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Anesth Analg 2004;99:457-463 © 2004 International Anesthesia Research Society doi: 10.1213/01.ANE.0000131967.69309.4F
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Abstract |
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Progressive tactile hypersensitivity (PTH) manifesting after sciatic nerve crush and spared nerve injury (SNI) are two distinct rodent experimental models of neuropathic pain. PTH develops months after recovery from the nerve crush in response to repeated intermittent low-threshold mechanical stimulation of the reinnervated sciatic nerve skin territory and represents a model of stimulus-induced pain. SNI is characterized by an early and sustained increase in stimulus-evoked pain sensitivity in the intact skin territory of the spared sural nerve after sectioning of the two other terminal branches of the sciatic nerve. We examined the effects of morphine (0.5–10 mg/kg), gabapentin (30–200 mg/kg), MK801 (0.01–0.02 mg/kg), amitriptyline (10–25 mg/kg), and carbamazepine (5–7.5 mg/kg) in both models. Morphine, gabapentin, and carbamazepine both reversed and prevented stimulus-induced PTH, whereas MK801 and amitriptyline reduced but did not prevent stimulus-induced PTH. In contrast, the stimulus-evoked behavioral hypersensitivity in the SNI model was poorly modified by these drugs. Independent neuropathic pain models show differential sensitivity to analgesic drug treatment. We suggest that this is due to the different mechanisms responsible for the neuropathic pain-related behavior. Multiple models are required, therefore, to study the mechanisms that contribute to neuropathic pain and to predict analgesic efficacy for different components of the neuropathic pain syndrome.
IMPLICATIONS: Analgesic effects of drugs often used for the treatment of neuropathic pain were evaluated in two independent animal models of neuropathic pain. The differential analgesic response between models suggests that different mechanisms are involved and that multiple models are required to study mechanisms and predict drug efficacy for neuropathic pain.
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Introduction |
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Peripheral neuropathic pain is characterized by a lesion to or dysfunction of the primary sensory neurons, and patients experience spontaneous and evoked pain. Gabapentin and other anticonvulsants, tricyclic antidepressants, opioids, and N-methyl- D-aspartate (NMDA) receptor antagonists ameliorate symptoms, but with relatively poor efficacy and significant side effects (1).
The underlying mechanisms of neuropathic pain are multiple, including ectopic activity and spontaneous discharge in primary sensory neurons, phenotypic changes, loss of inhibition and central sensitization, alteration of descending controls, and thalamic and cortical functional and structural reorganization (2,3). Different treatments may act on different facets of the global pain syndrome. NMDA receptor antagonists may reduce central sensitization and ion channel blockers ectopic activity, and nonselective monoamine reuptake inhibitors may boost inhibition. A major challenge is the need to identify the mechanisms responsible for neuropathic pain in patients for more accurate diagnosis, targeted therapy, and development of new analgesics (4).
Animal neuropathic pain models have been designed to mimic the pain symptoms encountered in humans. Injection of chemicals, nerve transection, and inflammation have all been used to model metabolic and toxic neuropathies, trauma, nerve compression, and neuritis (5). These models present signs of spontaneous pain-related behavior as well as stimulus-evoked pain-related behavior. Stimulus-evoked pain is pain immediately generated by an external innocuous stimulus (allodynia) or noxious stimulus (hyperalgesia). A newly recognized element of pain hypersensitivity is progressive tactile hypersensitivity (PTH), a cumulative buildup of mechanical pain sensitivity induced by successive intermittent light tactile stimulation that is present after peripheral inflammation (6) and after a peripheral nerve crush injury with reinnervation of the skin (7) but that is absent in the spared nerve injury (SNI) model (8). PTH is an example of stimulus-induced pain, where external stimuli alter sensory processing to generate pain hypersensitivity-related behavior that long outlasts the initiating stimulus. We have now compared the response of stimulus-evoked pain in the SNI model and stimulus-induced pain (PTH after sciatic nerve crush) with morphine, gabapentin, carbamazepine, amitriptyline, and the NMDA receptor antagonist MK801.
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Methods |
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Experiments were approved by the Animal Care Committee of the Massachusetts General Hospital according to the ethical guidelines of the International Association for the Study of Pain (9). Male Sprague-Dawley rats (Charles River Laboratories, Wilmington, MA), initially weighing 200–220 g, were housed in cages with a thick sawdust bedding, had free access to water and food, and were exposed to a standard 12:12-h light cycle. A total of 189 animals were used for the experiments.
All surgery was performed with rats under halothane anesthesia (1.5%–3.0%). For sciatic nerve crush, the sciatic nerve was exposed at midthigh level, and the entire nerve was crushed by a pair of hemostat forceps with protective pads placed perpendicularly to the sciatic trunk for 30 s (7). For SNI, the sciatic nerve was exposed at the midthigh level, and the tibial, common peroneal, and sural nerves were identified. The tibial and peroneal nerves were ligated with 5-0 silk and cut, with particular attention to prevent any lesion to the sural nerve (8). Animals were habituated to the tester, the environment, and the handling procedures before commencement of testing.
For PTH, 10 wk after sciatic nerve crush surgery, a first assessment of PTH was performed. This is the earliest time that PTH is reliably present after crush injury (6). Mechanical hypersensitivity was determined by using a series of calibrated von Frey monofilaments (1.0–200.0 g) applied 5 times on the lateral dorsal side of the hindpaw, ipsilateral to the nerve lesion. The mechanical withdrawal threshold corresponded to the minimum force (in grams) required to elicit a reproducible flexor withdrawal movement. Once the baseline threshold was determined, 8 light strokes were applied manually at 1 Hz to the dorsum of the paw at 5-min intervals, and this was continued for 120 min. The mechanical withdrawal threshold was reassessed immediately after the application of the train of light touches at the same interval of 5 min during the entire test period (7).
Mechanical and thermal sensitivity tests were performed before (baseline sensitivity) and after the SNI surgery twice a week before the pharmacological testing. von Frey monofilaments were applied in ascending forces to the lateral part of the plantar side of the paw until the animal withdrew the paw on at least one of five repeated stimuli (withdrawal threshold in grams). Paw withdrawal duration (in seconds) was also recorded after mechanical nociceptive stimulation (pinprick; a brief stimulus sufficient to indent but not penetrate the skin) and application of cold (an acetone drop placed on the paw) in the same territory (8). The pharmacological testing protocol was initiated, with a recording first of the baseline value followed by injection of the drug or the control saline solution and 2 tests at 20 or 60 min and 120 min. The treated and control animals were tested at the same experimental time, and the observer was blinded to the treatment applied (saline or drug).
Two weeks after the first control PTH measurements (i.e., 12 wk after the crush injury), the effect of intraperitoneal (ip) injections of morphine (0.5 and 2.5 mg/kg), amitriptyline (10 mg/kg), gabapentin (30 mg/kg), carbamazepine (5 mg/kg), and MK801 (0.01, 0.05, and 0.1 mg) was examined. The drugs were administered either 15 min before the PTH test period (pretreatment) or in a separate set of studies during the period of tactile stimuli, 60 min after its beginning (posttreatment). In some groups, the animals received several administrations of a drug after a washout period of at least 4 days.
For SNI, 2 and 4 wk after the development of the stimulus-evoked pain-related behavior, the behavioral tests were performed before and 20 and 120 min after the ip administration of 0.5, 1.0, 2.5, 5, and 10.0 mg/kg of morphine (or saline for the control groups). Two weeks after the SNI, carbamazepine (5 and 7.5 mg/kg), gabapentin (30 and 60 mg/kg), and saline were injected, and the same testing procedure was performed. In some groups, the animals received a second administration of a drug after a washout period of at least 4 days. Thresholds for all tests in these animals were verified to have completely returned to pretreatment baselines.
Two to 4 wk after SNI, the analgesic effect of chronic dosages of the following drugs on mechanical and thermal allodynia/hyperalgesia was investigated: over 5 days, gabapentin (40 and 100 mg/kg twice a day), amitriptyline (10 and 25 mg/kg), and carbamazepine (3 x 5 mg · kg–1 · d–1) were all administered ip. Behavioral testing was assessed 1, 2, 3, and 4 days after the beginning of drug administration, as well as 48 or 72 h after the last dose. Control groups of animals injected with ip saline 0.9% were always tested simultaneously during the same testing session.
For intrathecal delivery of MK801 in the SNI model, a 32-gauge catheter was inserted adjacent to the lumbar enlargement of the spinal cord in the subarachnoid space (10). After sensory-motor assessment, to exclude surgical sensory deficits, SNI surgery was performed. Thirteen days after SNI, 10 and 20 µg of MK801 or the same volume of saline was injected. Pain-related behavior was recorded 60 min and 2 h after the injection—times when peak action would be expected (11).
Data in the PTH experiments were expressed as mean ± SEM of the recorded mechanical withdrawal threshold as a percentage of the initial baseline value. A two-way analysis of variance for repeated measures was used to evaluate the overall effect of the treatment compared with PTH without drug followed by Dunnett’s test or a post hoc Student’s t-test. Data for SNI experiments were expressed as mean ± SEM of the recorded withdrawal threshold or withdrawal duration and were analyzed by using a two-way analysis of variance for repeated measures to compare the saline and treated groups, followed by post hoc Student’s t-tests and Bonferroni’s correction when appropriate. von Frey series present constant logarithmic differences between hairs, and logarithmic-transformed values were used for the analysis, enabling analysis of variance tests. Analyses were performed with JMP (Version 5.01; SAS Institute Inc., Cary, NC). Significance was chosen at P 
0.05.
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Results |
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All sciatic nerve crush-injured rats studied displayed PTH 10 wk after the crush lesion (Fig. 1A). The mechanical withdrawal threshold decreased progressively to 30% of its prestimulation basal value after 120 min of repeated intermittent innocuous mechanical stimulation.
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The establishment of PTH was prevented by gabapentin (30 mg/kg), morphine (2.5 mg/kg), and carbamazepine (5 mg/kg) (Fig. 1B). No statistically significant difference was observed between recording with and without treatment or between baseline and treated and nontreated. These drugs also reversed established PTH when administered 1 h after stimulation was started (Fig. 1C). MK801 (0.1 mg/kg) and amitriptyline (10 mg/kg) had smaller effects (Fig. 1, D and E). When gabapentin 30 mg/kg was administered 15 min before the start of the repeated tactile stimulation test (Fig. 1B), the mechanical withdrawal threshold did not decrease from baseline values over the entire test period (P > 0.05), in comparison to the significant threshold decrease during the control test period in the same animals (to 26.5% ± 17.0% of baseline; P < 0.01). The same dose of gabapentin administered 60 min after the beginning of the test reversed the effect induced by the repeated mechanical stimulation: the mechanical withdrawal threshold decreased at 60 min to 45.0% ± 15.0% of its baseline value before the drug administration and returned to 88.9% ± 10.9% (Fig. 1C). Similar actions (preventing PTH when administered before the test stimuli and reversing established PTH when administered during the course of the stimuli) were found after the administration of carbamazepine 5 mg/kg and morphine 2.5 mg/kg (Fig. 1, B and C). A smaller dose of morphine (0.5 mg/kg) did not significantly affect PTH (data not shown).
After the administration of amitriptyline (10 mg/kg), an attenuation of PTH (Fig. 1, D and E) was found, rather than a complete reduction (at 120 min: 54.1% ± 10.0% vs 26.7% ± 7.9% and 68.5% ± 0.0% vs 31.1% ± 7.9% when injected 15 min before and 60 min after the beginning of the test, respectively). MK801 (0.1 mg/kg) also attenuated PTH (Fig. 1, D and E). Smaller doses of MK801 (0.01 and 0.05 mg/kg) did not affect the course of stimulus-induced pain-related behavior (data not shown). Larger doses of systemic MK801 and amitriptyline were attempted but abandoned because the animals were sedated or showed abnormal behavior.
Morphine administered 2 or 4 wk after SNI surgery produced no analgesia except at the largest dose tested (10 mg/kg; Fig. 2A). Injection of this dose reduced the withdrawal duration evoked by acetone stimulation (0.1 ± 0.1 s versus 4.1 ± 1.5 s) compared with the control group (P < 0.05), but this dose also altered the contralateral response to mechanical stimulation (Fig. 2B) (49.1 ± 8.3 g versus 19.9 ± 4.6 g, respectively; P < 0.05), showing generalized analgesia and sedation. Gabapentin 30 and 60 mg/kg did not significantly change the mechanical and thermal evoked allodynia/hyperalgesia compared with preinjection or control group values (P > 0.05; Fig. 2C). Carbamazepine also did not change the SNI-induced pain-related behavior (P > 0.05; Fig. 2D). To simplify the overall data presentation, only significant changes or representative data for drugs are shown in the figures.
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To overcome the problem of the side effects produced by systemic MK801 that limit the dose that can be used, the drug was intrathecally delivered. MK801, at 20 µg, reduced the withdrawal behavior induced by acetone compared with saline controls (P < 0.01; n = 7 in each group; Fig. 2F), although no statistically significant effect was found on mechanical hypersensitivity (P > 0.05; Fig. 2E). At the smaller dose, no significant effects of intrathecal MK801 were observed (data not shown).
Repeated delivery over 5 days of 40 and 100 mg of gabapentin did not affect the mechanical threshold after SNI (P > 0.05) or in the control groups (Fig. 3A; P > 0.05). Gabapentin also did not affect cold allodynia (Fig. 3B) or mechanical hyperalgesia (data not shown). Chronic administration of carbamazepine 10 mg/kg had no significant effect on pinprick hypersensitivity (Fig. 3C), cold allodynia, or mechanical allodynia (data not shown). Chronic amitriptyline at 2 different dosages (10 and 25 mg/kg) did not change (P > 0.05) either the mechanical threshold (Fig. 3D) or the withdrawal duration after cold and noxious pinprick stimulation (data not shown).
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Discussion |
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This study has shown that two distinct animal models of neuropathic pain—SNI and PTH after a sciatic nerve crush—respond with different sensitivities to commonly used clinical analgesics. Morphine, gabapentin, amitriptyline, carbamazepine, and MK801 at nonsedative doses both prevented and reversed mechanical allodynia in the crush PTH model. In the SNI model, however, neither single doses nor repeated delivery of the same drugs had much effect on pain-related behavior. In general terms, then, stimulus-induced pain in the crush PTH model was found to be sensitive to most analgesics that are used to treat neuropathic pain in patients, whereas stimulus-evoked pain in the SNI model was essentially refractory to all the treatments tried at reasonable doses.
Current pharmacological therapy for patients with neuropathic pain includes treatment with antidepressants, anticonvulsants, local anesthetics, sodium channel blockers, opiates, and NMDA receptor antagonists. These treatments are believed to act by inhibiting excessive neural activity in afferent pathways, reducing central sensitization, and boosting inhibitory pathways. The drugs variously act to reduce monamine uptake, block voltage-gated sodium ion channels, bind to the 
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subunit of voltage-gated calcium channels, reduce gamma-aminobutyric acid uptake, activate the µ-opiate receptor, and block the NMDA glutamate receptor. Double-blinded randomized control trials and meta-analysis have shown that these therapies are effective (12–14); the number needed to treat to obtain one patient with more than 50% pain relief is generally between 2 and 3 (1), indicating that for every patient who responds, 1 or 2 do not. What is clear from clinical studies is that not all patients respond well, or at all, to many forms of treatment. Our experimental data indicate that not all neuropathic pain models respond well to analgesic therapy, and it is intriguing to postulate that these two observations may be linked.
Testing drugs for analgesic effects in animal neuropathic pain models is subject to considerable variability, and consequently the predictive value of such studies for assessing efficacy in patients is difficult to establish. This variation may reflect differences in the site, distribution, and peripheral and central action of the drug; the mechanism of action of the drug; the sensitivity and reliability of the outcome measures used; the presence of confounding factors such as motor dysfunction and sedation; the variability within and between laboratories (15); and the diverse nature of the neuropathic pain models studied. The same drug can affect different sensory modalities differently when tested in the same model, such as amitriptyline and dextrorphan, which alleviate heat hyperalgesia but not mechanical allodynia (16,17). Different analgesic drugs can act also differently on the same modality within the same model (18).
The effect of a drug on pain-related behavior may be related either to a specific action on one of the underlying mechanisms involved in generating the pain or to a nonspecific or widespread suppression/modification of neural activity in the periphery, the spinal cord, or the brain. This may be dose related, as with opioids or NMDA receptor antagonists. It is essential, where possible, that the mechanisms involved in producing a pain-related behavior are identified so that the specific action of drugs on these can be evaluated. These will include nociception in the case of basal responsiveness to noxious stimuli in naive animals, peripheral and central sensitization, disinhibition, increased descending facilitatory inputs from the brain, structural reorganization of central nervous system connectivity for reduced threshold or increased responsiveness, and ectopic afferent input for spontaneous pain behavior (3,4,19). Stimulus-induced tactile allodynia in the crush/PTH model is produced by repeated tactile stimulation of regenerated axons, whereas stimulus-evoked tactile pain-related behavior in the SNI model is a pain hypersensitivity that is directly evoked by stimulation of noninjured afferents (7,8). We assume that different mechanisms are responsible for the same symptom—mechanical allodynia—elicited in these models and that this contributes to the differential pharmacological responses we have observed.
Most studies in animals use stimulus-evoked tests of painlike behavior. A few have also used autotomy or paw position to measure spontaneous behavior, but the relationship of these to spontaneous pain is not clear (20). In clinical studies, although discrimination between spontaneous versus stimulus-evoked pain is possible, it is unfortunately rarely performed (21,22). Stimulus-induced pain has also been described in patients as a windup-like phenomenon to low-intensity repeated stimuli after nerve injury (23–25), and stimulus-induced pain may be one of the components of neuropathic pain that is relieved by the usual pain therapies. Stimulus-evoked and stimulus-induced pain are difficult to test in patients, for ethical reasons, and global pain assessments are likely to lack the sensitivity necessary to reveal an effect of a drug that is specific to a single mechanism.
If preclinical studies on compounds designed for use in patients with neuropathic pain are to have utility and predictive power, a sophisticated approach is required for their use—one that does not assume that all neuropathic models and all outcome measures are equivalent. With this information, preclinical screens for drugs that act on clinically relevant pain mechanisms can progress.
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Acknowledgments |
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This work was supported by the NINDS National Institute of Health (CJW) and the Swiss National Science Foundation (ID).
We thank D. R. Spahn, N. Gilliard, M. Pertin, and P. Frascarolo (Anesthesiology Department, University Hospital Lausanne, CHUV, Lausanne, Switzerland).
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Footnotes |
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ID and AA contributed equally to this study.
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