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BEHAVIORAL PHARMACOLOGY
Neuroscience Research, Pharmacology Laboratories, Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co. Ltd., Tsukuba, Japan
Received March 2, 2003; accepted April 21, 2003.
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Abstract |
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 Top Abstract Materials and MethodsResultsDiscussionReferences |
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; Jasmin et al.,
1998; Bertorelli et al.,
1999). The time courses of their progression after the CFA
inoculation, however, have not been fully analyzed. The first aim in the
present study, therefore, was to provide integrated information about the time
courses of pain (mechanical allodynia, thermal hyperalgesia, and joint
hyperalgesia) and other disease development (body weight, mobility, paw
volume, and joint stiffness) parameters after the CFA inoculation into the
single hind paw in rats. Surprisingly, there are no studies that have fully
evaluated the analgesic efficacies of different categories of analgesics on
mechanical allodynia, thermal hyperalgesia, and joint hyperalgesia in the
CFA-induced arthritic rat model. The second aim in the present study,
therefore, was to investigate this issue. Antipyretics (e.g., acetaminophen)
and nonsteroidal anti-inflammatory drugs (e.g., indomethacin and diclofenac)
are the first line drugs in the treatment of arthritic pain. Antidepressants
(e.g., amitriptyline) and antiepileptics (e.g., carbamazepine and gabapentin)
have been frequently used in the treatment of chronic pains in addition to
their original use. Opioid receptor agonists (e.g., morphine and tramadol)
have strong efficacies for various nociceptive pains. Morphine is a prototype
opioid receptor agonist although tramadol has two mechanisms of action (opioid
and monoaminergic). These different categories of agents were tested in the
present study. It has recently been considered that analysis of pain-related
parameters in arthritic rats should be conducted in the monoarthritic phase
when arthritis is localized around the affected site such as the hind paw,
because serious systemic disturbances occur in the polyarthritic phase, making
it difficult to attribute the obtained data exclusively to the effect on the
nociceptive system (Millan et al.,
1988; Stein et al.,
1988; Butler et al.,
1992). In the present study, the monoarthritic phase was
determined based on the balance between the pain parameters and other disease
development parameters. |
Materials and Methods |
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TopAbstractMaterials and MethodsResultsDiscussionReferences |
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Pain Parameters Measurement. Pain and other disease development
parameters were measured in the CFA- or saline-treated rats (n = 10
for each group) on postinoculation day (PID) 0 (i.e., just before inoculation)
and on PIDs 1, 3, 5, 7, 8, 9, 10, 11, 12, 14, 17, 21, and 28. The measurement
for pain parameters was conducted for both hind paws. The measurement of
mechanical allodynia was performed with a modified method of Gonzalez et al.
(2000). Briefly, the threshold
was measured using the von Frey hairs (Semmes-Weinstein Monofilaments,
Stoelting Co., IL). The rats were habituated to wire mesh bottom cages before
the start of the experiment. Static allodynia was tested in the unrestrained
rats by touching the plantar surface of the hind paw with von Frey hairs in
ascending order of force (1.2, 1.5, 2.0, 3.6, 5.5, 8.5, 12, 15, 29, and 76 g)
for up to 6 s or until a paw withdrawal response was elicited. The lowest
amount of force required to elicit a response was recorded as the withdrawal
threshold in log g. Thermal hyperalgesia was assessed using the plantar test
(model 7370; Ugo Basile, Varese, Italy) and a modified method of Hargreaves et
al. (1988). Briefly, the rats
were habituated to an apparatus consisting of individual Perspex boxes on an
elevated glass table. A mobile radiant heat source was located under the table
and focused on the hind paw, and the paw withdrawal latencies were defined as
the time taken by the rat to remove its hind paw from the heat source. The
cut-off point was set at 15 s to prevent tissue damage. The apparatus was
calibrated to give a paw withdrawal latency of approximately 10 s in naive
rats. The measurement of joint hyperalgesia was performed by a modification of
the previously reported method (Rupniak et
al., 1997). The body of rats was held from the back with the left
palm, and the bending and extension (one after the other and five times in
each direction) of the ankle within its limits of range of motion were
performed with the right fingers. The total number of vocalizations emitted
after the manipulation (the bending and extension, five times in each
direction) was recorded for each paw (the maximum score was 10 for each
paw).
Disease Development Parameters Measurement. The scoring of mobility
was performed by modifying the evaluation scale reported by Butler et al.
(1992): score 6, walks
normally; score 5, walks being protective toward the ipsilateral hind paw
(touches the ipsilateral hind paw fully on the floor); score 4, walks being
protective toward the ipsilateral hind paw (touches only the toe of the
ipsilateral hind paw on the floor); score 3, walks being protective toward
both hind paws (touches the contralateral hind paw fully on the floor); score
2, walks being protective toward both hind paws (touches only the toe of the
contralateral hind paw on the floor); score 1, crawls only using the fore
paws; and score 0, does not move. Paw volumes were measured by volume
displacement of electrolyte solution in the plethysmometer (model TK-105;
Unicom, Chiba, Japan). The hind paw was immersed to the junction of the hairy
skin, and the volumes were read on a digital display. The scoring of joint
stiffness was performed as follows. The body of rats was held from the back
with the left palm, and the bending and extension (once in each direction) of
the ankle within its limits of range of motion were performed with the right
fingers. It was confirmed beforehand that there was no restriction of ankle
joint movement in the bending and extension manipulations in naive rats, and
the scoring was performed according to the evaluation scale reported by Butler
et al. (1992): score 2, there
were restrictions of full range of movement of the ankle in both bending and
extension; score 1, there was a restriction of full range of movement of the
ankle in bending or extension; and score 0, no restriction. The measurements
for paw volume and joint stiffness were conducted for both hind paws. All the
time-course observations were performed by one of the authors to avoid
interobserver differences. The time-course measurement experiment was carried
out by the observer who was not blind to the CFA or saline treatment because
the difference between the ipsilateral and contralateral paw was apparent
mainly due to the difference in paw volume.
Drugs. Acetaminophen, indomethacin, diclofenac sodium and
amitriptyline hydrochloride were obtained from Sigma-Aldrich (St. Louis, MO).
Morphine hydrochloride and carbamazepine were purchased from Takeda Chemical
Industries (Osaka, Japan) and Wako Pure Chemicals (Osaka, Japan),
respectively. Crispin injection, which contained 100 mg of tramadol
hydrochloride per 2 ml, was purchased from Nippon Shinyaku Co., Ltd. (Kyoto,
Japan). Gabapentin was prepared by Yamanouchi Pharmaceutical Co., Ltd.
(Ibaraki, Japan). Acetaminophen, diclofenac, and carbamazepine were suspended
in 0.5% methylcellulose. Amitriptyline and morphine were dissolved in saline.
Gabapentin and indomethacin were dissolved in distilled water and 0.1 M Tris
buffer, respectively. Tramadol was diluted with saline. The conditions, under
which each drug had proved to exhibit its optimal analgesic effect in other
rat pain models, were used for each drug evaluation to evaluate sufficiently
the maximum efficacy. Indomethacin was administered at 3 to 30 mg/kg p.o. 1 h
before the pain parameter measurement
(Okuyama and Aihara, 1984).
Diclofenac was administered at 10 to 100 mg/kg i.p. 30 min before measurement
(Euchenhofer et al., 1998).
Acetaminophen was administered at 100 to 600 mg/kg p.o. 30 min before
measurement (Granados-Soto et al.,
1993). Amitriptyline was administered at 3 to 30 mg/kg i.p. 30 min
before measurement (Korzeniewska-Rybicka
and Plaznik, 1998). Carbamazepine was administered at 20 to 80
mg/kg p.o. 1 h before measurement
(Nakamura-Craig and Follenfant,
1995). Gabapentin was administered at 30 to 300 mg/kg p.o. 1 h
before measurement (Field et al.,
1999). Morphine was administered at 1 to 10 mg/kg s.c. 30 min
before measurement (Bertorelli et al.,
1999). Tramadol was administered at 9 to 88 mg/kg s.c. 30 min
before measurement (Giusti et al.,
1997). Drug concentrations were calculated according to the base
form.
Analgesic Efficacy Evaluation. Thirty-two rats (eight rats per dose and four doses per drug) treated with the CFA and another eight rats as naive controls were used for each drug evaluation. The analgesic effects were evaluated on PID 9, when mechanical allodynia, thermal hyperalgesia, joint hyperalgesia, and joint stiffness in the ipsilateral paw reached almost the maximum, although those parameters in the contralateral paw changed only slightly and the systemic disturbance shown by the change of mobility score was small. On the day before evaluation (PID 8), body weight, mechanical allodynia, thermal hyperalgesia, and joint hyperalgesia were measured for the 32 rats that were to be used for drug evaluation. The rats were allocated to four groups (eight rats per group) such that the differences in the averages of those parameters among the groups became small. The behavioral disturbance was small in the CFA-treated rats on PID 9 except that the rats walked being protective only toward the ipsilateral hind paw. During the evaluation of analgesic efficacy, the behavioral abnormalities that might be caused by the nonspecific drug effect such as reduction of motion were also checked by observing the animals. All the analgesic effect evaluations and behavioral observations were performed by one of the authors to avoid interobserver differences. All the analgesic effect evaluations and behavioral observations were carried out by the observer who was blind to the drug treatment.
Statistical Analysis. Data were expressed as the mean ± S.E.M. The time-course curves for mechanical allodynia, thermal hyperalgesia, joint hyperalgesia, body weight, and paw volume were subjected to two-way repeated measures analysis of variance with post hoc t test. In experiments for drug evaluation, the difference in scores between the vehicle-treated and naive control groups was analyzed by Student's t test to confirm significant changes in the pain parameters in the ipsilateral paw. The analgesic effects were analyzed by Dunnett's t test, and in each case, the drug-treated groups were compared with the vehicle-treated group. In each statistical analysis, the comparison was conducted for paws on the corresponding side. P < 0.05 was considered statistically significant.
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Results |
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TopAbstractMaterials and MethodsResultsDiscussionReferences |
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Time Courses of Other Disease Development Parameters. The time-course curves for body weight between the CFA- and saline-treated rats were significantly different. The CFA-treated rats showed a decreased rate of body weight gain compared with the saline-treated rats. The difference in the body weight between the CFA- and saline-treated rats grew almost constantly from PID 3 to 28. The differences in body weight between the CFA- and saline-treated rats were statistically significant on PIDs 1 to 28 (Fig. 2A). The mobility score in the CFA-treated rats decreased progressively from PID 1 to 17 and reached a plateau. The scores during PIDs 7 to 10 remained at around 4, indicating that the rats walked being protective only toward the ipsilateral hind paw and that the behavioral disturbance was small on those days (Fig. 2B). The time-course curves for hind paw volume between the CFA- and saline-treated rats were significantly different in both paws. The paw volumes in both paws in the saline-treated rats increased slightly but steadily throughout the observation period. The volume of ipsilateral paw in the CFA-treated rats increased progressively during the first 5 days, reached a first plateau, increased again progressively from PID 11 to 14 and reached a second plateau. The differences in the ipsilateral paw volume between the CFA- and saline-treated rats were statistically significant on PIDs 1 to 28. Paw volume of the contralateral paw in the CFA-treated rats for once decreased on PID 1, and then increased slightly but steadily from PID 1 to 10, increased rapidly from PID 11 to 17 and reached a plateau. The differences in the contralateral paw volume between the CFA- and saline-treated rats were statistically significant on PIDs 1 to 8 and PIDs 11 to 28. The increase of volume in the ipsilateral paw was significantly larger in magnitude than that in the contralateral paw (Fig. 2C). There was no restriction on the full-range movement of joints in any of rats on PID 0, and the joints of the saline-treated rats showed no restriction throughout the observation period. Joint stiffness score in the ipsilateral paw in the CFA-treated rats increased progressively during the first 8 days and reached a plateau. The joint stiffness score in the contralateral paw in the CFA-treated rats remained almost zero until PID 10, increased progressively from PID 11 to 17 and reached a plateau (Fig. 2D).
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Efficacies of Analgesics. Nonsteroidal anti-inflammatory drugs (NSAIDs) indomethacin and diclofenac did not significantly reduce mechanical allodynia (Fig. 3, A and B). They significantly reduced thermal hyperalgesia at 30 mg/kg p.o. for indomethacin (Fig. 3C) and 100 mg/kg i.p. for diclofenac (Fig. 3D). They significantly reduced joint hyperalgesia at 10 and 30 mg/kg p.o. for indomethacin (Fig. 3E) and 100 mg/kg i.p. for diclofenac (Fig. 3F). Neither indomethacin nor diclofenac affected scores in the contralateral paw (Fig. 3, A–F). Neither of them influenced the behavior of rats, at least, during the observation period. An antipyretic acetaminophen did not significantly improve any pain parameter tested. It did not affect scores in the contralateral paw (Fig. 4, A, C, and E). It did not influence the behavior of rats, at least, during the observation period. An antidepressant amitriptyline failed to improve mechanical allodynia (Fig. 4B). It, however, significantly and fully reduced thermal hyperalgesia (Fig. 4D) and significantly reduced joint hyperalgesia (Fig. 4F) at 30 mg/kg i.p. It did not affect mechanical threshold (Fig. 4B) or numbers of vocalization in the contralateral paw (Fig. 4F), although it significantly increased latency of response to the thermal stimulation in it (Fig. 4D) at 30 mg/kg i.p. It caused reduction of motion in rats at the dose (30 mg/kg i.p.) that showed significant analgesic effects. Antiepileptics carbamazepine and gabapentin did not reduce mechanical allodynia (Fig. 5, A and B). Carbamazepine significantly reduced thermal hyperalgesia at 80 mg/kg p.o. (Fig. 5C). Gabapentin failed to affect thermal hyperalgesia (Fig. 5D). Neither gabapentin nor carbamazepine reduced joint hyperalgesia (Fig. 5, E and F). Neither carbamazepine nor gabapentin affected scores in the contralateral paw (Fig. 5, A–F). Carbamazepine induced reduction of motion in rats at the dose (80 mg/kg p.o.) that showed a significant effect on thermal hyperalgesia. Opioid receptor agonists morphine and tramadol improved all the pain parameters tested. They recovered all the pain parameters to naive control level at higher doses (Fig. 6, A–F). Morphine significantly increased mechanical threshold and latency of response to the thermal stimulation in the contralateral paw (Fig. 6, A and C), although tramadol significantly increased only the latency of response to the thermal stimulation in it (Fig. 6D). Both morphine and tramadol produced reduction of motion in rats at the doses (10 mg/kg s.c. for morphine, 88 mg/kg s.c. for tramadol) that showed full efficacies in the ankle flexion test.
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Discussion |
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TopAbstractMaterials and MethodsResultsDiscussionReferences |
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). The
reason for the absence in the contralateral paw remains to be clarified,
although the inflammation induced directly by the CFA may have a critical role
in the induction of thermal hyperalgesia that occurs only in the ipsilateral
paw. The maximum scores of joint hyperalgesia and joint stiffness were almost
equal between the ipsilateral and contralateral paws, suggesting that the
CFA-induced conralateral arthritis has a potential to cause full joint
hyperalgesia without the inflammation induced directly by the CFA. On the
other hand, the maximum score of mechanical allodynia in the contralateral paw
was apparently smaller than that in the ipsilateral paw. It is unlikely that
the degree of inflammation is responsible for the difference because there
exists a clear difference in the mechanical allodynia score even when paw
volume scores are almost equal between the ipsilateral and contralateral paws
(for example, PID 9 in the ipsilateral paw versus PID 17 in the contralateral
paw). It is possible that some factors involved in the CFA-induced direct
inflammation have a critical role also in the induction of full mechanical
allodynia.
An antipyretic acetaminophen, the first line drug in the treatment of
arthritic pain, unexpectedly had rather small efficacies in reducing allodynia
or hyperalgesia in the present study. The weak effect on mechanical allodynia
may reflect the recently published report that shows that acetaminophen is
poorly active, giving only maximum 30% reversal of mechanical hyperalgesia
assessed with the paw pressure test in the CFA-induced arthritic rats
(Burgess et al., 2000). The
weak effect on thermal hyperalgesia is in accordance with the previous report
that shows that efficacy of acetaminophen in reducing thermal hyperalgesia
measured with the plantar test is very small at 300 mg/kg p.o. in the
CFA-induced arthritic rats (Bertorelli et
al., 1999). Because acetaminophen has been reported to be
effective in the test using electrical stimulation to the foot in the
CFA-induced arthritic rats (Okuyama and
Aihara, 1984), its effect seems test (stimulation)-dependent. The
present study, however, suggested that the acute dosing of acetaminophen was
not so effective in reducing mechanical allodynia, thermal hyperalgesia, or
joint hyperalgesia in the CFA-induced arthritic rats. NSAIDs, other first line
drugs in the treatment of arthritic pain, were also unexpectedly ineffective
in reducing mechanical allodynia in the present study. This result is
inconsistent with the previous report that shows that NSAIDs are effective in
reducing mechanical hyperalgesia assessed with the paw pressure test in the
CFA-induced arthritic rats (Attal et al.,
1988; Chau and Weichman,
1989). This discrepancy may be attributable to the different
methods used to measure mechanical thresholds, i.e., the paw pressure test
stimulates joints and surrounding deep tissues, whereas the von Frey hairs
used in the present study excite mainly cutaneous tissues. The limited
efficacy of NSAIDs in the plantar test and ankle flexion test observed in the
present study is in accordance with results of the previous studies, in which
indomethacin partially reduces number of vocalization in the ankle flexion
test at 10 mg/kg p.o. (Rupniak et al.,
1997) or reduces thermal hyperalgesia measured with the plantar
test at 3 mg/kg i.p. with limited efficacy
(Bertorelli et al., 1999) in
the CFA-induced arthritic rats. The limited efficacies of antipyretic and
NSAIDs observed in the present study may reflect the clinical situation that
their efficacies are not fully satisfactory although they are preferred
analgesics for the management of arthritic pain. It should, however, be noted
that they are chronically used in the clinic and their antiinflammatory
actions are considered to contribute to their therapeutic effects. Because the
anti-inflammatory effect has not been evaluated in the present study, the
results obtained may underestimate their potential in the treatment of
arthritic pain.
An anti-depressant amitriptyline induced a full recovery of thermal
hyperalgesia and partially attenuated joint hyperalgesia only at the sedative
dose, although it was ineffective for mechanical allodynia. There are few
reports concerning the analgesic efficacy after single administration of
antidepressants in the CFA-induced arthritic rats, although it has been
reported that chronic (4 weeks) administration of amitriptyline or imipramine
does not modify the mechanical threshold measured with the paw pressure test
(Butler et al., 1985). When the
survey is extended to other inflammatory pain models, it has been reported
that intrathecal amitriptyline reverses thermal hyperalgesia measured with the
plantar test in the carrageenan-induced inflamed rats
(Eisenach and Gebhart, 1995).
Most animal studies concerning analgesic effects of antidepressants have been
performed in acute pain models such as tail-flick test and acetic acid-induced
writhing test, and it has been shown that antidepressants are most potent in
the chemical test such as the rat acetic acid-induced writhing test, but
ineffective in tests using thermal or mechanical stimulus with some exceptions
(Korzeniewska-Rybicka and Plaznik,
1998). It was interesting that amitriptyline was most sensitive to
the plantar test, which used thermal stimulus in the present study, being
different from the results in the acute pain models. The reason for this
discrepancy remains to be studied.
A conventional antiepileptic carbamazepine or new generation one gabapentin
was almost completely ineffective in all of the pain parameters tested. These
negative results contradict results of the previous studies that have shown
that gabapentin attenuates mechanical hyperalgesia measured with the paw
pressure test in the carrageenan-induced inflamed rats
(Field et al., 1997) or
reduces thermal hyperalgesia measured with the plantar test in the
kaolin/carrageenan-induced inflamed rats
(Lu and Westlund, 1999). One
possible reason for this discrepancy is the difference of animal models used.
The CFA-induced arthritic pain model, a chronic inflammatory pain model, was
used in the present study, although acute inflammatory pain models such as the
carrageenan-induced inflamed rat model were used in the previous study. It has
recently been reported that gabapentin is only weakly active against
mechanical hyperalgesia measured with the paw pressure test even at
flaccidity-inducing doses in the CFA-induced arthritic rats
(Patel et al., 2001). It is
conceivable that different pain mechanisms underlie the CFA-induced arthritis
model and acute inflammatory pain models.
Opioid receptor agonists morphine and tramadol fully recovered all the pain
parameters tested to the naive control level in the present study. Morphine
has proved to exert strong analgesic effects in the CFA-induced arthritic rats
when assessed, in most cases, with the plantar test
(Bertorelli et al., 1999;
Fraser et al., 2000) or paw
pressure test (Maldonado et al.,
1994; Burgess et al.,
2000). The present study further showed that morphine exerted
strong analgesic effects also on mechanical allodynia and joint hyperalgesia
and that a less potent opioid receptor agonist tramadol, like morphine,
exerted full efficacies in all the pain parameters tested. The present study
suggested that opioid receptor agonists had full efficacies in reducing
mechanical allodynia, thermal hyperalgesia, and joint hyperalgesia in the
CFA-induced arthritic rats. It should be noted, however, that both morphine-
and tramadol-induced reduction of motion in rats at the doses that showed full
efficacies. This might reflect the clinical situation that the efficacy of
opioid receptor agonists is strong for various nociceptive pains, although
their side effects are the limits of their usability.
In conclusion, the present study provided integrated information about the time course of pain and other disease development parameters in the CFA-induced arthritic rats, and clarified acute efficacies of different categories of analgesics in reducing the allodynia and hyperalgesia by the evaluation on PID 9 (monoarthritic phase).
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Footnotes |
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ABBREVIATIONS: CFA, complete Freund's adjuvant; PID, postinoculation day; NSAID, nonsteroidal anti-inflammatory drug.
Address correspondence to: Dr. Yukinori Nagakura, Neuroscience Research, Pharmacology Laboratories, Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co. Ltd., 21 Miyukigaoka, Tsukuba, Ibaraki 305-8585, Japan. E-mail: nagakura{at}yamanouchi.co.jp
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V. Duric and K. E. McCarson Effects of Analgesic or Antidepressant Drugs on Pain- or Stress-Evoked Hippocampal and Spinal Neurokinin-1 Receptor and Brain-Derived Neurotrophic Factor Gene Expression in the Rat J. Pharmacol. Exp. Ther., December 1, 2006; 319(3): 1235 - 1243. [Abstract] [Full Text] [PDF]
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C. D. Cook and M. D. Nickerson Nociceptive Sensitivity and Opioid Antinociception and Antihyperalgesia in Freund's Adjuvant-Induced Arthritic Male and Female Rats J. Pharmacol. Exp. Ther., April 1, 2005; 313(1): 449 - 459. [Abstract] [Full Text] [PDF]
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