above baseline, suggesting that the
dose used in our experiments does not produce hyperalgesia. To our
knowledge, these experiments are the first demonstration that noxious
stimuli are able to activate a major brainstem component of a
descending pain modulation system to produce antinociception.
Interestingly, this activation does not appear to involve endogenous
opioids in the RVM, suggesting lack of involvement of another major
component of this system, the PAG.
Although noxious stimulation-induced heterosegmental antinociception
has been demonstrated previously, most notably in studies elucidating
the mechanisms of the diffuse noxious inhibitory controls (DNIC) (Le
Bars et al., 1979, 1992; Kraus et al., 1981; Dickenson and Le Bars,
1983), the novelty of the current findings is supported by observations
that DNIC is mediated in the caudal medulla and does not require brain
circuitry rostral to that point (Bouhassira et al., 1992, 1995),
including, specifically, the RVM (Bouhassira et al., 1993). Thus, our
findings that noxious stimulation-induced antinociception was blocked
by interventions administered to nucleus accumbens as well as the RVM
are inconsistent with mediation by DNIC.
The ability of intra-accumbens flupentixol to block noxious
stimulus-induced antinociception suggests that painful stimuli increase
mesolimbic dopamine release, although it is possible that dopamine in
nucleus accumbens plays a permissive role, modulating the input of
circuits such as glutamatergic corticostriate projections. This
observation appears to contradict the prevailing view that dopamine in
nucleus accumbens mediates responses only to appetitive or rewarding
stimuli (Koob, 1996; but see Salamone et al., 1997). On the other hand,
the well documented association between nucleus accumbens dopamine
levels and the reinforcing properties of stimuli suggests an
explanation for pain-seeking behavior, which, consistent with our
observation that intra-accumbens naloxone also blocks noxious
stimulus-induced antinociception, have been found to respond favorably
to naltrexone treatment (Casner et al., 1996; Roth et al., 1996).
Capsaicin-induced attenuation of the jaw-opening reflex was unaffected
in anesthetized animals with stress axis lesions (i.e., either
hypophysectomized or adrenalectomized), and plasma corticosterone levels in intact animals did not change when measured before capsaicin injection and again after the onset of antinociception (data not shown). It is possible that our findings represent a previously unreported form of stress-induced analgesia (SIA) and, if so, add new
information with regard to mechanisms of activation of SIA and to the
supraspinal circuitry mediating SIA. Thus, although we cannot exclude
stress as a factor, neither have we have been able to demonstrate that
noxious stimulus-induced antinociception is dependent on stress.
In summary, we show that intense chemical or thermal noxious
stimulation induces pain modulation by an ascending nociceptive control
and that this effect depends on both opioid and dopamine links in the
nucleus accumbens. In addition, our data suggest that noxious
stimulus-induced antinociception results from a nonopioid-mediated reduction in RVM GABAergic neurotransmission. These findings add substantially to our knowledge of the mechanisms of physiologically activated pain modulation and indicate that the mesolimbic system of reward responds to aversive, as well as to positive, stimuli.
| |
FOOTNOTES |
Received March 25, 1999; revised June 2, 1999; accepted June 4, 1999.
This work was supported by the State of California Tobacco-Related
Diseases Research program. We are grateful to Drs. Michael Gold, David
Reichling, Philip Heller, Kimberly Tanner, and Holly Strausbaugh for
many helpful discussions during the course of this work. We also thank
Justine Barletta and Alexander Riedel for excellent technical assistance.
Correspondence should be addressed to Dr. Jon D. Levine, National
Institutes of Health Pain Center (UCSF), C-522 (Box 0440), University
of California, San Francisco, CA 94143-0440.
| |
REFERENCES |
-
Altier N,
Stewart J
(1993)
Intra-VTA infusions of the substance P analogue, DiMe-C7, and intra-accumbens infusions of amphetamine induce analgesia in the formalin test for tonic pain.
Brain Res
628:279-285[Web of Science][Medline].
-
Basbaum AI,
Fields HL
(1978)
Endogenous pain control mechanisms: review and hypothesis.
Ann Neurol
4:451-462[Web of Science][Medline].
-
Bouhassira D,
Villanueva L,
Bing Z,
Le Bars D
(1992)
Involvement of the subnucleus reticularis dorsalis in diffuse noxious inhibitory controls in the rat.
Brain Res
595:353-357[Web of Science][Medline].
-
Bouhassira D,
Chitour D,
Villanueva L,
Le Bars D
(1993)
Morphine and diffuse noxious inhibitory controls in the rat: effects of lesions of the rostral ventromedial medulla.
Eur J Pharmacol
232:207-215[Web of Science][Medline].
-
Bouhassira D,
Chitour D,
Villanueva L,
Le Bars D
(1995)
The spinal transmission of nociceptive information: modulation by the caudal medulla.
Neuroscience
69:931-938[Web of Science][Medline].
-
Casner JA,
Weinheimer B,
Gualtieri CT
(1996)
Naltrexone and self-injurious behavior: a retrospective population study.
J Clin Psychopharmacol
16:389-394[Medline].
-
Cho HJ,
Basbaum AI
(1991)
GABAergic circuitry in the rostral ventral medulla of the rat and its relationship to descending antinociceptive controls.
J Comp Neurol
303:316-328[Medline].
-
Daghero AM,
Bradley ELJ,
Kissin I
(1987)
Midazolam antagonizes the analgesic effect of morphine in rats.
Anesth Analg
66:944-947[Abstract/Free Full Text].
-
Dickenson AH,
Le Bars D
(1983)
Diffuse noxious inhibitory controls (DNIC) involve trigeminothalamic and spinothalamic neurones in the rat.
Exp Brain Res
49:174-180[Web of Science][Medline].
-
Dill RE,
Costa E
(1977)
Behavioural dissociation of the enkephalinergic systems of nucleus accumbens and nucleus caudatus.
Neuropharmacology
16:323-326[Medline].
-
Drower EJ,
Hammond DL
(1988)
GABAergic modulation of nociceptive threshold: effects of THIP and bicuculline microinjected in the ventral medulla of the rat.
Brain Res
450:316-324[Web of Science][Medline].
-
Fields HL,
Basbaum AI
(1978)
Brainstem control of spinal pain-transmission neurons.
Annu Rev Physiol
40:217-248[Web of Science][Medline].
-
Fields HL,
Basbaum AI,
Clanton CH,
Anderson SD
(1977)
Nucleus raphe magnus inhibition of spinal cord dorsal horn neurons.
Brain Res
126:441-453[Web of Science][Medline].
-
Fields HL,
Heinricher MM,
Mason P
(1991)
Neurotransmitters in nociceptive modulatory circuits.
Annu Rev Neurosci
14:219-245[Web of Science][Medline].
-
Gear RW,
Levine JD
(1995)
Antinociception produced by an ascending spino-supraspinal pathway.
J Neurosci
15:3154-3161[Abstract].
-
Gilchrist HD,
Allard BL,
Simone DA
(1996)
Enhanced withdrawal responses to heat and mechanical stimuli following intraplantar injection of capsaicin in rats.
Pain
67:179-188[Web of Science][Medline].
-
Groenewegen HJ,
Russchen FT
(1984)
Organization of the efferent projections of the nucleus accumbens to pallidal, hypothalamic, and mesencephalic structures: a tracing and immunohistochemical study in the cat.
J Comp Neurol
223:347-367[Web of Science][Medline].
-
Heinricher MM,
Kaplan HJ
(1991)
GABA-mediated inhibition in rostral ventromedial medulla: role in nociceptive modulation in the lightly anesthetized rat.
Pain
47:105-113[Web of Science][Medline].
-
Kiefel JM,
Rossi GC,
Bodnar RJ
(1993)
Medullary µ and opioid receptors modulate mesencephalic morphine analgesia in rats.
Brain Res
624:151-161[Web of Science][Medline].
-
Koob GF
(1996)
Hedonic valence, dopamine and motivation.
Mol Psychiatry
1:186-189[Web of Science][Medline].
-
Kraus E,
Le Bars D,
Besson JM
(1981)
Behavioral confirmation of "diffuse noxious inhibitory controls" (DNIC) and evidence for a role of endogenous opiates.
Brain Res
206:495-499[Medline].
-
Le Bars D,
Dickenson AH,
Besson JM
(1979)
Diffuse noxious inhibitory controls (DNIC). I. Effects on dorsal horn convergent neurones in the rat.
Pain
6:283-304[Web of Science][Medline].
-
Le Bars D, Villanueva L, Bouhassira D, Willer
JC (1992) Diffuse noxious inhibitory controls (DNIC) in
animals and in man. Patol Fiziol Eksp Ter 55-65.
-
Mason P,
Strassman A,
Maciewicz R
(1985)
Is the jaw-opening reflex a valid model of pain?
Brain Res
357:137-146[Medline].
-
Paxinos G,
Watson C
(1986)
In: The rat brain in stereotaxic coordinates. New York: Academic.
-
Roth AS,
Ostroff RB,
Hoffman RE
(1996)
Naltrexone as a treatment for repetitive self-injurious behaviour: an open-label trial.
J Clin Psychiatry
57:233-237[Medline].
-
Roychowdhury SM,
Fields HL
(1996)
Endogenous opioids acting at a medullary µ-opioid receptor contribute to the behavioral antinociception produced by GABA antagonism in the midbrain periaqueductal gray.
Neuroscience
74:863-872[Web of Science][Medline].
-
Salamone JD,
Cousins MS,
Snyder BJ
(1997)
Behavioral functions of nucleus accumbens dopamine: empirical and conceptual problems with the anhedonia hypothesis.
Neurosci Biobehav Rev
21:341-359[Web of Science][Medline].
-
Sim LJ,
Joseph SA
(1991)
Arcuate nucleus projections to brainstem regions which modulate nociception.
J Chem Neuroanat
4:97-109[Medline].
-
Taiwo YO,
Coderre TJ,
Levine JD
(1989)
The contribution of training to sensitivity in the nociceptive paw-withdrawal test.
Brain Res
487:148-151[Web of Science][Medline].
-
Tseng LF,
Wang Q
(1992)
Forebrain sites differentially sensitive to
 -endorphin and morphine for analgesia and release of Met-enkephalin in the pentobarbital-anesthetized rat.
J Pharmacol Exp Ther
261:1028-1036[Abstract/Free Full Text]. -
Yu LC,
Han JS
(1989)
Involvement of arcuate nucleus of hypothalamus in the descending pathway from nucleus accumbens to periaqueductal grey subserving an antinociceptive effect.
Int J Neurosci
48:71-78[Web of Science][Medline].
Copyright © 1999 Society for Neuroscience 0270-6474/99/19167175-07$05.00/0
This article has been cited by other articles:
|
|
|
|
 
S. Koyanagi, S. Himukashi, K. Mukaida, T. Shichino, and K. Fukuda
Dopamine D2-Like Receptor in the Nucleus Accumbens Is Involved in the Antinociceptive Effect of Nitrous Oxide
Anesth. Analg.,
June 1, 2008;
106(6):
1904 - 1909.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
D. J. Scott, C. S. Stohler, C. M. Egnatuk, H. Wang, R. A. Koeppe, and J.-K. Zubieta
Placebo and Nocebo Effects Are Defined by Opposite Opioid and Dopaminergic Responses
Arch Gen Psychiatry,
February 1, 2008;
65(2):
220 - 231.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
T. S. Brink, K. M. Hellman, A. M. Lambert, and P. Mason
Raphe Magnus Neurons Help Protect Reactions to Visceral Pain From Interruption by Cutaneous Pain
J Neurophysiol,
December 1, 2006;
96(6):
3423 - 3432.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. E. Kennedy, R. A. Koeppe, E. A. Young, and J.-K. Zubieta
Dysregulation of endogenous opioid emotion regulation circuitry in major depression in women.
Arch Gen Psychiatry,
November 1, 2006;
63(11):
1199 - 1208.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
D. J. Scott, M. M. Heitzeg, R. A. Koeppe, C. S. Stohler, and J.-K. Zubieta
Variations in the human pain stress experience mediated by ventral and dorsal Basal Ganglia dopamine activity.
J. Neurosci.,
October 18, 2006;
26(42):
10789 - 10795.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
Y. R. Smith, C. S. Stohler, T. E. Nichols, J. A. Bueller, R. A. Koeppe, and J.-K. Zubieta
Pronociceptive and Antinociceptive Effects of Estradiol through Endogenous Opioid Neurotransmission in Women
J. Neurosci.,
May 24, 2006;
26(21):
5777 - 5785.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J.-K. Zubieta, J. A. Bueller, L. R. Jackson, D. J. Scott, Y. Xu, R. A. Koeppe, T. E. Nichols, and C. S. Stohler
Placebo Effects Mediated by Endogenous Opioid Activity on {micro}-Opioid Receptors
J. Neurosci.,
August 24, 2005;
25(34):
7754 - 7762.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
G. R. Kracke, K. A. Uthoff, and J. D. Tobias
Sugar Solution Analgesia: The Effects of Glucose on Expressed Mu Opioid Receptors
Anesth. Analg.,
July 1, 2005;
101(1):
64 - 68.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. E. Belforte and J. H. Pazo
Striatal Inhibition of Nociceptive Responses Evoked in Trigeminal Sensory Neurons by Tooth Pulp Stimulation
J Neurophysiol,
March 1, 2005;
93(3):
1730 - 1741.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. Ellrich
Electric Low-Frequency Stimulation of the Tongue Induces Long-Term Depression of the Jaw-Opening Reflex in Anesthetized Mice
J Neurophysiol,
December 1, 2004;
92(6):
3332 - 3337.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
K. Stiasny-Kolster, W. Magerl, W. H. Oertel, J. C. Moller, and R.-D. Treede
Static mechanical hyperalgesia without dynamic tactile allodynia in patients with restless legs syndrome
Brain,
April 1, 2004;
127(4):
773 - 782.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
L. Becerra, M. Iadarola, and D. Borsook
CNS Activation by Noxious Heat to the Hand or Foot: Site-Dependent Delay in Sensory But Not Emotion Circuitry
J Neurophysiol,
January 1, 2004;
91(1):
533 - 541.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. Lorenz, S. Minoshima, and K. L. Casey
Keeping pain out of mind: the role of the dorsolateral prefrontal cortex in pain modulation
Brain,
May 1, 2003;
126(5):
1079 - 1091.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Barrot, J. D. A. Olivier, L. I. Perrotti, R. J. DiLeone, O. Berton, A. J. Eisch, S. Impey, D. R. Storm, R. L. Neve, J. C. Yin, et al.
CREB activity in the nucleus accumbens shell controls gating of behavioral responses to emotional stimuli
PNAS,
August 20, 2002;
99(17):
11435 - 11440.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
B. L. Schmidt, C. H. Tambeli, J. Barletta, L. Luo, P. Green, J. D. Levine, and R. W. Gear
Altered Nucleus Accumbens Circuitry Mediates Pain-Induced Antinociception in Morphine-Tolerant Rats
J. Neurosci.,
August 1, 2002;
22(15):
6773 - 6780.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J.-K. Zubieta, Y. R. Smith, J. A. Bueller, Y. Xu, M. R. Kilbourn, D. M. Jewett, C. R. Meyer, R. A. Koeppe, and C. S. Stohler
{micro}-Opioid Receptor-Mediated Antinociceptive Responses Differ in Men and Women
J. Neurosci.,
June 15, 2002;
22(12):
5100 - 5107.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J.-K. Zubieta, Y. R. Smith, J. A. Bueller, Y. Xu, M. R. Kilbourn, D. M. Jewett, C. R. Meyer, R. A. Koeppe, and C. S. Stohler
Regional Mu Opioid Receptor Regulation of Sensory and Affective Dimensions of Pain
Science,
July 13, 2001;
293(5528):
311 - 315.
[Abstract]
[Full Text]
|
|
|
|
|
|
|
J. Ma, B. Shen, L. S. Stewart, I. A. Herrick, and L. S. Leung
The Septohippocampal System Participates in General Anesthesia
J. Neurosci.,
January 15, 2002;
22(2):
RC200 - RC200.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
TOP
ABSTRACT
INTRODUCTION
