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Anesth Analg 2005;101:1763-1769
© 2005 International Anesthesia Research Society
doi: 10.1213/01.ane.0000184182.03203.61

PAIN MEDICINE

The Effects of Diacerhein on Mechanical Allodynia in Inflammatory and Neuropathic Models of Nociception in Mice

Nara L. M. Quintão, MSc, Rodrigo Medeiros, MSc, Adair R.S. Santos, PhD, Maria M. Campos, PhD, and João B. Calixto, PhD

Departments of Pharmacology and Physiology, Center of Biological Sciences, Universidade Federal de Santa Catarina, Florianópolis, SC, Brazil

Address correspondence and reprint requests to João B. Calixto, PhD, Department of Pharmacology, Campus Universitário, Universidade Federal de Santa Catarina, 88049–900, Florianópolis SC, Brazil. Address e-mail to calixto{at}farmaco.ufsc.br or calixto3{at}terra.com.br.


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
In this study we analyzed the systemic antiallodynic properties of diacerhein, a drug used to treat osteoarthritis, in inflammatory and neuropathic models of nociception in mice. The effects of diacerhein were compared with those of gabapentin, a drug used clinically for the management of neuropathic pain. Similar to gabapentin, diacerhein was able to significantly reverse the mechanical allodynia induced by carrageenan. A significant inhibition of carrageenan-induced nociception was also observed when diacerhein was administered by the intrathecal but not by the intraplantar route. The treatment with diacerhein or with gabapentin also inhibited the mechanical allodynia induced by complete Freund’s adjuvant (CFA) or after the partial ligation of the sciatic nerve (PLSN). In the same range of doses, diacerhein or gabapentin did not affect the locomotor activity, motor coordination, or body temperature of the animals. The present results indicate that diacerhein produces marked antiallodynic effects in carrageenan and CFA nociception models and also inhibits the neuropathic pain after PLSN, with an efficacy similar to that observed for gabapentin. Diacerhein may be a potentially interesting tool for the management of inflammatory and neuropathic pain.


   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 References
 
Diacerhein (4,5-diacetoxy-9,10-dihydro-9,10-dioco-2-anthracenecarboxylic acid) is a drug used in some countries for the treatment of osteoarthritis (OA) (1). Clinical studies have suggested that diacerhein exerts beneficial effects on the symptoms of OA, including articular pain (2), a degenerative pathology without cure that affects the cartilaginous tissue of joints (1). Further clinical studies have suggested that diacerhein can relieve the symptoms of OA (2). Diacerhein also exhibited antiarthritic and chondroprotective effects when assessed in a rat model of OA (3). It has also been demonstrated that diacerhein prevents cartilage breakdown by reducing the levels of proinflammatory cytokines (4) through the down-regulation of gene expression and production of matrix metalloproteases or by up-regulating the production of tissue inhibitor of metalloproteases-1 in rabbit articular chondrocytes (5). Moreover, there is evidence that diacerhein also inhibits the nitric oxide production induced by interleukin (IL)-1ß in chondrocytes of patients with OA without reducing prostaglandin (PGE)2 production (6).

The primary function of pain is to protect the organism from potential tissue-damaging stimuli through the activation of spinal reflex withdrawal mechanisms. In some situations, a more insidious type of pain persists beyond its biological usefulness and compromises the quality of life (7). Chronic pain states are usually correlated with hyperalgesia (an increase in the pain elicited by a noxious stimulus) and allodynia (pain evoked by an innocuous stimulus). It is worth mentioning that chronic pain is a multi-mediated condition, where the available therapy has been found to be only partially effective. Furthermore, therapeutic tools currently used for the treatment of chronic pain are usually associated with several undesirable effects. In this context, there is intense interest on the part of the pharmaceutical industry in the identification of more effective therapeutic options without side effects for the treatment of chronic pain (8).

In the present study we analyzed the antiallodynic effects of diacerhein on acute and persistent inflammatory and neuropathic models of nociception in mice. Moreover, we sought to compare the antiallodynic effects of diacerhein with those of gabapentin, a drug used clinically for the treatment of neuropathic pain.


   Methods
Top
 Abstract
 Introduction
 Methods
Results
 Discussion
 References
 
Female Swiss mice (20–28 g) were used throughout this study. Animals were housed under conditions of optimum light, temperature, and humidity (12-h light-dark cycle, 22°C ± 1°C, 60% to 80% humidity), with food and water provided ad libitum. Experiments were conducted in accordance with the current guidelines for the care of laboratory animals and ethical guidelines for the investigation of experimental pain in conscious animals suggested by Zimmermann (9). The ethical committee of the Federal University of Santa Catarina approved the experimental procedures. There was no significant difference between the responses observed in male and female mice, although females presented slightly more intense responses in our models. The number of animals and the intensity of noxious stimuli used were the minimum necessary to demonstrate the consistent effects of the drug treatment.

For the induction of inflammatory pain, mice received an intraplantar injection of 0.05 mL of carrageenan (300 µg/paw) in the surface of the right hindpaw (10). To assess the acute effect of drug treatment, mice were treated by oral gavage with diacerhein (25, 50, and 100 mg/kg; TRB Pharma, São Paulo, Brazil) or gabapentin (70 mg/kg), both of which were dissolved in saline (NaCl 0.9%, 10 mL/kg) 1 h before the carrageenan injection. To evaluate the possible site of action (central or peripheral) of diacerhein, separate groups of animals received an intraplantar injection of diacerhein (25, 50, and 100 µg/paw) coadministered with carrageenan (300 µg/paw). Other animals received an intrathecal injection of 5 µL of diacerhein (25, 50, and 100 µg/site) 10 min before the carrageenan application. Control animals received saline (0.9%, 10 mL/kg) by the same routes of administration. The mechanical allodynia of all groups was assessed at 3, 4, 6, 24, and 48 h after the carrageenan administration as described below.

To produce a persistent inflammatory response, mice received an intraplantar injection of 0.02 mL of complete Freund’s adjuvant (CFA) (1 mg/mL heat-killed and dried Mycobacterium tuberculosis; each mL of vehicle contained 0.85 mL paraffin oil plus 0.15 mL mannide monooleate) in the plantar surface of the right hindpaw (10). Mice were treated orally with diacerhein (25, 50, and 100 mg/kg) or gabapentin (70 mg/kg) 2 h after the CFA injection. The mechanical allodynia was measured 1, 2, 4, 6, 12, and 24 h after diacerhein administration.

To evaluate the effects of chronic treatment, diacerhein (50 mg/kg) or gabapentin (70 mg/kg) were administered orally twice a day (12 x 12 h) for a period of 5 days. The treatment was interrupted on the fifth day and reinitiated after 2 days to investigate the possible development of tolerance. Control animals received saline (0.9%, 10 mL/kg). The evaluation of the allodynic response was performed 6 h after the first daily administration.

For assessing neuropathic pain, the procedure used was similar to that described by Malmberg and Basbaum (11). Mice were anesthetized with 7% chloral hydrate (0.6 mL/kg intraperitoneally). Partial ligation of the sciatic nerve (PLSN) was performed by tying 1/3 to 1/2 of the dorsal portion of the sciatic nerve. In sham-operated control groups, the sciatic nerve was exposed without ligation. Animals submitted to PLSN were treated with diacerhein (25, 50, and 100 mg/kg per os) or gabapentin (70 mg/kg per os) 4 days after the surgery (after a period of recovery) and then evaluated 1, 2, 4, 6, 12, and 24 h subsequent to diacerhein administration. To assess the long-lasting effects of drugs, diacerhein (50 mg/kg) or gabapentin (70 mg/kg) were administered orally twice a day (12 x 12 h) for 6 days. Control animals received saline (0.9%, 10 mL/kg). Allodynia was evaluated 6 h after the first daily administration, throughout the entire period of treatment.

To evaluate the mechanical allodynia, mice were placed individually in clear Plexiglas boxes (9 x 7 x 11 cm) on elevated wire mesh platforms to allow access to the ventral surface of the hindpaws. The withdrawal response frequency was measured after 10 applications (duration of 1 s each) of von Frey hairs (VFH) (Stoelting, Chicago, IL). Previous studies performed in our laboratory have indicated that 0.4 g VFH produces a mean withdrawal frequency of approximately 15%, which is considered to be an adequate value for the measurement of mechanical allodynia (10). Therefore, 0.4 g VFH alone was used in these experiments.

To investigate the possible effects of diacerhein on locomotor activity, mice were assessed in the open-field test as previously described (10). The open field apparatus consists of a transparent glass circular arena, 60 cm in diameter and 50 cm high, with a floor divided into 12 quadrants by intersecting lines drawn on the floor. The number of squares crossed with all paws ("crossings") was counted in a 6-min session. Mice were treated orally with diacerhein (50 mg/kg per os) or gabapentin (70 mg/kg per os) 1 h before testing. Control mice received saline (0.9%, 10 mL/kg).

To exclude the possible nonspecific effects of diacerhein on motor coordination, mice were subjected to the rotarod test (12). This test was performed using a horizontal rotarod device (Ugo Basile, Italy) set to rotate at 22 rpm. Mice that were able to remain on the apparatus for more than 60 s were selected and then treated with diacerhein (50 mg/kg per os) or gabapentin (70 mg/kg per os) 1 h before testing. The control group received saline (0.9%, 10 mL/kg). The time (in seconds) to falling off (in a total period of 60 s) was recorded.

Rectal temperature was measured using a digital thermometer (BD, Franklin Lakes, NJ). The probe (2 mm diameter) was dipped into liquid paraffin before insertion and held in the rectum until steady readings were obtained for 20 s. Mice were treated with diacerhein (50 mg/kg per os) or gabapentin (70 mg/kg, per os) 1 h prior to temperature measure. The control group was given saline (0.9%, 10 mL/kg).

The results are presented as the mean ± sem of 5 to 7 animals, except for the ID50 values (i.e., the dose of diacerhein that reduced the allodynic responses by 50% relative to control values), which are presented as the means accompanied by their respective 95% confidence limits. The ID50 value was determined by the use of the least-squares method. The percentages of inhibition are reported as the mean ± sem of inhibitions obtained for each individual experiment. Statistical comparison of the data was performed by two-way analysis of variance followed by Bonferroni’s post-test or one-way analysis of variance followed by Newman-Keuls’ test. P values <0.05 (P < 0.05 or less) were considered significant.


   Results
Top
 Abstract
 Introduction
 Methods
 Results
Discussion
 References
 
As observed in Figure 1A, the intraplantar injection of carrageenan was able to induce significant mechanical allodynia, as indicated by a large increase from baseline values in response to 0.4 g VFH stimulation (P < 0.001). The systemic administration of diacerhein or gabapentin produced a significant inhibition of mechanical allodynia induced by carrageenan. The effect of diacerhein remained for 48 h after the treatment, whereas that of gabapentin persisted for only up to 24 h. However, diacerhein’s antiallodynic effects were not dose-dependent, as no statistical difference was found when distinct doses of the drug were tested in this model. The inhibitions obtained 6 h after carrageenan application were: 48% ± 5%, 66% ± 6%, and 50% ± 9% for diacerhein (25, 50, and 100 mg/kg per os) and 69% ± 4% for gabapentin (70 mg/kg per os), respectively (Fig. 1A).



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  		Figure 1. Response frequency of the right hindpaw assessed in control group and in mice treated (A) orally with diacerhein (25–100 mg/kg, 1 h before) or with gabapentin (70 mg/kg per os 1 h before) at different intervals after intraplantar injection of carrageenan (300 µg/paw). Effect of diacerhein administrated by intra the cal (B; 25–100 µg/site, 10 min before) or intraplantar (C; 25–100 µg/paw, coadministrated) routes on carrageenan-induced allodynia. Significantly different from control values: *P < 0.05, **P < 0.01, ***P < 0.001 (two-way analysis of variance followed by Bonferroni‘s post hoc test).

 

In an attempt to verify the possible site of action of diacerhein, the drug was administered by intrathecal or intraplantar routes. Figure 1B demonstrates that intrathecal administration of diacerhein (25–100 µg/site; 10 min before) reduced mechanical allodynia induced by carrageenan (300 µg/paw) in a dose-dependent fashion. The estimated mean ID50 value (accompanied by the 95% confidence interval) was 55.7 (50.6–63.5) µg/site, the maximal inhibition being obtained with the dose of 100 µg/site (68.0% ± 2.4%). On the other hand, the intraplantar administration of diacerhein (25–100 µg/paw) with carrageenan (300 µg/paw) did not significantly affect mechanical allodynia (Fig. 1C).

We next investigated whether systemic treatment with diacerhein was able to reverse the persistent mechanical allodynia after CFA application. All animals presented a significant mechanical allodynia after CFA injection, as indicated by a large increase from baseline values in response to VFH (0.4 g) stimulation (P < 0.001) (Fig. 2A–B). The acute administration of diacerhein (25–100 mg/kg per os) caused a significant decrease in the mechanical allodynia induced by CFA injection, the maximal inhibition being obtained at the dose of 50 mg/kg (73% ± 1%) (Fig. 2A).



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  		Figure 2. Response frequency of the ipsilateral (A) and contralateral (B) hindpaws injected with complete Freud’s adjuvant (CFA, 20 µL/paw) in control group and in mice treated with diacerhein (25–100 mg/kg per os 1 h before) or gabapentin (70 mg/kg per os 1 h before) at different time intervals after the treatment with these drugs. Significantly different from control values: *P < 0.05, **P < 0.01, ***P < 0.001 (two-way analysis of variance followed by Bonferroni‘s post hoc test).

 

When administered chronically twice a day by the oral route, diacerhein produced a marked inhibition of the mechanical allodynia induced by CFA. On the fifth day after CFA application, only the doses of 50 and 100 mg/kg of diacerhein produced a significant inhibition of mechanical allodynia, with 75% ± 7% and 71% ± 6% of inhibition, respectively. Two days after the interruption of treatment, mechanical allodynia was re-established. When treatment was restarted, diacerhein significantly reduced mechanical allodynia, excluding the possibility of the development of tolerance (with a similar inhibition) (Fig. 2A). Again, the diacerhein effect was not dose-dependent. Furthermore, the treatment with gabapentin (70 mg/kg per os) also produced a significant inhibition of CFA-induced mechanical allodynia (without developing tolerance) with 85% ± 3% of inhibition (Fig. 2A).

Mechanical allodynia was also observed in the contralateral hindpaw after 3 days of CFA injection (P < 0.001) (Fig. 2B). The treatment of mice with diacerhein (50 and 100 mg/kg per os) or with gabapentin (70 mg/kg per os) caused a significant decrease in the mechanical allodynia in the contralateral hindpaw, with percentages of inhibition of 68% ± 14%, 84% ± 7%, and 68% ± 7%, respectively. The dose of 25 mg/kg of diacerhein did not significantly affect the mechanical allodynia in the contralateral paw (Fig. 2B).

We next evaluated the effects of diacerhein on neuropathic pain after PLSN. PLSN induced a significant increase of baseline values in response to VFH 0.4 g (P < 0.001) in comparison to the sham-operated group. Diacerhein (25–100 mg/kg per os) was markedly effective in reducing the mechanical allodynia induced by PLSN but not in a dose-dependent manner (Fig. 3). On the fifth day of treatment, only the doses of 50 and 100 mg/kg significantly inhibited mechanical allodynia caused by PLSN, with 75% ± 4% and 87% ± 5% of inhibition, respectively (Fig. 3). Gabapentin (70 mg/kg per os) also caused a significant inhibition of mechanical allodynia induced by PLSN (88% ± 4%) (Fig. 3). However, the antiallodynic effects of diacerhein and gabapentin ceased 2 days after interruption of the treatment.



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  		Figure 3. Response frequency of the right hindpaw in sham-operated and operated partial ligation of the sciatic nerve (PLSN) mice treated with saline (10 mL/kg), diacerhein (25–100 mg/kg per os 1 h prior) or gabapentin (70 mg/kg per os 1 h prior) at different intervals of time after drug treatment. Significantly different from control values: *P < 0.05, **P < 0.01, ***P < 0.001 (two-way analysis of variance followed by Bonferroni‘s post hoc test).

 

Treatment with diacerhein (50 mg/kg, per os) or gabapentin (70 mg/kg, per os), both administered 1 h before testing, did not significantly affect locomotor activity of the animals in the open-field test (Table 1). Again, diacerhein (50 mg/kg, per os) or gabapentin (70 mg/kg, per os), given 1 h before testing, did not significantly affect the motor coordination of the animals in the rotarod test (Table 1). Finally, the same treatment with diacerhein or gabapentin did not produce any significant change in basal body temperature in comparison to the control group (Table 1).


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  		Table 1. Effects of Diacerhein or Gabapentin on Locomotor Activity, Motor Performance and Rectal Temperature

 


   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
Interest in identifying new alternative options for the treatment of persistent pain of both inflammatory and neuropathic origin has increased significantly in the last decade. The currently available therapies are only partially effective, and most of the available analgesic drugs induce severe side effects that hamper their continuous use (13). Diacerhein is a drug of the anthraquinone chemical class, which is currently used in some countries for the management of OA patients and provides a significant improvement of clinical symptoms (1). In the present study, we analyzed the antiallodynic effects of diacerhein in inflammatory and neuropathic models of nociception in mice. The effects of diacerhein were compared to those produced by the analgesic gabapentin.

The nociception induced by intraplantar injection of carrageenan is widely used for the evaluation of new antiinflammatory and antihyperalgesic drugs (14). Data obtained in the present study clearly demonstrate that oral pretreatment of mice with diacerhein produces long-lasting antiallodynic effects (up to 24 h) in the acute model of pain induced by carrageenan. Very similar antiallodynic properties were observed after oral treatment with the analgesic-reference drug gabapentin. Interestingly, intrathecal administration of diacerhein was markedly effective in inhibiting carrageenan-induced mechanical allodynia in mice, whereas the intraplantar coinjection of diacerhein completely failed to alter this response. These results suggest that diacerhein exerts its effects by interfering with central, but not peripheral, nociceptive transmission pathways. It is important to mention that carrageenan evokes a very characteristic inflammatory and nociceptive response, which is mediated by different groups of endogenous substances depending on the interval of time analyzed (15–16). It is possible that diacerhein might be interfering more specifically with some group of mediators (in this case possibly prostanoids and nitric oxide). Furthermore, the delayed effects of diacerhein could be related to the time necessary for carrageenan to promote the sensitization of the central nervous system’s pathways.

To assess the effects of diacerhein in persistent models of pain, we analyzed its profile in inflammatory nociception induced by intraplantar injection of CFA or in neuropathic pain induced by PLSN. The present results clearly show that therapeutic treatment with diacerhein (as well as with gabapentin) consistently inhibited mechanical allodynia induced by intraplantar injection of CFA or after PLSN. It is noteworthy that the efficacy of both diacerhein and gabapentin was quite similar.

Intraplantar injection of CFA produces an inflammatory response that develops within a few hours, an effect that is associated with a striking modification in the activity of superficial (I and II) and deep (V and VI) laminal dorsal horn neurons receiving noxious inputs (17). On the other hand, neuropathic pain is a complex pathology that is originated and modulated in both peripheral and central nervous systems (13). Proinflammatory cytokines released by activated immune cells participate in the process of pain perpetuation. Furthermore, injured small-diameter and large-diameter primary afferent fibers show marked alterations in their pattern of excitability and conduction during evoked and spontaneous activity. These alterations reflect changes in the density and/or operating characteristics of multiple ion channels, including the novel expression of calcium ion channels (18). A massive inflammatory response is observed at the time of maximal tactile allodynia after peripheral nerve injury. Inflammatory cells, such as monocytes/macrophages and cytokines (e.g., IL-6, IL-1 and tumor necrosis factor-{alpha}), seem to be closely linked to the presence to tactile hypersensitivity (19). In addition, the sensitization of primary afferent nerve fibers by proinflammatory cytokines, such as IL-1ß and tumor necrosis factor-{alpha}, after peripheral nerve injury seems to be mediated by a complex signaling cascade involving the secondary production of nitric oxide, bradykinin, and PGE (20).

The mechanisms through which diacerhein exerts its antiallodynic effects are unknown. It has been reported that diacerhein is able to abolish neutrophil migration in carrageenan pleurisy model in mice (21). It has also been found that diacerhein is effective in reducing IL-1 converting enzyme activity and that it decreases both IL-1ß and IL-18 levels in human osteoarthritic cartilage cells (22). Moreover, in vitro studies have shown that diacerhein has the ability to reduce the inducible nitric oxide synthase expression and nitrite production induced by IL-1ß (23). It has been demonstrated that oral treatment with diacerhein (in doses ranging from 10 to 200 mg/kg) results in a marked inhibition of paw edema evoked by carrageenan, dextran, and zymosan in rats (24). These authors have also demonstrated that diacerhein, given alone or coadministered with naproxen, is effective in reducing inflammatory responses after intraplantar injection of CFA in rats (24). Therefore, the antiallodynic actions of diacerhein (first reported here) could be, at least partially, related to the blocking of one or more of these mechanisms, depending on the dose and administration pathway. Further functional, electrophysiological and molecular studies are necessary to clarify the precise mechanisms through which diacerhein exerts its antiallodynic actions in persistent models of pain.

Of relevance are the results indicating that diacerhein and gabapentin presented similar efficacy in all analyzed models of nociception. Gabapentin is an anticonvulsant drug that has been used clinically for the treatment of long-lasting pain states. The primary site of action of gabapentin is the central nervous system, with little or no activity in peripheral tissues (25). There is evidence that gabapentin interacts specifically with the {alpha}2{delta} subunit of voltage-sensitive calcium channels (26). To what extent diacerhein might interfere with the same pathways as gabapentin remains to be investigated.

Interestingly, the antiallodynic actions of diacerhein, at a pharmacologically active dose, do not seem to be directly associated with nonspecific sedative or muscle-relaxant actions, as this drug, at therapeutic doses, did not affect the performance of mice on the rotarod apparatus or their locomotor activity in the open-field test. Furthermore, diacerhein did not cause hypothermia in mice. These data are quite favorable to a possible therapeutic use for diacerhein for treating long-lasting pain, when chronic treatment is required. Nevertheless, well-conducted clinical trials are still necessary to confirm such a possibility.

In summary, the data reported in the present work demonstrates for the first time that diacerhein, a drug used clinically to treat OA, has relevant oral antinociceptive properties for persistent inflammatory or neuropathic nociception in mice. Diacerhein has an efficacy comparable to that observed for gabapentin. The mechanisms through which diacerhein exerts its antinociceptive actions still remain currently unclear and require further study. Diacerhein could well constitute a new and attractive alternative for the management of human persistent inflammatory and neuropathic pain.


   Footnotes
 
Supported, in part, by grants from CNPq (Conselho Nacional de Desenvolvimento Científico e Tecnológico), FINEP (Financiadora de Estudos e Projetos), PRONEX (Programa de Apoio aos Núcleos de Excelência) and FUNCITEC (Fundação de Ciência e Tecnologia do Estado de Santa Catarina), Brazil. N.L.M.Q. and R.M. are PhD students in pharmacology receiving a grant from CAPES (Coordenação de Aperfeiçoamento de Pessoal de Nível Superior) and CNPq, respectively. M.M.C. holds a Postdoctoral fellowship from CAPES.

Accepted for publication June 9, 2005.


   References
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 

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Lippincott, Williams & Wilkins Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins with the assistance of Stanford University Libraries' HighWire Press®. Copyright 2006 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999 HighWire Press