![[Feedback]](/icons/banner/feedbackACT.gif){kind=icon}
![[For Subscribers]](/icons/banner/subscriberACT.gif){kind=icon}
![[Archive]](/icons/banner/archiveACT.gif){kind=icon}
![[Search]](/icons/banner/searchACT.gif){kind=icon}
![[Contents]](/icons/banner/tocACT.gif){kind=icon}
|
|
|
|
|
||
Vol. 284, Issue 2, 678-686, February 1998
Anesthesiology Research Laboratory, Department of Anesthesiology, Tufts University School of Medicine, Baystate Medical Center, Springfield, Massachusetts
 |
Abstract |
|---|
Top
Abstract
Introduction
Methods
Results
Discussion
References
|
|---|
The opioid abstinence syndrome is associated with spinal excitatory amino acid (EAA) release, hyperalgesia and long-term changes in dorsal horn cellular excitability. N-Methyl-D-aspartate (NMDA) receptor antagonism attenuates opioid tolerance but also blocks EAA release during abstinence. This study examines the effect of repetitive abstinence, and NMDA receptor antagonism during abstinence, on thermal nociceptive thresholds and spinal tolerance. An intrathecal catheter system driven by a miniosmotic pump (Alzet 2002 0.5 µl/h) was implanted in rats (n = 4-8/group) and delivered alternating daily infusions of morphine (40 nmol/h), saline or MK801 (MK) (10 nmol/h). Abstinence was induced by infusion of saline or MK. Groups were: saline, 7 days; morphine, 7 days; abstinence (saline), day 6; abstinence (saline), days 4 and 6; abstinence (saline), days 2, 4 and 6; morphine, except on days 2, 4 and 6 when morphine (8 nmol/h) was infused; abstinence (MK), day 6; abstinence (MK), days 2, 4 and 6; and saline with MK, days 2, 4 and 6. Analgesia was measured daily (hot plate). Sixteen hours after termination of the infusion period (day 8) groups received intrathecal morphine (100 nmol) to assess tolerance. Hyperalgesia was most pronounced in groups subjected to repetitive abstinence, and least evident in groups in which continuous infusion was maintained or in which MK was administered during abstinence. MK administered during abstinence did not prevent tolerance. These results show that repetitive opioid abstinence is associated with progressive hyperalgesia mediated via NMDA receptor activation, but that NMDA receptor antagonism during such periods of abstinence does not prevent progressive opioid tolerance.
| |
Introduction |
|---|
|
Top
Abstract
Introduction
Methods
Results
Discussion
References
|
|---|
The
opioid abstinence syndrome is a series of signs or symptoms that occur
in the opioid-dependent state when abrupt drug withdrawal occurs. One
of the signs of abstinence in the rat is hyperalgesia (Tilson et
al., 1973
; Johnson and Duggan, 1981; Ekblom et al.,
1993; Feng and Kendig, 1995). This sign can be prevented by the
preadministration of an NMDA receptor antagonist MK before opioid
withdrawal (Dunbar and Yaksh, 1996a). Antagonism at this receptor also
attenuates hyperalgesia in other models of pain in which secondary
hyperalgesia and long-term potentiation occur (Collingdridge and Bliss,
1987; Yamamoto and Yaksh, 1992; Sluka and Westlund, 1993). Abstinence
is associated with dorsal horn cellular hyperexcitability (Johnson and
Duggan, 1981; Zhao and Duggan, 1987), and isolated cell preparations
have shown that this hyperexcitability is sensitive to NMDA receptor
antagonism (Yukhananov and Larson, 1994). In vivo spinal
release studies have shown that glutamate and taurine are released
during abstinence and also that this release can be prevented by NMDA
receptor antagonism (Jhamandas et al., 1996). Conversely,
the administration of glutamate (Ferreira and Lorenzetti, 1994; Okano
et al., 1995) or NMDA (Raigorodsky and Urca, 1987; Sher and
Mitchell, 1990) intrathecally induces hyperalgesia and will also
antagonize the antinociceptive effects of spinal morphine (Srivastava
et al., 1995). The hyperalgesia observed in behavioral
studies (Gold et al., 1994) and the hyperexcitability observed in isolated cellular studies (Crain and Shen, 1995) can persist for periods long outlasting the usual rapid decay of tolerance that occurs with opioid withdrawal. Thus several lines of evidence show
that, during abstinence, release of EAAs may lead to an EAA-mediated hyperexcitability of dorsal horn neurons which may last beyond the
duration of the abstinence syndrome itself, so that repetitive episodes
of abstinence might be expected to produce progressive excitation of
the dorsal horn network with progressive facilitation of nociception.
Although hyperexcitability and hyperalgesia associated with single
episodes of abstinence have been demonstrated, to our knowledge, the
effect of repetitive abstinence on nociception has not been examined.
In addition to examining the effect of repetitive abstinence on
nociceptive thresholds, the effect of repetitive abstinence on
tolerance was also examined. Opioid withdrawal predictably will lead to
a decline in tolerance. However, if release of EAAs during abstinence
leads to NMDA receptor activation, and if tolerance is associated with
activation of this receptor (Trujillo and Akil, 1991; Marek et
al., 1991a, b; Ben Eliyahu et al., 1992; Gutstein et al., 1993; Dunbar and Yaksh, 1996a), then its blockade
during abstinence should have a significant effect on tolerance to the analgesic effects of further opioid administration. Although
coadministration of naloxone with morphine blocks tolerance (Yano and
Takemori, 1977), intermittent antagonism with naloxone appears to
increase the magnitude of spinal opioid tolerance (Ibuki et
al., 1997), which supports the hypothesis that EAA release and
NMDA receptor activation during abstinence may increase the degree of
tolerance. To examine the hypothesis that abstinence-induced NMDA
receptor activation may be a significant factor in the development of
tolerance, a repetitive model of abstinence was used which allowed for
NMDA receptor antagonism during abstinence. Previous studies have shown that coadministration of MK with morphine attenuates tolerance (Marek
et al., 1991a, b; Ben Eliyahu et al., 1992;
Gutstein et al., 1993; Dunbar and Yaksh, 1996a), but neither
the preadministration of MK as a bolus dose (Marek et al.,
1991b), nor the administration of MK in the established tolerant state
(Trujillo and Akil, 1991; Dunbar and Yaksh, 1996a) has a significant
effect on tolerance. None of these studies have examined the effect of
NMDA receptor antagonism on the progression of tolerance when
administered only during abstinent periods when maximal EAA release
occurs (Jhamandas et al., 1996).
This study thus examined the effect of repetitive opioid abstinence on
nociception and tolerance in a model of repetitive opioid withdrawal.
An intrathecal model provided the means to assess spinal tolerance at
the termination of the infusion period. Although chronic, continuous
infusion of intrathecal opioid does not limit exposure to the spinal
portion of the central nervous system, a spinal bolus dose directed
toward the lumbar area is believed to limit its antinociceptive effect
mostly to that region allowing for the assessment of spinal tolerance
(Stevens et al., 1988; Stevens and Yaksh, 1989a, b).
The following hypotheses were addressed specifically: (a) repetitive opioid abstinence causes progressive thermal hyperalgesia (progressively lowers nociceptive thresholds), (b) this hyperalgesia is sensitive to NMDA receptor blockade and (c) NMDA receptor antagonism during abstinence attenuates spinal opioid tolerance development.
| |
Methods |
|---|
|
Top
Abstract
Introduction
Methods
Results
Discussion
References
|
|---|
Animals. Approval for this study was obtained from the Institutional Animal Care and Use Committee of Baystate Medical Center. Male Sprague-Dawley rats (350-400 g) were implanted at 4:00 P.M. and thereafter housed in individual standard cages at room temperature on a 12-h light/12-h dark cycle (lights on 7:00 A.M.). Testing was performed during the light cycle at 12:00 P.M.. Each rat was implanted with a subarachnoid catheter system attached to a subcutaneous osmotic pump filled with saline, as described below. Animals had free access to food and water. Rats (four or more) were randomly assigned to one or the other group; experimental groups were run in tandem. All rats received a 7-day infusion followed by 16 h of saline infusion to clear the catheter, and after testing on the last (8th) day at 12:00 P.M. were sacrificed by an overdose of barbiturate.
Preparation of the catheter with infusion pump and
implantation.
The preparation of the catheter was as follows: A
5-mm piece of silastic tubing, previously soaked in chloroform to
increase its internal diameter, was passed over both ends of a 120-mm
length of PE-10 tubing to form a 10-mm loop at a distance of 15 mm from one free end and 95 mm from the other free end. The short end was then
connected by heat fusing with a hot air jet to a 189-mm piece of PE-60
tubing which was coiled and emersed first in hot, then cold water to
maintain this coil of 2 cm in diameter. Coiling enabled the catheter
system to be inserted subcutaneously in the animal without the
mechanical stress of uncoiling that would have otherwise occurred when
implanted. This resulted in a coiled PE60 reservoir connected to an
intrathecal PE-10 catheter similar to that described previously (Yaksh
and Stevens, 1986). The whole catheter system was soaked in alcohol
(70%) overnight, and then flushed with saline before priming on the
day of implantation. Alzet osmotic minipumps (model 2002 delivering 0.5 µl/h; Alzet, Palo Alta, CA) were filled with saline in a sterile
fashion. This pump is designed to deliver a constant infusion of 0.5 µl/h for 14 days after an initial activation period in the animal of
4 h. The catheter was filled with a sterile technique from the
PE-60 end. A ruler was placed below a sterile transparent sheet to
enable measurement of the catheter. Saline, drug or air bubble was
carefully injected into the catheter by a 1-ml syringe as follows. Each 24-h period consisted of 27 mm of catheter. For each 24-h period the
first 5 mm of the infusion was air (equivalent of approximately 4.4 h). This was followed by 22 mm (equivalent of approximately 19.6 h) of drug or saline. Thus 24 h of morphine was prepared by injecting 5 mm of air and then 22 mm of morphine solution. This was
continued so that the pump was primed for a 7-day infusion period. The
end of this period also had a 5-mm air bubble to separate it from the
saline-filled pump solution, which hydraulically drove the system. The
pumps are designed to run for 14 days, so the last day of the infusion
(day 8) was saline which for 16 h flushed the catheter of any
residual drug without needing to handle the animal. Pilot studies
showed that daily latencies were unaffected by the addition of air
bubbles.
). Animals were anesthetized with halothane and
placed in a stereotaxic head holder. A midline incision was made to
expose the atlanto-occipital membrane. The membrane was pierced and the
PE-10 end of the catheter was passed intrathecally to a distance of 8.5 cm, i.e., caudal to the level of the thoracolumbar junction.
The coiled PE-60 part of the system with the pump attached was then
implanted subcutaneously in a pouch to lie behind the shoulders. The
loop end of the catheter was passed rostrally to exit percutaneous on
the top of the skull. This PE-10 loop was cut on the 8th day, at 1200 hours, 16 hours after clearance of the catheter by saline from the pump
and used to administer the probe dose of morphine. The wound was
sutured, including a loose ligature at the base of the loop to prevent it from moving. Animals fully recovered 15 to 30 min after
implantation. Rats showing any signs of motor impairment were
sacrificed with an overdose of barbiturate. Pilot studies in
vivo, and in vitro (37°C water bath), with methylene
blue, morphine and saline solutions were conducted to assess the
accuracy of this system. These studies showed that minimal mixing
occurred in vivo or in vitro, and that the
pumps flowed at the stated rate so that at the end of the 7-day period
all of the contents of the catheter had pumped through. A lag time of
4 h occurred after implantation before the pump started and the
animal began to receive morphine. All pumps were examined when the
experiments were terminated. Any systems found to be defective (in all
cases either disconnected or blocked by blood) were eliminated from the
study entirely. All animals were sacrificed by overdose of barbiturate
after testing on day 8.
Drugs and injection.
The following drugs were used for
continuous spinal infusion: morphine sulfate (morphine) (Merck, Sharp
and Dohme, West Point, PA), and (+)MK801 hydrogen maleate (MK)
(Research Biochemicals International, Natick, MA). Drugs were dissolved
in sterile normal saline. Drug doses, calculated as the free base, were
expressed in nanomoles per hour for the infusion concentrations, or
nanomoles per rat for the post-infusion probe dose. The morphine
infusion concentration, unless otherwise stated, was 40 nmol/0.5 µl/h
in all animals, because in pilot studies this dose yielded a
near-maximal increase in hot-plate latency on day 1 after implant
without any attendant motor effects, and closely resembled the infusion
concentration used in previous studies (Dunbar and Yaksh, 1996a). The
MK infusion concentration was 10 nmol/0.5 µl/h as this was also found
to cause the maximal effect in attenuating the hyperalgesia of
withdrawal without any attendant side effects in this or in previous
studies (Dunbar and Yaksh, 1996a). The probe dose of morphine
administered on day 8 was 100 nmol in 10 µl per rat because based on
preliminary studies this dose produced a sub maximal effect in the
least tolerant group and a measurable effect in the most tolerant
group.
Experimental paradigms. Animals were first tested on the hot plate and then implanted. Testing was carried out daily on the hot plate, at 4:00 P.M. on day 0 before implantation and at 12:00 P.M. subsequently. This allowed for the 4-h lag time to pass before the pump began to pump and ensured that animals were tested 16 h after the start of the infusion, close to the midcycle of each 24-h period. Abstinence was induced by infusion of saline solution [abstinence (saline)], or MK solution [abstinence (MK)]. The groups were: (1) saline for 7 days (SAL); (2) morphine for 7 days (MOR); (3) morphine with abstinence (saline) on day 6 (MORSAL6); (4) morphine with abstinence (saline) days 4 and 6 (MORSAL46); (5) morphine with abstinence (saline) on days 2, 4 and 6 (MORSAL246); (6) morphine except on days 2, 4 and 6 when morphine 8 nmol/h was infused (MORMOR(8)246); (7) morphine with abstinence (MK) on day 6 (MORMK6); (8) morphine with abstinence (MK) on days 2, 4 and 6 (MORMK246); and (9) saline with MK on days 2, 4 and 6 (SALMK246). On day 8, after testing on the hot plate at 12:00 P.M., 16 h after infusion of saline, the external loop of catheter was cut and the probe dose of morphine (100 nmol in 10 µl i.t.) was administered. Hot-plate latencies were measured at 0, 15, 30, 60 and 120 min. Rats were randomly assigned to each group and groups were run in tandem until four or more rats were obtained for each group. A summary of the experimental paradigms is provided in table 1.
|
Antinociceptive testing and data analysis. The effects of i.t. infusions were assessed by the hot-plate test. The hot-plate apparatus was a water bath, the stainless steel surface of which was the test surface. This surface was maintained at a temperature of 52.5 ± 0.5°C by a proportional feedback controller. Licking of either hind paw was taken as the endpoint. A cutoff time of 60 sec was used to avoid tissue damage. Hot-plate data were expressed as %MPE, which was calculated as follows:
|
Statistics. Analysis of the dose-response curves and statistics were obtained with computer software programs (Abacus Concepts, Stat View, Abacus Concepts, Inc., Berkeley, CA, 1992). Unless stated otherwise, data from daily hot-plate testing and the probe dose response were converted to %MPE and analyzed by one-way ANOVA to detect differences between groups. When differences were found, these findings were subjected to a Scheffe F-test (significance at 95%). Differences yielding critical values corresponding to P < .05 were considered significant.
| |
Results |
|---|
|
Top
Abstract
Introduction
Methods
Results
Discussion
References
|
|---|
Time Course of the Effect of Spinal Infusions
The infusion of saline, morphine or MK had no observable effect on motor function. All rats entered into the study after implantation survived for the interval of the infusion without motor deficits. The daily hot-plate response latencies for all groups presented as %MPE ± S.E. are summarized in table 2 and appear in figures 1 (a-f) and 2 (a-c). In all cases of significance, a post hoc Scheffe value was found to be significant also.
|
|
|
Base-line latencies. There was no significant difference in base-line latencies (seconds, unpaired t test, P > .05) on day 0 between the saline-infused group (13 ± 1 sec) and all other groups.
Saline and saline-MK controls. Saline-infused rats (SAL; n = 6) showed no significant difference in escape latencies from day to day during days 1 to 8, which demonstrates no significant effect of implantation, infusion of saline vehicle or daily testing (fig. 1a). Latencies in the SALMK246 group (n = 4) were also not significantly different from the saline group on any of days 1 to 8, which indicates that MK by itself did not alter daily latencies (fig. 2a).
Morphine Groups
MOR. This group (n = 6) had a maximal increase in latencies on day 1 that remained greater than those of the saline group from days 1 to 5. On days 6 and 7 latencies returned to values not significantly different from the saline group. There was no significant difference between this group on day 8, the first day of abstinence, and the saline group on day 8 (fig.1b).
MORSAL6. No significant difference occurred between latencies in this group (n = 6) and the MOR group on days 1 to 8 (fig.1c).
MORSAL46. No significant difference occurred between latencies in this group (n = 6) and the MOR group on days 0 to 3. On days 4 and 5, latencies were not significantly different from the saline group, but on days 6 (the second day of abstinence), 7 and 8 (the third day of abstinence), latencies were significantly less than the saline group (fig.1d). Latencies on days 4, 7 and 8 were also significantly less than the MOR group (fig.1d).
MORSAL246. Latencies in this group (n = 8) on days 1 to 8 showed a similar increase that was not significantly different from any of the other morphine-infused groups on day 1. On day 2, the first period of abstinence, latencies returned to values not significantly different from the saline group. On day 3 there was no significant difference from the MOR or SAL groups, and on day 4, the second period of abstinence, latencies were significantly less than the MOR group but not significantly less than the saline group. On days 5 and 6 (the third period of abstinence) and 7 and 8 (the fourth period of abstinence), latencies were significantly lower than both the MOR and saline groups. Latencies also decreased significantly on day 6, the third day of abstinence, compared with those on day 2, the first day of abstinence on (paired t test, P < .05) (fig.1e).
MORMOR(8)246. No significant difference occurred in latencies between this group (n = 7) and the MOR group on any of the days 1 to 8. However, compared with the MORSAL246 group, latencies on days 4 through 8 were significantly higher (fig. 1f).
MORMK6. No significant difference occurred in latencies between this group (n = 4) and the MOR group on any day (fig. 2b). Latencies on day 6 were not significantly different from the MORSAL6 or SAL groups.
MORMK246. Latencies in this group (n = 7) showed an increase on day 1 that was not significantly different from any of the other morphine groups. There was no significant difference on days 2 or 3 between this group and the MORSAL246 group (fig. 2c vs. fig. 1e). Latencies from days 4 to 8 were significantly higher than the MORSAL246 group (fig. 2c). However, latencies declined during the infusion period so that there was no significant difference between this group and the MOR group on day 7. Furthermore, latencies on days 5 and 7 were significantly lower than day 1, and latencies on day 7 were not significantly different from base line.
Assessment of Tolerance by Administration of Probe Dose of Morphine 100 nmol i.t. on Day 8
Effect of successive periods of abstinence on tolerance. The SAL and SALMK246 groups achieved latencies that were not significantly different from each other after administration of the probe dose of 100 nmol of morphine. Latencies in the SAL group were significantly higher than MOR, MORSAL6 or MORSAL46 groups, but not significantly different from the MORSAL246 group. Maximum latencies in the MOR group were also significantly less than those of the SAL and MORSAL246 groups, but not significantly different from the MORSAL6 or MORSAL46 groups. Maximum latencies in the MORMOR(8)246 group were not significantly different from those of the MOR group, but they were significantly less than the MORSAL246 group (fig. 3).
|
The effect of MK administration during abstinence on tolerance. No significant difference occurred in maximal latencies obtained in the MORSAL6 group and the comparative MORMK6 group. There was no significant difference in maximal latencies between the MORSAL246 group and the comparative MORMK246 group (fig. 4).
|
| |
Discussion |
|---|
|
Top
Abstract
Introduction
Methods
Results
Discussion
References
|
|---|
We hypothesized that abstinence associated with EAA release and NMDA receptor activation, if repetitive, would cause progressive hyperalgesia in a manner similar to the progressive nociceptive sensitization seen in other models of chronic pain in which activation of this receptor occurs. In addition we hypothesized that NMDA receptor blockade during abstinence should have a significant effect on tolerance to the antinociceptive effects of further opioid administration.
Repetitive abstinence progressively lowered nociceptive pain
thresholds.
Continuous infusion of morphine was associated with
rapid onset of tolerance without the development of hyperalgesia even after cessation of the infusion period (fig. 1b). An additional preceding period of abstinence was also not associated with
hyperalgesia (fig. 1c), but when two preceding periods of abstinence
were introduced before the end of the infusion period, significant
hyperalgesia developed (fig. 1d). When a third preceding period of
abstinence was introduced, hyperalgesia increased within this same
group so that latencies decreased significantly between the first and third periods of abstinence (fig. 1e). This shows that progressive hyperalgesia developed with repetitive drug withdrawal in conjunction with repetitive periods of opioid administration. If hyperalgesia was
secondary to tolerance alone, then it would have been most pronounced
after termination of the infusion period in the continuously infused
group, but this was not so (day 8 latencies; fig.1b vs. fig.
1e). Furthermore, infusion of a lower maintenance concentration of
morphine in lieu of complete drug withdrawal prevented hyperalgesia entirely (fig. 1f). Conversely, as successive periods of abstinence were introduced, each group showed greater sensitivity (or less tolerance) to the probe bolus dose of morphine administered on day 8 (fig. 3). The greater preservation of sensitivity to the probe dose of
morphine observed on day 8 in groups in which drug withdrawal occurred
is consistent with previous studies which have shown that the
concentration of agonist and the duration of agonist receptor occupancy
are the predominant requirements for development of tolerance
(Orahovats et al., 1953; Bharagava, 1978; Yano and Takemori,
1977; Crain et al., 1979). Thus we found, as predicted, a
direct relationship between the degree of tolerance and the total
duration of opioid exposure during the infusion period. Previous
studies have indicated that the severity of the opioid abstinence
syndrome is proportional to the underlying tolerant state of the
animal, so that the ED50 of naloxone required to precipitate abstinence decreases as the animal is exposed to more intensive pretreatment with morphine (Tilson et al., 1973).
In other studies a close temporal relationship between tolerance and
dependence has been observed (Cox et al., 1975), which led investigators to propose that these two phenomena are part of the same
process. However in this study, hyperalgesia, a manifestation of opioid
dependence, and tolerance seem to develop as separate entities. This
observation contrasts with previous studies which have reported
hyperalgesia as a direct manifestation of opioid tolerance (Mao
et al., 1994). These studies used intermittent dosing of
opioid as a model of tolerance, a factor which we believe may have led
to this conclusion.
; Sastry, 1979; Carstens et al., 1979). Abstinence can
cause enhanced sensitivity to a variety of excitatory neurotransmitters
(Collier, 1966; Satoh et al., 1976). Thus with drug
withdrawal, persistent hyperexcitability of the dorsal horn network may
occur, resulting in insensitivity of spinal afferents to the
hyperpolarizing antinociceptive effect of morphine. The loss of effect
of morphine cannot be explained simply by opioid tolerance alone,
because when abstinence was introduced, greater sensitivity to the
higher bolus dose of morphine occurred at the end of the infusion
period (fig. 3). We thus propose that there may be two factors that
contribute to the loss of antinociceptive effect of morphine during
abstinence-induced hyperalgesia: (1) abstinence-induced
hyperexcitability in dorsal horn afferents rendering these neurons
less susceptible to the hyperpolarization usually produced by morphine,
and (2) tolerance secondary to a variety of other possible causes (G
protein uncoupling, etc.). In support of this proposal are the
observations described in the next section that NMDA receptor
antagonism during abstinence blocked hyperalgesia but did not prevent
the progressive development of tolerance.
The effect of NMDA receptor antagonism during abstinence on nociception and tolerance. NMDA receptor antagonism blocked hyperalgesia when administered during periods of abstinence (fig. 2c), which demonstrates that NMDA receptor activation is an integral part of abstinence-induced hyperalgesia. This did not significantly prevent the progressive development of tolerance, however, as indicated by (1) the progressive loss of effect observed during the infusion period as shown by (a) latencies on days 5 and 7 in the MORMK246 group, which were significantly less than latencies on day 1, and (b) latencies on day 7 in this same group, which were not significantly different from base line (fig. 2c, table 2); (2) the response to the probe bolus dose of morphine administered at the end of the infusion period, which was not significantly different from that of the comparative MORSAL246 group, which did not receive MK during periods of abstinence (fig. 4); and (3) the failure of MK to reverse tolerance already established as indicated by comparison of latencies on day 7 in groups MORSAL6 (fig. 1c) and MORMK6 (fig. 2b). Although latencies were significantly high in the MORMK246 group from day 4 until the end of the infusion period when compared with the MORSAL246 group. This does not necessarily represent an attenuation of tolerance in the MORMK246 group, because it may simply reflect the ability of MK to block hyperalgesia in this group.
The effect of MK on tolerance when administered only during periods of abstinence contrasts with chronic spinal infusion studies in which continuous co-infusion of the same concentration of MK with morphine for 7 days appeared to block tolerance entirely (Dunbar and Yaksh, 1996a). In these studies, however, an apparent state of
hypersensitivity to morphine (as well as to another G protein-coupled
agonist ST91) developed when MK was infused alone, i.e., in
the morphine or ST91 naive rat (Dunbar and Yaksh, 1996b). This gives
rise to the possibility that other, as yet unknown effects may result
from chronic infusion of MK leading to altered sensitivity to these
agents. In this study preadministration of MK for 24-h periods did not
cause this hypersensitivity as indicated by an equivalent response to
the probe dose of morphine on day 8 in groups infused with MK and
similar groups that were not infused with MK (fig. 4). However, it is
possible that full dose-response curves in these groups at the end of
the infusion period may reveal more subtle differences between them
that was not apparent from this single probe dose study.
If EAA release and NMDA receptor activation are primary factors in the
development of tolerance, their blockade would also be expected to
attenuate tolerance, but this was not observed. Thus these observations
would not support the hypothesis outlined in the introduction that EAA
release during abstinence is a substantive factor in opioid tolerance.
Periodic drug withdrawal and the disassociation of agonist and receptor
appears to have been the predominant effect in determining the
magnitude of tolerance.
Association between abstinence, nociception and tolerance. The findings above show that the manner in which tolerance is induced (intermittent dosing vs. continuous infusion) may have a substantial effect on thermal escape tests of antinociception. Thus daily dosing regimens with morphine may alter nociceptive thresholds negatively and potentially lead to an erroneous interpretation of thermal hyperalgesia as an indication of the animals' underlying tolerant state. It is conceivable that compounds other than MK, which also block hyperalgesia, may alter daily escape latencies in the same fashion, giving rise to the erroneous impression of having "attenuated tolerance." The administration of a probe dose of opioid to assess tolerance may circumvent this problem providing that the hyperalgesia itself does not significantly alter the magnitude at which tolerance develops. In this study we found that hyperalgesia was not a substantive factor in the development of tolerance as compared with the effect of continuous opioid exposure.
Recent studies have suggested that there are similarities between the cellular adaptations that occur in nociception and tolerance (for review, see Basbaum, 1995). Nociception and tolerance may share the
same NMDA receptor mechanism (Neugebauer et al., 1993) and
several spinal postsynaptic second messengers, such as intracellular calcium, protein kinase and nitric oxide. Thus nitric oxide synthetase inhibition (Adams et al., 1993; Cappendijk et
al., 1993; Sorkin, 1993; Elliott et al., 1994;
Bhargava, 1995), protein kinase inhibition (Vaccarino et
al., 1987; Coderre and Melzack, 1992; Mayer et al., 1993) and NMDA receptor antagonism have been reported to attenuate the
development of both hyperalgesia and opioid tolerance. It is possible,
and it has been proposed, that these similarities account for the
relative failure of opioids to provide analgesia in some studies of
chronic pain (Mao et al., 1995; Dickenson, 1994), although
this has been disputed (Backonja et al., 1995; Neil et
al., 1990).
From the observations made herein, it is possible that the effects of
NMDA receptor antagonists in "preventing" tolerance may in part be
secondary to their ability to block the hyperexcitability and
hyperalgesia seen with daily thermal testing when models of tolerance
are used that include repetitive abstinence. In addition, other
effects, perhaps neurotoxic (Nakki et al., 1995; Farber et al., 1995), behavioral (Hargreaves and Cain, 1995) or
unexplained sensitization (to opioid and alpha-2 agonists)
(Dunbar and Yaksh, 1996a, b), may account for reports of their ability
to attenuate tolerance. Furthermore, their ability to block dependence
is also unclear. NMDA receptor antagonists are reported in several
studies to block only some aspects of the abstinence syndrome (Thorat et al., 1994; Ben Eliyahu et al., 1992; Dunbar
and Yaksh, 1996a). This discrepancy between attenuation of tolerance
and attenuation of only some signs of dependence may reflect their
ability to block manifestations of abstinence which are spinal in
origin (hypersensitivity to thermal and other non-noxious stimuli such as light touch) and relate to activation of the NMDA receptor during
abstinence at this level, whereas other signs such as head shaking and
teeth chattering remain unaffected.
This study suggests that abstinence, especially when repetitive, leads
to long-term changes in the central nervous system which may enhance
nociception. These changes most likely result from the effects of EAA
release and NMDA receptor activation which, as discussed above, occur
during abstinence. It would appear that these effects outlast the
duration of opioid drug withdrawal and evolve independently from the
process of tolerance itself. This effect of abstinence may resemble the
"wind-up phenomenon" or long-term potentiation of hyperalgesia and
chronic pain models (Woolf and Thompson, 1991). The site, or sites, of
these changes leading to this hyperexcitability, or hyperalgesia, could
be spinal or could involve more rostral sites. However, although
glutamatergic projections play a role in activation of the locus
ceruleus during abstinence, this site is not susceptible to NMDA
receptor blockade (Rasmussen, 1995), which perhaps suggests that the
hyperalgesia of abstinence may be a predominantly spinal cord
phenomenon. The above-mentioned study is an intrathecal study in the
rat, and these findings may be peculiar to the rat in this model.
Furthermore, they involve relatively high doses of spinally infused
morphine, and as such, may have more relevance to the spinal
administration of opioids in such a potent fashion. However, the
observations made in these experiments that repetitive periodic opioid
abstinence can lower pain thresholds may have significance for chronic
opioid therapy in the management of chronic pain.
Conclusion. This study shows that repetitive opioid abstinence progressively lowers nociceptive thresholds in the rat. This effect can be blocked by NMDA receptor antagonism and prevented by the administration of a continuous lower maintenance concentration of morphine providing for constant receptor agonist occupancy. Although known to prevent EAA release, NMDA receptor antagonism during abstinence did not prevent progressive tolerance development, which suggests that mechanisms other than amino acid release are responsible for opioid tolerance.
| |
Acknowledgment |
|---|
We thank Dr. Tony Yaksh for his advice in designing the spinal infusion system.
| |
Footnotes |
|---|
Accepted for publication October 7, 1997.
Received for publication March 25, 1997.
1 This work was supported an unrestricted starter grant from Baystate Health Systems.
Send reprint requests to: Stuart Dunbar, M.B., Assistant Professor, Dept. of Anesthesiology, Tufts University School of Medicine, Baystate Medical Center, Springfield, MA 01199.
| |
Abbreviations |
|---|
%MPE, percentage maximal possible effect; EAA, excitatory amino acid; MK, (+) MK801 (dizocilpine hydrogen maleate); i.t., intrathecal; NMDA, N-methyl-D-aspartate; S.E., standard error of the mean; ANOVA, analysis of variance.
| |
References |
|---|
|
Top
Abstract
Introduction
Methods
Results
Discussion
References
|
|---|
0022-3565/98/2842-0678$03.00/0
THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Copyright © 1998 by The American Society for Pharmacology and Experimental Therapeutics
This article has been cited by other articles:
|
|
 |
|
  D. P. Alford, P. Compton, and J. H. Samet Acute Pain Management for Patients Receiving Maintenance Methadone or Buprenorphine Therapy Ann Intern Med, January 17, 2006; 144(2): 127 - 134. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 V. L. Tawfik, M. L. LaCroix-Fralish, N. Nutile-McMenemy, and J. A. DeLeo Transcriptional and Translational Regulation of Glial Activation by Morphine in a Rodent Model of Neuropathic Pain J. Pharmacol. Exp. Ther., June 1, 2005; 313(3): 1239 - 1247. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. W. H. Peng, P. S. Tumber, and D. Gourlay Review article: Perioperative pain management of patients on methadone therapy: [Expose de synthese : Traitement de la douleur perioperatoire chez les patients sous therapie a la methadone] Can J Anesth, May 1, 2005; 52(5): 513 - 523. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C.-P. Yang, C.-C. Yeh, C.-S. Wong, C.-T. Wu, S. Mercadante, P. Villari, P. Ferrera, and E. Arcuri Local Anesthetic Switching for Intrathecal Tachyphylaxis in Cancer Patients with Pain * Response Anesth. Analg., February 1, 2004; 98(2): 557 - 558. [Full Text] [PDF]
|
|
|
|
|
|
X. Li and J. D. Clark Hyperalgesia During Opioid Abstinence: Mediation by Glutamate and Substance P Anesth. Analg., October 1, 2002; 95(4): 979 - 984. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Mao, B. Sung, R.-R. Ji, and G. Lim Chronic Morphine Induces Downregulation of Spinal Glutamate Transporters: Implications in Morphine Tolerance and Abnormal Pain Sensitivity J. Neurosci., September 15, 2002; 22(18): 8312 - 8323. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Mao, B. Sung, R.-R. Ji, and G. Lim Neuronal Apoptosis Associated with Morphine Tolerance: Evidence for an Opioid-Induced Neurotoxic Mechanism J. Neurosci., September 1, 2002; 22(17): 7650 - 7661. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
X. Li, M. S. Angst, and J. D. Clark Opioid-Induced Hyperalgesia and Incisional Pain Anesth. Analg., July 1, 2001; 93(1): 204 - 209. [Abstract] [Full Text] [PDF]
|
|
