Neuraminidase inhibitor, oseltamivir blocks GM1 ganglioside-regulated excitatory opioid receptor-mediated hyperalgesia, enhances opioid analgesia ...
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Brain Research 995 (2004) 260 – 266
www.elsevier.com/locate/brainres
Research report
Neuraminidase inhibitor, oseltamivir blocks GM1 ganglioside-regulated
excitatory opioid receptor-mediated hyperalgesia, enhances opioid
analgesia and attenuates tolerance in mice
Stanley M. Crain *, Ke-Fei Shen
Department of Neuroscience, Albert Einstein College of Medicine, Yeshiva University, 1300 Morris Park Ave. Bronx, NY 10461, USA
Accepted 26 September 2003
Abstract
The endogenous glycolipid GM1 ganglioside plays a critical role in nociceptive neurons in regulating opioid receptor excitatory signaling
demonstrated to mediate ‘‘paradoxical’’ morphine hyperalgesia and to contribute to opioid tolerance/dependence. Neuraminidase (sialidase)
increases levels of GM1, a monosialoganglioside, in these neurons by enzymatic removal of sialic acid from abundant polysialylated
gangliosides. In this study, acute treatment of mice with the neuraminidase inhibitor, oseltamivir enhanced morphine analgesia. Acute
oseltamivir also reversed ‘‘paradoxical’’ hyperalgesia induced by an extremely low dose of morphine, unmasking potent analgesia. In chronic
studies, co-administration of oseltamivir with morphine prevented and reversed the hyperalgesia associated with morphine tolerance. These
results provide the first evidence indicating that treatment with a neuraminidase inhibitor, oseltamivir, blocks morphine’s hyperalgesic effects
by decreasing neuronal levels of GM1. The present study further implicates GM1 in modulating morphine analgesia and tolerance, via its
effects on the underlying excitatory signaling of Gs-coupled opioid receptors. Finally, this work suggests a remarkable, previously
unrecognized effect of oseltamivir—which is widely used clinically as an antiviral agent against influenza—on glycolipid regulation of
opioid excitability functions in nociceptive neurons.
D 2003 Elsevier B.V. All rights reserved.
Theme: Neurotransmitters, modulators, transporter and receptors
Topic: Opioids: anatomy, physiology and behavior
Keywords: Neuraminidase inhibitor; Excitatory Gs-coupled opioid receptors; Opioid analgesia; Opioid hyperalgesia; Opioid tolerance
1. Introduction enous GM1 to nociceptive dorsal-root ganglion (DRG)
neurons in vitro [24] enhances the efficacy of low-dose
Previous in vitro and in vivo work demonstrates that the opioids in prolonging the calcium-dependent component of
monosialoganglioside GM1 [15,16] regulates opioid recep- the action potential duration (APD) [3,27]. The APD pro-
tor signal transduction in nociceptive neurons by enhancing longation results from excitatory signaling of opioid recep-
excitatory (Gs-mediated) but not inhibitory (Gi/Go-mediat- tors mediated by an adenylate cyclase/cyclic AMP/protein
ed) signaling [2,3,5 – 8,22,23,26,27,34,36,37]. Much exper- kinase A second-messenger system linked to K+ and Ca2 +
imental evidence suggests that this excitatory mode of opioid channels [1,2,5,21,24]. These directly evoked excitatory
receptors contributes to opioid tolerance and physical de- opioid receptor-mediated effects on the APD of DRG neuron
pendence [2,5 – 8,23,26] and mediates the ‘‘paradoxical’’ perikarya may also result in increased Ca2 + influx in
hyperalgesia seen with very low doses of opioid agonists presynaptic DRG terminals and thereby account for the
[9]. Acute application of low (nM) concentrations of exog- observed low-dose opioid stimulation of high K+-evoked
release of substance P (and probably other excitatory neuro-
transmitters) in trigeminal neurons [30], as well as in
* Corresponding author. Tel.: +1-718-430-2481 or +1-814-867-8609;
fax: +1-718-430-3381 or +1-814-867-7094.
dissociated rat DRG neurons in culture [31]. By contrast,
E-mail addresses: smcrain@aecom.yu.edu, stanleycrain@aol.com activation of Gi/Go-coupled inhibitory opioid receptors by
(S.M. Crain). higher concentrations of opioid agonists shortens the APD of
0006-8993/$ - see front matter D 2003 Elsevier B.V. All rights reserved.
doi:10.1016/j.brainres.2003.09.068S.M. Crain, K.-F. Shen / Brain Research 995 (2004) 260–266 261
DRG neurons and attenuates transmitter release [17]. Appli- the application of GM1 itself, markedly enhances the
cation of exogenous GM1 alone does not alter the APD of efficacy of low-dose opioids in prolonging the APD (Shen,
these DRG neurons [3,5,6,27]. Crain and Ledeen, unpublished). Neuraminidase provides,
In mice, systemic administration of low doses of GM1 therefore, a significant metabolic means to supplement
rapidly attenuates morphine’s analgesic effects [7]. In con- direct synthesis of GM1 by a cyclic AMP-dependent gly-
trast, co-administration of the non-toxic B-subunit of chol- cosyltransferase system [2,6,16,20].
era toxin (CTX-B), which selectively binds to GM1 on cell The aim of the present work was to pharmacologically
membranes, appears to interfere with GM1’s modulation of decrease levels of endogenous GM1 in vivo in order to
excitatory opioid receptor signaling. Even at low doses,
cotreatment with CTX-B markedly enhances morphine’s
analgesic potency and blocks opioid tolerance/dependence
[26].
These studies demonstrating opposing effects of GM1
and CTX-B on opioid analgesia were based on electrophys-
iologic analyses of nociceptive DRG neurons in vitro
[1,5,21,24]. In contrast to the enhancement of excitatory
opioid signaling after GM1 [27], application of CTX-B
rapidly blocks excitatory, but not inhibitory, signaling of
opioid receptors stimulated by morphine and other bimo-
dally acting opioid agonists on DRG neurons [22]. This
selective blockade of opioid receptor excitatory signaling by
CTX-B enhances opioid analgesia and attenuates the devel-
opment of opioid tolerance and dependence [5,6,22,23,26].
The blockade of morphine’s effects on excitatory opioid
receptors by CTX-B closely resembles the selective antag-
onism of excitatory opioid receptor signaling by ultra-low-
dose naloxone (NLX) or naltrexone (NTX) [4,5,25]. We
hypothesize that CTX-B binds to and blocks an allosteric
GM1-modulatory site on opioid receptors [5,6,22,26],
whereas ultra-low-dose NLX and NTX act as selective
competitive antagonists at excitatory opioid receptors [4 –
6,25].
Neuraminidase is present in the plasma membrane of
neurons [16] and in vitro studies demonstrate that adminis-
tration of exogenous neuraminidase markedly increases the
concentrations of GM1 in DRG and other nerve cell
membranes by enzymatic removal of neuraminic (sialic)
acid from abundant polysialylated ligands of the gangliote-
traose series in these neurons [10,14,16,32,33,35,37]. Acute
application of neuraminidase to DRG neurons in vitro, like
Fig. 1. Analgesic effects of morphine are enhanced by cotreatment with
oseltamivir. (Hot water-immersion mouse tail-flick assays.) (a) Morphine
elicited a relatively small analgesic effect lasting < 2 h (z). Cotreatment
with morphine (1 mg/kg) plus oseltamivir (1 mg/kg) produced a dramatic
increase in the magnitude and duration of analgesia, lasting for about 5 h
(q). Oseltamivir alone did not induce analgesia (o) nor did the saline
control (.). (b) Pretreatment of mice with oseltamivir (1 mg/kg) for 16 h
prior to simultaneous cotreatment with morphine resulted in a stronger
enhancement in the magnitude and duration of morphine analgesia, lasting
>6 h (o). Morphine alone elicited a relatively small analgesic effect, lasting
< 2 h (.) and oseltamivir alone did not induce analgesia (z). (c) Histogram
bars indicate mean tail-flick latency (s) calculated during 0 – 6-h time-effect
tests as in (a), following cotreatment with morphine plus oseltamivir at 1,
10, 100 or 1000 Ag/kg. Morphine analgesia was significantly enhanced by
cotreatment with oseltamivir at 10 Ag/kg and higher doses. Note: In all
figures, the data are presented as mean F S.E.M. (n = 8). Asterisks indicate
statistically significant differences between time-points on curves of
cotreated vs. morphine alone groups (*p < 0.05, **p < 0.01).262 S.M. Crain, K.-F. Shen / Brain Research 995 (2004) 260–266
further elucidate the role of GM1 in regulating excitatory latencies >6 s were excluded from these tests and a 10-s
signaling of opioid receptors and associated hyperalgesic cutoff was used to minimize tissue damage. Five sequential
effects. Oseltamivir was recently designed to act as a control tests were made, each with a 10-min interval. The
neuraminidase inhibitor that can attenuate viral removal of latencies of the last four tests were averaged to provide a
sialic acid from cell surface glycoproteins (12). It is now predrug value. Time-effect curves were plotted using tail-
widely used as a clinical antiviral agent to inhibit influenza flick latencies as the ordinate. Experimentally induced
(13). Because oseltamivir was the first well-defined neur- increases in control tail-flick latency provide a measure of
aminidase inhibitor to become available for systemic ad- antinociceptive or analgesic effect, whereas decreases in
ministration in vivo, we decided to determine if it might also tail-flick latency indicate hyperalgesic effects [9,26]. For
inhibit enzymatic conversion of abundant polysialoganglio- preparation of the histograms in Figs. 1c and 3a, the mean
sides to GM1 ganglioside in neurons in nociceptive systems. tail-flick latencies during 0 –6-h test periods were used.
The effects of systemic oseltamivir administration in mice All drugs were administered s.c. immediately following
were therefore examined on acute morphine analgesia, on baseline antinociception measurements. Morphine was ad-
the hyperalgesia caused by low-dose morphine and on ministered at 0.1 Ag/kg in the hyperalgesia experiment (Fig.
morphine analgesic tolerance. 2) and at 1 mg/kg in all other experiments. Oseltamivir was
administered at doses ranging from 1 Ag/kg to 1 mg/kg. In
chronic experiments, mice were dosed b.i.d. (at 9 a.m. and 5
2. Materials and methods p.m.), with nociception testing carried out during 6 h after
a.m. injection on test days.
2.1. Animal test groups
2.4. Statistical analyses
Swiss – Webster (SW) male mice (20 – 25 g, Charles
River, NY) were housed separately in groups of five, The magnitude and duration of antinociception as mea-
maintained on a 12-h light/dark cycle, and provided water sured by latency to tail-flick was tested by repeated
and food ad libitum for 1– 3 days prior to anti-nociception measures analysis of variance (ANOVA). Results reported
testing. There were eight mice per treatment group. Com- as differences between treatments over the full 6 h are F
parative tests were generally carried out on the same day. tests of the main effects from the repeated ANOVA.
All animal test groups were used for only one assay, except Overall time by treatment interactions that were significant
in chronic treatment tests where analgesia was tested after at the 0.05 level or less were followed by paired t-tests of
1 –6 days. The protocols of this research project including each treatment group vs. the comparison group (e.g., saline
the care and humane use of the mice were approved by the or oseltamivir at each time point) using the Bonferroni
Animal Institute Committee at the Albert Einstein College adjustment.
of Medicine.
2.2. Materials
The oseltamivir phosphate (‘‘Tamiflu’’) used in this study
is a product of Hoffmann-La Roche (Nutley, NJ). Morphine
and NLX were purchased from Sigma (St. Louis, MO).
2.3. Antinociception and hyperalgesia assays
Antinociceptive and hyperalgesic effects of opioids on
these mice were measured using a hot-water-immersion tail-
flick assay similar to methods previously described [7,9].
Each mouse was permitted to enter a tapered plastic cylinder
(with air holes). The cylinder was slightly larger than the
body size, with the tail freely hanging outside the cylinder.
The cylinder provided a secluded environment into which
the animals voluntarily enter. During the tail-flick assay, the
cylinder was handled without direct contact with the animal. Fig. 2. Oseltamivir blocks low-dose morphine-induced hyperalgesia,
One-third of the tail from the tip was immersed into a water- unmasking potent opioid analgesia. A dose of 0.1 Ag/kg morphine alone
bath maintained at 52 jC ( F 0.1j) with an electronic (z) elicited hyperalgesia indicated by a decrease in tail-flick latency in the
following 4 h. Cotreatment with morphine plus oseltamivir (q) blocked the
thermoregulator (Yellow Springs). The latency to a rapid morphine-induced hyperalgesia, unmasking prominent analgesia lasting
tail-flick was recorded and the mouse was returned to its >5 h. Administration of oseltamivir alone (o) did not alter baseline tail-
cage during the period between tests. Mice with control flick latency nor did the saline control (.).S.M. Crain, K.-F. Shen / Brain Research 995 (2004) 260–266 263
3. Results drug injection and rapidly decreased to baseline levels
during the next hour. By contrast, the tail-flick latency of
3.1. Cotreatment of mice with oseltamivir enhances morphine plus oseltamivir-treated mice reached a peak of
morphine’s analgesic effects 7.2 s at 2 h post-drug injection and continued to be
significantly longer than the latency of saline-control mice
Cotreatment of mice with 1 mg/kg morphine plus 1 mg/ through 6 h. Oseltamivir alone did not alter baseline tail-
kg oseltamivir markedly increased both the magnitude and flick latency. The effects of morphine alone and of morphine
duration of morphine’s antinociception in a hot water (52 plus oseltamivir differed from the effect of oseltamivir alone
jC) tail-flick assay (Fig. 1a, P < 0.01). The analgesia of ( P < 0.01 in both cases).
cotreated mice lasted >2 h longer than the analgesia from A stronger enhancement of the magnitude and duration
morphine alone. The mean baseline tail-flick latency in the of morphine analgesia by oseltamivir occurred when an
saline control group was about 4 s. Morphine alone elicited additional pretreatment of 1 mg/kg oseltamivir was given 16
a peak tail-flick latency of 6.3 s that occurred at 30 min after h prior to simultaneous cotreatment with morphine and
Fig. 3. Chronic cotreatment with morphine plus oseltamivir attenuates development of morphine tolerance. (a) After 5 days of treatment, mice that received
oseltamivir (1 mg/kg) plus morphine (1 mg/kg) retained a prominent analgesic response, whereas mice treated with morphine alone became markedly
hyperalgesic to morphine. Treatment with oseltamivir alone did not alter baseline tail-flick latency. (b) On day 6, a single co-administration of oseltamivir with
morphine (.) to the same group of morphine-tolerant mice shown in (a) restored prominent analgesia. Conversely, analgesic tolerance developed within 1 day
after withdrawal of oseltamivir from the group of mice previously cotreated with morphine plus oseltamivir (o; cf. (a)).264 S.M. Crain, K.-F. Shen / Brain Research 995 (2004) 260–266
oseltamivir (Fig. 1b; P < 0.01 for morphine vs. morphine with oseltamivir alone showed no change in tail-flick
plus oseltamivir). This group of mice showed peak tail-flick latency from baseline over all test days. Repeated measures
values of 8.6 s within 30 min after administration of ANOVA of days 1, 3 and 5 revealed a main effect of
morphine plus oseltamivir and significant analgesia was treatment ( P < 0.001) and a treatment by time interaction
maintained for >6 h (Fig. 1b, cf. Fig. 1a). Morphine alone ( P = 0.002). There were statistically significant differences
elicited a relatively small analgesic effect, reaching a peak for morphine vs. morphine plus oseltamivir ( P < 0.001), for
tail-flick value of 6.2 s and lasting < 2 h. Nevertheless, in morphine plus oseltamivir vs. oseltamivir ( P < 0.001), but
order to demonstrate the remarkable efficacy of oseltamivir not for morphine vs. oseltamivir ( P = 0.365). While the
to rapidly enhance morphine analgesia, no pretreatment difference between morphine vs. oseltamivir averaged over
with oseltamivir was given prior to cotreatments in all of the 3 days was not significant, on day 5, the mean difference
the subsequent experiments in the present study. was statistically significant ( P < 0.001).
Dose– response assays showed that a dose of oseltamivir Furthermore, a single cotreatment of oseltamivir (b.i.d.)
as low as 10 Ag/kg significantly enhanced the analgesic plus morphine to morphine-tolerant, hyperalgesic mice
potency of 1 mg/kg morphine with only minor additional restored prominent analgesia, seen by a peak tail-flick
enhancement during cotreatments with 100 Ag/kg or 1 mg/ latency of 7.8 s (Fig. 3b). By contrast, tolerance developed
kg oseltamivir (Fig. 1c, P < 0.01 for 10 Ag/kg, 100 Ag/kg within 1 day after withdrawal of oseltamivir and adminis-
and 1 mg/kg vs. morphine alone). tration of morphine (b.i.d.) alone to mice that had main-
tained prominent analgesia during 5 days of cotreatment
3.2. Oseltamivir blocks acute hyperalgesia elicited by low- with morphine plus oseltamivir (Fig. 3b, P < 0.01 for day 5
dose morphine in mice and unmasks potent opioid analgesia vs. day 6 values for this group; cf. Fig. 3a).
Acute administration of an extremely low dose of mor-
phine (0.1 Ag/kg) elicited prominent thermal hyperalgesia in 4. Discussion
contrast to saline-treated mice ( P < 0.01), manifested by a
decrease in tail-flick latency to a latency as low as 2.6 s The effects of the neuraminidase inhibitor oseltamivir
at 1 h ( P = 0.001). It remained significantly lower than combined with morphine in the present work further sup-
the 4-s baseline tail-flick latency in saline-control mice and ports the role of GM1 in modulating opioid analgesia and
lasted 4 h after drug injection (Fig. 2). This decrease in tail- tolerance via its effects on the underlying excitatory signal-
flick latency from 4 to 2.6 s evoked by low-dose morphine ing by opioid receptors in nociceptive neurons. Inhibition of
treatment indicates a substantial hyperalgesic effect (note neuraminidase, the enzyme responsible for conversion of
that the minimum possible tail-flick latency in this assay is abundant polysialogangliosides to GM1 [16], had dramatic
limited by the spinal reflex time, ca. 1.5 s). Acute cotreat- effects on opioid analgesia and hyperalgesia. Co-adminis-
ment of mice with oseltamivir (1 mg/kg) plus morphine tration of oseltamivir with morphine markedly enhanced
(0.1 Ag/kg) blocked the hyperalgesia seen with this dose of morphine-induced analgesia within the first hour of cotreat-
morphine alone and resulted in dramatic analgesia: the ment. A stronger enhancement of the magnitude and dura-
latency increased to a peak of 7.2 s at 1 h and was still 5.6 tion of morphine analgesia by oseltamivir occurred when an
s at 6 h ( P < 0.05 compared to saline; P < 0.01 compared to additional pretreatment of 1 mg/kg oseltamivir was given 16
morphine alone). Administration of oseltamivir alone did h prior to simultaneous cotreatment with morphine and
not change tail-flick latency more than 0.3 s in either oseltamivir (Fig. 1b). This result can be accounted for by
direction compared to baseline and tail-flick latency of this a further decrease in GM1 levels in nociceptive neurons
group did not differ from that of the saline group. after a longer period of neuraminidase inhibition. Oseltami-
vir reversed the well-documented, ‘‘paradoxical’’ hyper-
3.3. Chronic cotreatment with morphine plus oseltamivir algesia induced by an extremely low, acute dose of
attenuates opioid tolerance morphine [9], unmasking a prominent analgesia from this
dose of morphine lasting for >6 h. Chronic co-administra-
Chronic cotreatment of mice with 1 mg/kg morphine plus tion of oseltamivir with morphine strongly attenuated mor-
1 mg/kg oseltamivir for 5 days (b.i.d.) attenuated develop- phine tolerance, preventing the development of hyperalgesia
ment of opioid tolerance, whereas control mice chronically after initial analgesia and even reversed an established
treated with 1 mg/kg morphine alone became markedly hyperalgesia caused by repeated doses of morphine alone.
hyperalgesic after 3 days (Fig. 3a). After 5 days of treat- Our previous work has attributed these anti-analgesic
ment, mice receiving oseltamivir plus morphine retained a tolerance effects of chronic opioid administration, as well as
prominent analgesic response and showed a mean tail-flick the hyperalgesia induced by acute, very low-dose morphine,
latency of 6.0 vs. 4.2 s in oseltamivir-alone control mice to the efficacy of GM1-regulated excitatory signaling by Gs-
( P < 0.05). Mice treated with morphine alone became even coupled opioid receptors in nociceptive neurons [2,5 – 9].
more hyperalgesic to morphine, resulting in a mean tail-flick Endogenous GM1 levels are significantly elevated by
latency of 2.9 vs. 4.2 s ( P < 0.05) (Fig. 3a). Mice treated chronic opioid treatment of neuroblastoma DRG neuronS.M. Crain, K.-F. Shen / Brain Research 995 (2004) 260–266 265
hybrid F-11 cells [34] (see also Ref. [11]), a finding that Cotreatment with oseltamivir or other similarly acting
adds support to the hypothesis that oseltamivir blocks neuraminidase inhibitors may, therefore, enhance the clini-
chronic morphine-induced hyperalgesia and tolerance by cal efficacy of morphine, oxycodone and other bimodally
decreasing GM1 levels in nociceptive neurons. acting opioid analgesics by blocking excitatory, GM1-reg-
In vitro application of a specific neuraminidase inhibitor ulated opioid receptor-mediated hyperalgesic effects, there-
has previously been shown to decrease GM1 levels in the by markedly increasing analgesic potency and attenuating
plasma membrane of neuroblastoma cells, indicated by a opioid tolerance.
decrease in the binding of 125I-labeled CTX-B [38]. A
functional effect of inhibition of plasma membrane neur-
aminidase in vitro is the blockade of GM1-mediated axonal Acknowledgements
elongation in hippocampal neurons [19]. Interestingly, elec-
trophysiological tests on DRG neurons in culture showed This study was supported by an unrestricted research
that application of polysialogangliosides, e.g. GD1a and grant from Pain Therapeutics, CA. We thank Dr. Lindsay
GD1b, enhance excitatory opioid effects at 34 jC; however, Burns for helpful editorial contributions in the preparation
this enhancement is delayed by 1 –2 h at 24 jC, suggesting of this manuscript and Dr. Polly Bijur for valuable
that the efficacy of neuraminidase in converting the poly- assistance with the statistical analyses.
sialogangliosides to GM1 is compromised at the lower
temperature [6,27]. Application of GM1 was rapidly effec-
tive at both temperatures [6,27]. References
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