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NEUROPHARMACOLOGY
- and µ-Opioid Receptor-Mediated Antinociception in the Mouse
Department of Anesthesiology, Medical College of Wisconsin, Milwaukee, Wisconsin (H.M., A.S., R.L., H.-E.W., L.F.T.); and Pharmaceutical Research Laboratory, Toray Industries Inc., Kamakura, Japan (H.N.)
Received January 6, 2003; accepted April 15, 2003.
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Abstract |
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 Top Abstract Materials and MethodsResultsDiscussionReferences |
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- and µ-opioid
receptors were characterized in 
-endorphin- and
[D-Ala2,N-Me-Phe4,Gly5-ol]-enkephalin
(DAMGO)-induced antinociception, respectively, with the tail-flick test in
male ICR mice. -Opioid receptor agonist -endorphin (0.1–1
µg), µ-opioid receptor agonist DAMGO (0.5–20 ng), or buprenorphine
(0.1–20 µg) administered i.c.v. dose dependently produced
antinociception. The antinociception induced by 10 µg of buprenorphine
given i.c.v. was completely blocked by the pretreatment with
-funaltrexamine (-FNA) (0.3 µg i.c.v.), indicating that the
buprenophine-induced antinociception is mediated by the stimulation of the
µ-opioid receptor. The antinociceptive effects induced by -endorphin
(1 µg i.c.v.) and DAMGO (16 ng i.c.v.) were dose dependently blocked by
pretreatment with smaller doses of buprenorphine (0.001–1 µg i.c.v.),
but not by a higher dose of buprenorphine (10 µg i.c.v.). -FNA at a
dose (0.3 µg i.c.v.) that strongly attenuated DAMGO-induced antinociception
had no effect on the antinociception produced by -endorphin (1 µg
i.c.v.). However, pretreatment with buprenorphine (0.1–10 µg) in mice
pretreated with this same dose of -FNA was effective in blocking
-endorphin-induced antinociception. -FNA was 226-fold more
effective at antagonizing the antinociception induced by DAMGO (16 ng i.c.v.)
than by -endorphin (1 µg i.c.v.). The antinociception induced by
-opioid receptor agonist [D-Ala2]deltorphin II
(10 µg i.c.v.) or 
1-opioid receptor agonist
trans-3,4-dichloro-N-methyl-N-(2-[1-pyrrolidinyl]cyclohexyl)benzeneacetamine
methanesulfonate salt [(–)-U50,488H] (75 µg i.c.v.) was not affected
by pretreatment with buprenorphine (0.1–1.0 µg i.c.v.). It is
concluded that buprenorphine, at small doses, blocks -opioid
receptor-mediated -endorphin-induced antinociception and µ-opioid
receptor-mediated DAMGO-induced antinociception, and at high doses produces a
µ-opioid receptor-mediated antinociception.
;
Dum and Herz, 1981; Kamei et
al., 1995,
1997). Buprenorphine
antagonizes the antinociceptive actions of morphine in the mouse and rat with
the tail-flick test, but is not effective in the rat tail-pressure test
(Cowan et al., 1977), and also
suppresses and precipitates abstinence in morphine-dependent dogs, mice,
monkeys and rats (Martin et al.,
1976; Cowan et al.,
1977; Dum and Herz,
1981). Evidence also supports a -opioid antagonism
associated with buprenorphine. Buprenorphine shows potent -opioid
antagonist properties in the in vitro [35S]GTP
S binding
assay (Romero et al., 1999).
Buprenorphine also blocks the -opioid agonist U-50,488H-induced
inhibition of abdominal stretching induced by intraperitoneal injection of
acetic acid in mice (Leander,
1988). However, less data are known for the involvement of
buprenorphine to stimulate -opioid receptors or to block -opioid
receptors, and some findings are contradicting. The antinociception produced
by buprenorphine administered intrathecally is blocked by the -opioid
antagonist Win 44,441-3 (Tejwani and
Rattan, 2002), whereas buprenorphine given systemically is blocked
by pretreatment with selective -opioid receptor antagonist
nor-binaltorphimine (Kamei et al.,
1995). Neilan et al.
(1999) demonstrate that
buprenorphine acts as a -opioid antagonist in the
[35S]GTPS binding assay using C6 glioma cells expressing the
cloned -opioid receptor. On the other hand, no differences were found
in the dose-response curves in mice treated with either DPDPE alone, or DPDPE
and buprenorphine in the hot water tail-flick technique
(Pick et al., 1997).
Buprenorphine is also identified to exhibit -opioid receptor binding
activity using the nonselective ligand
(–)[3H]ethylketocyclazocine, in the presence of selective
µ-, -, and 1-opioid receptor agonists (Nock et
al., 1990,
1993;
Nock, 1995). Unlike
-endorphin, whose affinity to the -opioid receptor is decreased by
high concentration of NaCl, the affinities of buprenorphine to the
-opioid receptor are increased by high concentration of NaCl, suggesting
that buprenorpine might be an antagonist for the -opioid receptor
(Nock et al., 1990).
Buprenorphine blocks the increase of [35S]GTPS binding
induced by -agonist -endorphin in the pons/medulla membrane
obtained from µ-opioid receptor knockout mice
(Mizoguchi et al., 2002). This
finding indicates that buprenorphine acts as an -opioid receptor
antagonist to block the -endorphin-induced G protein activation in the
pons/medulla membrane of mice that genetically lack µ-opioid receptors.
The present study was designed to further characterize the antagonistic
properties of buprenorphine for - and µ-opioid receptor-mediated
antinociception induced by -opioid receptor agonist -endorphin and
µ-opioid receptor agonist
[D-Ala2,N-Me-Phe4,Gly5-ol]-enkephalin
(DAMGO), in mice. We report here for the first time that buprenorphine blocks
-and µ-opioid receptor-mediated antinociception induced by
i.c.v.-administered -endorphin and DAMGO, respectively. In addition,
antinociceptive property induced by high doses of buprenorphine, which is
mediated by the stimulation of µ-opioid receptors, was also
characterized.
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Materials and Methods |
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TopAbstractMaterials and MethodsResultsDiscussionReferences |
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Assessment of Antinociception. Antinociception was determined by the
tail-flick test (D'Amour and Smith,
1941). For measurement of the latency of the tail-flick response,
mice were gently held by hand with their tail positioned in an apparatus
(model TF6; EMDIE Instrument Co., Maidens, VA) for radiant heat stimulation on
the dorsal surface of the tail. The intensity of heat stimulus was adjusted so
that the animal flicked its tail after 3 to 5 s. The inhibition of the
tail-flick response was expressed as percent maximum possible effect, %MPE,
which was calculated as follows: [(T1 –
T0)/(T2 –
T0)] x 100, where T0 and
T1 are the tail-flick latencies before and after the
treatments, respectively, and T2 is the cutoff time, set
at 10 s to avoid injury of the tail.
Intracerebroventricular Injection. Intracerebroventricular injection
was performed following the method described by Haley and McCormick
(1957) using a 10-µl
Hamilton syringe. The volume for i.c.v. injection was 4 µl.
Drugs. The drugs used were human -endorphin
(Calbiochem-Novabiochem, San Diego, CA), DAMGO (Bachem California, Torrance,
CA), [D-Ala2]deltorphin II (Calbiochem-Novabiochem),
-funaltrexamine (-FNA; National Institute on Drug Abuse,
Baltimore, MD), and (–)-U50,488H and buprenorphine (Sigma/RBI, Natick,
MA). -FNA was dissolved in sterile saline solution. Human
-endorphin and DAMGO were dissolved in sterile saline solution
containing 0.01% Triton X-100. [D-Ala2]deltorphin II and
(–)-U50,488H were dissolved in sterile saline solution containing 10%
(w/v) 2-hydroxypropyl--cyclodextrin (Sigma/RBI). Buprenorphine was
dissolved in sterile saline solution containing 0.1% (w/v) dimethyl sulfoxide
(DMSO).
Statistical Analysis. The data are expressed as the mean and S.E.M. The ID50 values were calculated by computer-assisted curve-fit program (Prism; GraphPad Software, Inc., San Diego, CA). Statistical analysis of difference between groups was assessed using an F test and one-way or two-way analysis of variance (ANOVA) following Bonferroni's test.
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Results |
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TopAbstractMaterials and MethodsResultsDiscussionReferences |
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-Endorphin, DAMGO, and Buprenorphine. Groups of mice were
injected i.c.v. with various doses of -endorphin (0.3–1 µg),
DAMGO (5–16 ng), or buprenorphine (1–20 µg) and the tail-flick
response was measured at various times after the injection. -Endorphin
given i.c.v. dose dependently inhibited the tail-flick response. The
inhibition of the tail-flick response developed slowly, reached a peak in 10
to 20 min, and the tail-flick latency returned to the preinjection level in 60
min (Fig. 1A). Similarly, the
tail-flick inhibition induced by i.c.v. injection of DAMGO developed slowly,
reached a peak in 20 min, and the tail-flick latency returned to the
preinjection level 60 min after injection
(Fig. 1B). Buprenorphine given
i.c.v. at doses of 3, 10, and 20 µg, but not 1 µg, also dose dependently
inhibited the tail-flick response. The inhibition induced by 10 and 20 µg
of buprenorphine reached a peak in 10 or 20 min after injection and the
tail-flick latency returned to preinjection level within 60 min after
injection (Fig. 1C).
Buprenorphine at a low dose (1 µg) did not significantly cause any
inhibition of the tail-flick response. Doses of buprenorphine (up to 1 µg)
were then used to study the effects of buprenorphine in blocking the
tail-flick inhibition induced by -endorphin or DAMGO. In the following
experiments, the -endorphin- and DAMGO-induced tail-flick inhibitions
were investigated at 20 min after i.c.v. injection of -endorphin or
DAMGO.
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Effect of i.c.v. Pretreatment with Buprenorphine on the Tail-Flick
Inhibition Induced by i.c.v. Administered -Endorphin. Groups
of mice were pretreated i.c.v. with buprenorphine (0.001–10 µg) or
vehicle (0.1% DMSO/saline, 4 µl) 10 min before -endorphin (1 µg
i.c.v.) administration, and the tail-flick response was measured 20 min after
-endorphin administration. Pretreatment with buprenorphine at doses of
0.01 to 1 µg dose dependently attenuated the -endorphin-produced
tail-flick inhibition. Buprenorphine at 0.1 µg markedly reduced the
-endorphininduced tail-flick inhibition to 12.7% MPE from 90.5% MPE in
the vehicle pretreatment. However, i.c.v. pretreatment with a high dose (10
µg) of buprenorphine did not attenuate the tail-flick inhibition induced by
-endorphin (Fig. 2A).
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In another experiment, the effect of pretreatment with 0.1 µg of
buprenorphine on the tail-flick inhibition induced by various doses of
-endorphin (0.1–4 µg) was studied. -Endorphin at doses
between 0.1 and 4 µg given i.c.v. dose dependently inhibited the tail-flick
response in mice pretreated with vehicle for 10 min. The i.c.v. pretreatment
with 0.1 µg of buprenorphine for 10 min significantly attenuated the
tail-flick inhibition induced by -endorphin and the dose-response curve
for -endorphin-induced tail-flick inhibition was significantly shifted
to the right 3.5-fold compared with that of vehicle-pretreated mice
(Fig. 3A; Table 1).
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Effect of i.c.v. Pretreatment with Buprenorphine on the Tail-Flick Inhibition Induced by i.c.v. Administered DAMGO. Groups of mice were pretreated i.c.v. with buprenorphine (0.001–10 µg) or vehicle (0.1% DMSO/saline; 4 µl) 10 min before DAMGO (16 ng i.c.v.) injection, and the tail-flick response was measured 20 min after the DAMGO injection. The pretreatment with buprenorphine (0.1 µg), but not 0.001, 0.01, or 1 µg, significantly attenuated the tail-flick inhibition induced by DAMGO to 22.9% MPE from 70.3% MPE of the control (Fig. 2B).
In another experiment, the effect of the i.c.v. pretreatment with 0.1 µg of buprenorphine on the tail-flick inhibition induced by various doses of DAMGO given i.c.v. was studied. DAMGO at doses between 5 and 40 ng given i.c.v. dose dependently inhibited the tail-flick response in mice pretreated with vehicle. Pretreatment with 0.1 µg of buprenorphine attenuated the tail-flick inhibition induced by DAMGO, and the dose-response curve for DAMGO-induced tail-flick inhibition was significantly shifted to the right 1.96-fold (Fig. 3B; Table 1).
Time Course of the i.c.v. Pretreatment with Buprenorphine on the
Tail-Flick Inhibition Induced by i.c.v. Administered
-Endorphin. Groups of mice were pretreated with 0.1 or 10 µg
of buprenorphine given i.c.v. at various times before i.c.v. injection of
-endorphin (1 µg) (Fig. 4, A and
B), respectively, and the tail-flick inhibition was measured 20
min after injection. Another group of mice was pretreated i.c.v. with vehicle
and challenged with the same dose of -endorphin to serve as controls.
The i.c.v. administration of -endorphin (1 µg) produced consistent 83
to 91% MPE of the maximum tail-flick inhibition in mice pretreated i.c.v. with
vehicle. Pretreatment with 0.1 µg of buprenorphine for 10 min, but not 30
min or 1 h, attenuated the -endorphin-induced tail-flick inhibition
(Fig. 4A). On the other hand,
pretreatment with 10 µg of buprenorphine for 3 h only, but not 10 min, 1 h,
2 h, or 4 h, attenuated the -endorphin-induced tail-flick inhibition
(Fig. 4B).
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Effects of i.c.v. Pretreatment with -FNA on the Tail-Flick
Inhibition Induced by i.c.v. Administered -Endorphin, DAMGO, or
Buprenorphine. We have previously demonstrated that i.c.v. pretreatment
with -FNA at a dose of 2.5 µg for 24 h completely blocks the
tail-flick inhibition induced by i.c.v.-administered morphine, but not
-endorphin (Suh and Tseng,
1988). The present experiment was extended to determine the
relative potency of -FNA, administered i.c.v., for blocking tail-flick
inhibition induced by i.c.v.-administered -endorphin and DAMGO. Groups
of mice were pretreated i.c.v. with various doses of -FNA 24 h before
i.c.v. injection of -endorphin (1 µg) or DAMGO (16 ng), and the
tail-flick response was measured 20 min after injection. -FNA at 0.001
to 0.1 µg and 0.3 to 10 µg dose dependently blocked the tail-flick
inhibition induced by DAMGO and -endorphin, respectively. -FNA at
0.1 µg, which markedly blocked the tail-flick inhibition induced by DAMGO,
did not affect the tail-flick inhibition induced by -endorphin.
-FNA even at a dose up to 0.3 µg did not have any effect on
-endorphin-induced tail-flick inhibition. The ID50 value of
-FNA for attenuating the tail-flick inhibition induced by DAMGO and
-endorphin was 0.023 and 5.2 µg, respectively; -FNA was
226-fold more effective in blocking the antinociception induced by DAMGO than
-endorphin (Fig. 5). -FNA (0.3 µg) was then chosen as the dose to use in the following
experiment to eliminate the µ-opioid component of -endorphin
antinociception.
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Groups of mice were pretreated i.c.v. with -FNA (0.3 µg) for 24 h
and various doses (0.001–10 µg) of buprenorphine for 10 min, and the
tail-flick response for i.c.v. administration of 1 µg of -endorphin
was measured 20 min thereafter. Pretreatment with -FNA (0.3 µg) did
not have any effect on the tail-flick inhibition induced by 1 µg of
-endorphin in mice pretreated with saline i.c.v. for 10 min. However,
the tail-flick inhibition induced by -endorphin was markedly blocked by
0.1 to 10 µg of buprenorphine in mice pretreated with -FNA
(Fig. 6).
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In another experiment, two groups of mice were pretreated i.c.v. with
-FNA (0.3 µg) or saline (4 µl) 24 h before the i.c.v. injection of
10 µg of buprenorphine, and the tail-flick response was measured 20 min
after injection. The tail-flick inhibition induced by 10 µg of
buprenorphine was completely blocked by the pretreatment with -FNA
(burenorphine produced 53.4 ± 13.5% MPE in saline-pretreated mice
versus 10.2 ± 3.1% MPE in -FNA pretreated mice).
Effect of i.c.v. Pretreatment with Buprenorphine on the Tail-Flick Inhibition Induced by i.c.v. Administered [D-Ala2]Deltorphin II and U50,488H. Groups of mice were pretreated i.c.v. with buprenorphine (0.1 or 1 µg) or vehicle (0.1% DMSO/saline; 4 µl) 10 min before i.c.v. injection of [D-Ala2]deltorphin II (10 µg) or U50,488H (75 µg), and the tail-flick response was measured 10 min after the injection. The tail-flick inhibition induced by [D-Ala2]deltorphin II or U50,488H was not affected by pretreatment with buprenorphine (Fig. 7).
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Discussion |
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TopAbstractMaterials and MethodsResultsDiscussionReferences |
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-FNA. Our present
finding is consistent with the reports of others (Kamei et al.,
1995,
1997) that the antinociception
induced by buprenorphine is mediated by the stimulation of µ-opioid
receptors. Buprenorphine, currently used clinically as an analgesic
(Cowan and Lewis, 1995), is
reported to show weaker partial agonistic property for the µ-opioid
receptor in cell membranes expressed with cloned µ-opioid receptors than
morphine or fentanyl (Selley et al.,
1997).
Buprenorphine at Small Doses Blocks Both - and
µ-Opioid Receptor-Mediated -Endorphin- and DAMGO-Induced
Antinociception, Respectively. It has been documented that the
antinociception induced by -endorphin given supraspinally is mediated by
the stimulation of the -opioid receptors (for reviews, see Tseng,
1995,
2002). This view is supported
by the finding that the antinociception induced by -endorphin given
i.c.v. is not blocked by the pretreatment with the µ-opioid receptor
antagonists D-Phe-Cys-Tyr-Orn-Thr-Pen-Thr-NH2 or -FNA, the
-opioid receptor antagonist naltrindole, or the -opioid receptor
antagonist nor-binaltorphimine, but is blocked by the -opioid receptor
antagonist -endorphin(1–27)
(Suh et al., 1988;
Suh and Tseng, 1990;
Tseng and Collins, 1991;
Tseng, 2002).
-Endorphin(1–27) was the only compound previously used as an
-opioid receptor antagonist to characterize the -receptor
properties. We report here for the first time that buprenorphine blocks the
-mediated antinociception induced by i.c.v.-administered
-endorphin. We found that antinociception induced by -endorphin
given supraspinally was not affected by the pretreatment with µ-opioid
receptor antagonist -FNA (0.3 µg), but was effectively blocked by the
pretreatment with buprenorphine in mice pretreated with the same dose of
-FNA. These findings indicate that buprenorphine blocks the
antinociception by blocking the -opioid receptors stimulated by
-endorphin.
We found that the i.c.v. pretreatment with buprenorphine at doses 0.01,
0.1, and 1 µg, which given alone did not produce any tail-flick inhibition,
effectively and dose dependently attenuated the antinociception induced by
i.c.v.-administered -endorphin. In addition, buprenorphine at 0.1 µg,
but not 0.01 or 1 µg, also attenuated the antinociception induced by
µ-opioid receptor agonist DAMGO. Thus, buprenorphine at small doses blocks
both - and µ-opioid receptors.
Buprenorphine at Doses that Block - and µ-Opioid
Receptors Does Not Block - and -Opioid
Receptors. Pretreatment with these same doses (0.1 and 1 µg) of
buprenorphine given i.c.v., which blocked antinociception induced by
i.c.v.-administered -endorphin or DAMGO, did not affect the
antinociception induced by i.c.v. injected -opioid receptor agonist
[D-Ala2]deltorphin II or -opioid receptor agonist
U50,488H. Our results are consistent with the work done by Pick et al.
(1997) showing buprenorphine
is unable to block the antinociceptive affects of 1-opioid
agonist U50,488H or -opioid agonist DPDPE. Although other groups have
shown -opioid (Leander,
1988; Pick et al.,
1997; Romero et al.,
1999) and -opioid
(Neilan et al., 1999)
antagonistic effects with buprenorphine, we simply conclude that buprenorphine
given i.c.v. at doses 0.1 to 1 µg does not show any significant - or
-opioid antagonistic components with the respective agonists we
administered. Inconsistency in the literature is possibly due to different
subtypes of opioid receptors involved in buprenorphine action, different
routes of administration and the receptor density at administration sites, and
different efficacy requirements for different experiments.
In conclusion, buprenorphine at high doses produced antinociception, which
is mediated by stimulation of µ–opioid receptors. At low doses,
buprenorphine blocked the antinociception induced by -opioid receptor
agonist -endorphin and µ-opioid receptor agonist DAMGO.
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Footnotes |
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ABBREVIATIONS: GTPS, guanosine
5'-O-(3-thio)triphosphate; DPDPE,
[D-Pen2,D-Pen5]-enkephalin; DAMGO,
[D-Ala2,N-Me-Phe4,Gly5-ol]enkephalin;
% MPE, percent maximum possible effect; -FNA, -funaltrexamine;
DMSO, dimethyl sulfoxide; ANOVA, analysis of variance; (–)-U50, 488H,
trans-3,4-dichloro-N-methyl-N-(2-[1-pyrrolidinyl]cyclohexyl)benzeneacetamine
methanesulfonate salt; Win 44,441-3,
1-cyclopenthyl-5-(1,2,3,4,5,6-hexahydroxy-3,6,11-trimethyl-2-methano-3-benzazocin)-3-pentatone
methane sulfonate.
Address correspondence to: Dr. Leon F. Tseng, Department of Anesthesiology, Medical College of Wisconsin, 8701 Watertown Plank Rd., Milwaukee, WI 53226. E-mail: ltseng{at}mcw.edu
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