Anesth Analg 2005;101:457-464
© 2005 International Anesthesia Research Society
doi: 10.1213/01.ANE.0000158471.41575.F0
PAIN MEDICINE
A Behavioral and Pharmacological Validation of the Acetone Spray Test in Gerbils with a Chronic Constriction Injury
Kris Vissers, MD, PhD*, and
Theo Meert, PhD, PhD
*Multidisciplinary Pain Center, Ziekenhuis Oost-Limburg, Genk, Belgium; J&J PRD, a division of Janssen Pharmaceutica, Beerse, Belgium
Address correspondence and reprint requests to Kris Vissers, MD, PhD, Multidisciplinary Pain Center, Ziekenhuis Oost-Limburg, Campus André Dumont, Stalenstraat 2, 3600 Genk, Belgium. Address e-mail to kris.vissers{at}skynet.be.
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Abstract
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Cold and mechanical allodynia are important symptoms in patients with neuropathic pain. The study of cold allodynia in animals can help us to understand the underlying pathophysiological mechanisms of neuropathic pain and to validate drugs. The evaluation of cold allodynia in gerbils with a chronic constriction injury of the sciatic nerve on the cold plate is not always stable. We developed a new application method of acetone using a specific spray technique with an Eppendorf® multistepper pipette. The chronic constriction injury of the sciatic nerve in gerbils resulted in a long-lasting mechanical and acetone spray-induced hyperreactivity throughout the testing period, which is clearly different from what was seen in sham-operated animals. The acetone spray test incorporates a multimodal stimulus different from direct cold stimulation. The reactivity to the acetone spray coincides in time and strength with the reactivity observed in mechanical allodynia in gerbils and with mechanical and thermal allodynia in other species. Furthermore, a pharmacological validation of the acetone spray test by different reference compounds was performed. Different compounds effective in neuropathic pain models in rodents influence the hyperreactivity to the acetone spray after acute and chronic administration. This study indicates that the multimodal acetone spray test is a valuable tool in the study of neuropathic pain in rodents.
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Introduction
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Neuropathic pain is characterized by the presence of allodynia and hyperalgesia and can be provoked in several animal models (1–3). The neuropathic pain behavior in these specific models is attributed to peripheral or central sensitization either in the afferent fibers or in the central nervous system (4). Mechanical, thermal, and chemical stimuli are used to evaluate the specific pain behavior of the animals (1,5). Patients with neuropathic pain conditions may suffer cold and pressure allodynia that can seriously interfere with the quality of life (6). Cold allodynia is easily measurable in animal models for the study of neuropathic pain behavior and can be an important tool to unravel the underlying pathophysiological mechanisms and to validate drugs. In rodents, different methods for testing cold allodynia have been described: paw or tail withdrawal after immersion in cold water (7,8), water-alcohol bath (9), ethyl chloride spray (10), direct application of acetone (11–13), and contact with a Peltier thermode (14) or a cold plate (1,15). Each test has advantages and disadvantages. With the immersion tests or Peltier devices, variable temperatures can be used but animals must be restrained or sedated and the contact area may vary; an ethyl chloride spray allows the observation of freely moving animals, but it produces olfactory and auditory stimuli, which can lead to conditioned responses (15). The cold plate test enables observation of freely moving animals in a minimal-stress environment and variation of temperatures and observation time, but the measurement depends on the contact of the tested limb with the cold plate in animals that, as the result of a specific nerve injury, withdraw a limb or put an insignificant weight on the affected limb, which can cause substantial variations (15). In the acetone test the duration of exposure to cold is dependent on the spread and the evaporation of acetone. The acetone spray test incorporates not only an innocuous cold stimulus but simultaneously, because of the spray technique and the chemical composition of acetone, possible cold, mechanical, and chemical stimulations. The various characteristics of the acetone spray test described in this study, along with its ease and standardization of use, make it possible to apply this multimodal stimulus in different animal species.
Because the pharmacological profile of a specific human receptor is not always comparable to that of the equivalent receptor in a given species, it is necessary to study those animal species in which the targeted receptor most closely resembles the human one (16). For instance, on the basis of binding studies, the NK-1 receptor of gerbils was found to be comparable to the human NK-1 receptor, which makes the gerbil model suitable for studying the effects of substance P and neurokinin receptor antagonists (17). In a previous study, the chronic constriction injury (CCI) model of neuropathic pain (1) was adapted for use in the gerbil (17). CCI of the sciatic nerve clearly resulted in long-lasting mechanical hyperalgesia whereas, on the cold and warm plate, a cold and heat allodynia could not be uniformly demonstrated (17). The acetone spray test can be a more appropriate alternative to the cold plate test for the evaluation of cold allodynia in this species. In this study, the acetone spray test in CCI gerbils was evaluated and pharmacologically validated by the use of various reference drugs that target pain transmission.
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Methods
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The CCI model of neuropathic pain (1) was modified (17) and performed in adult male gerbils (Meriones unguiculatus, Crl(MON)BR, Charles River Deutschland, Sulzfeld, Germany) weighing 60–75 g at the beginning of the experiments. The gerbils were housed individually in plastic cages under artificial lighting with a fixed 12-h light-dark cycle. Food and water were available ad libitum. The guidelines for animal research issued by the International Association for the Study of Pain were adhered to, and the Institutional Ethical Committee approved the study.
All animals were anesthetized with pentobarbital (60 mg/kg body weight). In one group of animals the sciatic nerve was exposed, and 4 loose chromic catgut ligatures (6-0 chromic catgut; Ethicon Inc, Somerville, NJ) were placed around the sciatic nerve (1,17). In another group of animals a sham operation was performed by exposing but not ligating the sciatic nerve. After checking for hemostasis, the muscle, the adjacent fascia, and the skin were closed with sutures.
Mechanical allodynia was assessed by placing the animals in cages with a metal mesh floor and touching the plantar surface of the hindpaw with a metal probe (tip diameter, 1 mm) connected to a pressure transducer (Somedic Sales AB, Hörby, Sweden) and increasing the force applied to the paw until the animal withdrew it (17,18). The animals were allowed to habituate to the testing chambers for 30 min before the first measurement. The mean of three consecutive readings on both hindlimbs in each animal was used for analysis.
For an acetone or water challenge test, the animals were housed in a similar fashion as in the Von Frey test. After habituation, 50 µL fluid (acetone or water) was vaporized on the plantar surface of the paw with the aid of an Eppendorf® multistepper pipette with a Combitip holding 2.5 µL (Fig. 1). The total duration of paw withdrawal, defined as the total time of flinching, licking or biting of the limb, was measured over a 5-min test period. For the water spray test, mineral water at 0°C, 22°C, and 35°C was used.
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Figure 1. Photograph of the acetone spray test in the laboratory showing the gerbil in the observation cage with open mesh floor and the Eppendorf® pipette projecting the acetone on the hindpaw of the animal.
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In a first experiment, the reactivity of CCI gerbils to acetone was evaluated. Animals were screened with the Von Frey test on both hindpaws. Groups of 7 to 12 CCI and sham-operated animals were challenged on the ipsilateral and contralateral hindpaws with either acetone or water. The animals were tested 7 days after surgery.
In a second experiment, the effects of an acetone spray were repeatedly evaluated over time after surgery. A group of 10 CCI and sham-operated animals were tested 1 day before the operation and on several days up to 34 days thereafter. Also in this experiment, to analyze tactile allodynia, a Von Frey test was always performed before the acetone spray test.
A third series of experiments evaluated the effects of several compounds on acetone-induced hyperreactivity in CCI animals. On each test day, animals were screened for mechanical allodynia (>50% difference in nearly 99% of the tested animals between operated and non-operated hindpaws). Only animals with a well defined mechanical allodynia in the operated hindpaw (i.e., lifting of the hindpaw on <15 g) were used for further drug testing. Only those dosages that were proven not to cause sedation in specific screening tests, such as the Rotarod and the open field analysis, were withheld. The tests were performed from days 7 to 25, post-CCI operation. Each animal was administered a given compound only once. After each pharmacological test a washout period of 4 days was observed before another compound was tested. The test compounds used for a dose-response evaluation were saline or vehicle, the tricyclic antidepressants amitriptyline, desipramine, and imipramine, the anticonvulsants carbamazepine, gabapentin, lamotrigine, and topiramate, the N-methyl-d-aspartic acid (NMDA) antagonist MK-801, the NK-1 antagonist R116301, the para-aminophenol paracetamol, the µ-opioid agonists codeine, fentanyl, and morphine, and the analgesic tramadol. Drugs were injected subcutaneously 60 min before testing. Five animals per drug treatment and 60 controls were evaluated.
In the fourth experiment, the effects were tested of a subchronic treatment with vehicle, and one of the following reference analgesics at different dosages: amitriptyline (10–40 mg/kg), carbamazepine (10–40 mg/kg), gabapentin (10–40 mg/kg), morphine (0.63–2.5 mg/kg), or topiramate (10–40 mg/kg). Animals (drug treatment group: n = 7; controls: n = 14) were randomized at day 4 after surgery on the basis of the results of the Von Frey and the acetone spray tests. From day 7 postoperation, the animals were treated subcutaneously twice daily for up to 18 days. Behavioral testing was always performed in the morning 1 h after drug administration at 7, 11, 14, and 18 days after surgery. Only the data on acetone testing are reported in this article.
Results are expressed as the mean (± sem). The Mann-Whitney U-test with correction for multiple comparisons and the Wilcoxon test were used for statistical analysis as appropriate. The two-tailed significance level was set at P < 0.05.
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Results
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In gerbils, a CCI operation of the sciatic nerve induced a mechanical allodynia of the operated hindpaw that started within 1 day of surgery and lasted for more than 34 days. The automatic Von Frey test showed a decrease in the pressure threshold compared with the preoperation values in the ipsilateral hindpaw at all time points during the testing of the CCI gerbils from day 1 to day 34. This mechanical allodynia was not observed in the contralateral hindpaw or in the sham-operation animals (Fig. 2). The automatic Von Frey test was also performed to compare mechanical allodynia in the animals used in the acetone and in the water spray test. No significant differences were found between these two experimental groups (P > 0.05) (Table 1).
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Figure 2. Effects on sham-operated and chronic constriction injury (CCI) gerbils in the Von Frey test. The mean (± sem) paw pressures (in grams) are given for the ipsilateral and contralateral hindpaw (HP). Statistically significant differences between groups are indicated by asterisks; significance level was P < 0.05 (two-tailed).
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A water spray test at different temperatures, used as both a temperature and a mechanical control for the acetone spray test, disclosed no differences in pain behavior between sham-operated and CCI animals for either the operated and non-operated hindpaw (P > 0.05) (Table 2).
The acetone spray test resulted in a significant increase in reactivity in CCI animals for the operated hindpaw (P < 0.05), whereas in the non-operated hindpaw of the CCI animals and both hindpaws of the sham-operated animals only limited pain reactivity was observed (Table 3).
The increased duration of paw withdrawal after the acetone test in CCI gerbils displayed a time course comparable to that of mechanical allodynia (Fig. 3). Hyperreactivity to the acetone spray for the CCI hindpaw persisted for at least 34 days after surgery. During the same period the acetone spray induced no increased lifting behavior in the sham-operated or non-operated animals. (P < 0.05).
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Figure 3. Effects of the acetone spray over 34 days in the ipsilateral hindpaw (HP) of chronic constriction injury (CCI) (open circles) and sham-operated (triangles) gerbils. Statistically significant differences between groups are indicated by asterisks; significance level was P < 0.05 (two-tailed).
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After acute subcutaneous treatment with vehicle injection, the CCI animals showed on average an increase in withdrawal reactivity in the acetone spray test of 110.2 ± 8.7 s. After acute treatment, opioids, such as codeine, fentanyl, and morphine, and tricyclic antidepressants, such as amitriptyline, desipramine, and imipramine, completely suppressed the acetone-induced hyperreactivity in a dose-dependent manner (P < 0.05). Anticonvulsants, such as carbamazepine, gabapentin, lamotrigine, and topiramate, the NMDA antagonist MK-801, the NK-1 antagonists R116301, and the analgesic tramadol resulted in a clear reduction of the acetone-induced hyperreactivity. The effect of the para-aminophenol paracetamol was limited (Table 3).
A dosage of 2.5 mg/kg morphine resulted in a complete inhibition of the acetone-induced hyperreactivity on day 7 after the CCI operation (P < 0.05). The morphine-induced inhibition of reactivity diminished over time after repeated treatment, and at day 18 after surgery, differences among the different treatment groups and the vehicle controls were no longer present (P > 0.05) (Fig. 4, Tables 3 and 4).
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Figure 4. Effects over time of several reference compounds in the acetone spray test in chronic constriction injury (CCI) gerbils. The mean (± sem) durations of paw withdrawal during a 5-min measurement period are given for different time points before and during treatment. Statistically significant differences from vehicle controls are indicated by an asterisk (two-tailed, P < 0.05).
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Table 4. Effect on Body Weight on Days 4, 7, and 14 of Repetitive Treatment with Reference Compounds in the Acetone Spray Test in Chronic Constriction Injury Gerbils
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Different dosages (10–40 mg/kg) of amitriptyline resulted in a dose-dependent inhibition of the acetone-induced hyperreactivity, which persisted throughout the testing period from day 7 to day 18. Clear effects on body weight were present at 40 mg/kg, the largest dosage tested (Fig. 4, Table 3).
Carbamazepine and topiramate resulted in a dose-dependent reduction but not a complete inhibition of the acetone effects. Both compounds significantly decreased body weight at 40 mg/kg (P < 0.05) (Fig. 4, Tables 3 and 4).
Also for gabapentin, a dosage of 40 mg/kg resulted in a reduction of the acetone-induced hyperreactivity, an activity that also persisted over time; no effects on body weight were observed (Fig. 4, Tables 3 and 4).
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Discussion
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The CCI of the sciatic nerve in gerbils resulted in a long-lasting mechanical allodynia and acetone spray-induced hyperreactivity for the entire 1-month testing period. For all animals in the experiments, a clear differentiation between the CCI and the sham-operated hindpaw was possible. Furthermore, both tests also clearly distinguished between sham-operated and CCI animals, illustrating that the acetone spray test could be used to differentiate between neuropathic and control animals. Comparable results have been obtained by other investigators who used mechanical and cold allodynia in the CCI model in different animals, such as mice (19), rats (20), and primates (11). Previously, we described the validation of the automatic Von Frey test in gerbils as a useful tool for differentiating normal from neuropathic animals (17). In this experiment, we demonstrated that the acetone spray test can give comparable results and that pharmacological validation of this stimulus modality by different reference compounds is possible. It has been shown that cold-induced allodynia in gerbils as measured with the cold plate test resulted in variable responses (17) that may be related to thermoregulative adaptations of these animals that enable survival in extreme desert temperatures (21,22). In CCI gerbils, the evaluation of the sensorial changes induced by the acetone spray test showed that this test was reliable, that all animals responded maximally in it, and that it did not result in the development of tolerance to the stimulus.
The technique of acetone application performed in these experiments is different from that described by Choi et al. (12), in which an acetone droplet was applied gently to the heel of a rat and the acetone spread passively. In contrast, we projected the acetone by means of a standardized Eppendorf® multistepper pipette. This method had a thermal and mechanical impact on the hindpaw of the animal. Two distinct types of mechanical allodynia were detected: static mechanical allodynia induced by application of pressure on the skin and dynamic mechanical allodynia induced by lightly stroking the surface of the skin (23,24). Both mechanical responses are present in this stimulus modality of the acetone spray test and they are signaled by different sensory fibers (24). The increased responsiveness of CCI animals to the acetone spray cannot be explained simply by a mechanical or cold allodynia or both because the projection of water at different temperatures with comparable mechanical impact on the peripheral sensory field caused no increase in sensitivity in the CCI animals.
Other investigations raise the possibility of chemical stimulation by acetone. Bennett and Xie (1) established that the application of mustard oil caused an increased responsiveness of the hindpaw of CCI-operated rats. The application of mustard oil in humans causes a burn and secondary hyperalgesia, which demonstrates a central sensitization induced by a chemical stimulus (25). The application of acetone on the skin in humans causes a direct shrinkage reaction that cannot be attributed to cold alone. Algogenic chemicals could be more active than heat in the induction of central sensitization with stimuli of similar intensity, depending on the specific conducting fibers. Because reactivity in the acetone spray test was stable and long lasting in this set of experiments in CCI gerbils and because thermal allodynia was not long lasting and not very reproducible with a cold plate in previous experiments (17), the acetone spray test does not seem to model a pure thermal cold allodynic effect. On the basis of these observations, the acetone spray test can be described as incorporating a more complex, multimodal stimulus comprising simultaneously active cold, mechanical, and chemical components, and probably this multimodal stimulus activates multiple types of nociceptors in the peripheral nociceptive field of the affected hindpaw of CCI gerbils.
Various new therapeutic options for neuropathic pain have emerged (26). However, the correlation between animal data and the results observed in clinical practice vary (27). Therefore, the specificity of the animal model and the stimulus modality used may be important in understanding the predictability of clinical efficacy (28). The pharmacological validation of the acetone-spray test has correlated well with other stimulus modalities in animals with a neuropathic pain behavior. The reversal of cold allodynia induced by the cold plate test in rats and gerbils with clinically used analgesics has resulted in comparable outcomes. Consequently, the acetone spray test is a good model for evaluating the effect of novel treatments in neuropathic pain conditions in gerbils.
A pharmacological validation and analysis of different stimulus modalities provides an opportunity to look more deeply into the specific mechanisms of neuropathic pain in different pain conditions (28). Most treatments have focused on drugs that reduce neuronal hyperexcitability either peripherally or centrally (29). In this approach, the predictive validity of the drug under study is important as a prognostic factor in the clinical setting. In the animal models for the investigation of neuropathic pain that are most frequently used today, a good predictive validity of pharmacological studies can be achieved (28). The CCI model has generated the largest body of evidence on this predictability. However, no drug is effective in all neuropathic pain patients. Therefore, examination of the specific mechanism underlying the neuropathic pain condition and a meticulous description of the conditions of increased pain behavior can be important in the future validation of different targets. Currently, most neuropathic pain conditions are described in terms of the subjacent pathology and anatomical site. This classification does not consider the underlying mechanism (29). As it is rather difficult to evaluate spontaneous neuropathic pain behavior in animals, further validation of the different stimulus-provoked pain behaviors is needed. The thermal, mechanical or chemical exogenous stimuli generally used in research are mostly unimodal and possibly activate specific nociceptors and fibers. However, the induction of neuropathic pain in patients is mostly multimodal and the response varies only with the specific condition causing the neuropathic pain.
Because the reactivity to the acetone spray coincides in time and strength with the mechanical allodynia in gerbils and with mechanical and thermal allodynia in other species and because the hyperreactivity to the acetone spray can be influenced by different pharmacological compounds, with a proven efficacy in several other neuropathic pain models in rodents, the present pharmacological results indicate that the multimodal acetone spray is a valuable tool to study neuropathic pain.
Pharmacological validation has also been obtained in chronic experiments. For morphine, tolerance to analgesia in neuropathic animals after repeated administration is consistent with the findings of others (30,31). For amitriptyline, carbamazepine, topiramate, and gabapentin, more stable efficacy on repeated administration has been found; this has been confirmed by clinical evidence (32). Whether repetitive stimulation of the animals can influence the specific pharmacological response in a long-term treatment regimen of several weeks remains to be elucidated.
In conclusion, the present results indicate that the acetone spray test can be used as a multimodal stimulus to validate altered nociceptive processing in gerbils with a CCI. Further validation studies need to be conducted to explore the mechanism of receptor, sensorial nerve, and spinal cord activation in the acetone spray test.
The authors wish to thank Vesa Kontinen, MD, PhD for his comments on the manuscript, Nicole Van den Hecke and Jeffrey Lubbin for editing the paper and Ria Biermans and Frank Geenen for their assistance with the laboratory work.
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Footnotes
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Accepted for publication January 20, 2005.
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Abstract
Introduction
