Chemotherapy-evoked neuropathic pain is one of the major side effects of cancer chemotherapy.1 The associated pain state can be severe enough to lead to termination of treatment.2 Cisplatin (cis-diamminedichloroplatinum II) is a chemotherapy drug used to treat a variety of cancers. The platinum complex drugs that are widely used antineoplastic agents serve to crosslink DNA leading to apoptosis.2,3 Common to many antineoplastic drugs, the therapeutic protocols for cisplatin used to treat cancers will typically yield sensory neuropathies characterized by pain and paresthesias in distal extremities occurring over intervals of days to weeks.4
Although the exact etiology of chemotherapy-induced neuropathy is unknown,5 advances in understanding this phenomena and the development of potentially ameliorating pain therapies has resulted in the development of robust preclinical models. In the mouse, platin agents such as cisplatin and oxaliplatin produce a tactile allodynia as measured by von Frey hairs and thermal hyperalgesia when used at total doses up to 15 mg/kg with treatment delivered over 20 days.6,7 Several studies have suggested that the pathology resembles that of neuropathic rather than an inflammatory condition. One example of this has been changes in the dorsal root ganglion (DRG) expression of activating transcription factor 3 (ATF3), a reported marker of nerve injury in paclitaxel- and cisplatin-treated but not vincristine-treated animals.8–10
An important element of this work on chemotherapeutic models has been that all of the paradigms have used threshold measurement. As noted in humans, aside from changes in mechanical sensitivity, patients report continuing dysesthesia. Recent work has indicated that aside from threshold measurements, the “painful” nature of the treatment may be addressed by the conditioned place preference (CPP) paradigm.11–13 In this paradigm, if the animal (i) has pain and (ii) if a drug ameliorates that pain, then that drug will have a positive reinforcing property such that if the drug is given in a particular environment, the animal will come to demonstrate a preference for that environment, e.g., a CPP. Conversely, such drugs would not have rewarding properties in the absence of the hypothesized pain state. This phenomenon has hitherto not been examined in a chemotherapeutic polyneuropathy model.
Accordingly, in the present studies, we sought to determine (i) the effects of cisplatin treatment on thermal and mechanical thresholds, (ii) the effects of this treatment on DRG ATF3 and spinal glial activation, (iii) the effects of drugs with antihyperalgesic actions after tissue and/or nerve injury (ketorolac, gabapentin, morphine, and etanercept; because these drugs are nonsteroidal antiinflammatory drugs, anticonvulsants, opioids, and tumor necrosis factor TNF-α antagonist used in pain control, respectively) on the cisplatin-induced hyperalgesia, and (iv) whether the cisplatin-treated animals would display a preference for a chamber in which they had received a drug treatment that relieved allodynia. The present results support the assertion that the cisplatin model is indeed representative of a hyperalgesic state and that state responds to the antihyperalgesic drug gabapentin, but not the nonsteroidal antiinflammatory drug ketorolac.
This study was approved by the Institutional Animal Care and Use Committee at the University of California San Diego. Male C57BL/6 mice (25–30 g) were used in these studies. Food and water were provided freely. Up to 4 mice were housed in plastic cages with soft bedding, and were maintained on a 12:12-hour light-dark cycle.
Mice received intraperitoneal (IP) injections of either cisplatin (Spectrum Chemical Mfg., Gardena, CA) (2.3 mg/kg/d; n = 6, respectively) or saline every other day, 6 times over 2 weeks for a total dose of 13.8 mg/kg. Between cisplatin injection days, lactated Ringer’s solution (0.25 mL) was injected to maintain hydration and to protect the kidney and liver. This treatment/dosing paradigm was selected on the basis of preliminary studies demonstrating that this treatment regimen resulted in robust allodynia with acceptable body weight loss. On day 15, animals that showed a foot withdrawal response to von Frey filaments with an applied bending force of ≤0.6 g were considered neuropathic and used in subsequent studies.
Neuropathic mice, on or around day 15, were randomly assigned to receive IP gabapentin (100 mg/kg), etanercept (20 and 40 mg/kg), ketorolac (15 mg/kg), morphine (1, 3, and 10 mg/kg), or saline (vehicle). In another group of animals, we undertook a pretreatment regimen of etanercept (40 mg/kg) or saline delivered just before the first cisplatin injection (n = 4–6 per group).
All behavioral tests were conducted at fixed times (9:00 AM to 5:00 PM). The behavioral test for mechanical allodynia was conducted just before the daily injection during the course of cisplatin treatment. For the drug treatment studies, mechanical allodynia was determined preadministration and at 15, 30, 60, 90, 120, 180, 240, and 1440 minutes after IP drug administration. The thresholds for mechanical allodynia were measured with a series of von Frey filaments (Semmes Weinstein von Frey aesthesiometer; Stoelting Co., Wood Dale, IL), ranging from 2.44 to 4.31 (0.03–2.00 g) using the up-down method.14 We assessed thermal escape responses using a Hargreaves-type testing device (UARDG, Department of Anesthesiology, University of California San Diego) as described previously.15 All results are reported as the mean value of readings from each of the hindpaws.
Using a modification of the method previously described,12 we tested CPP for gabapentin and ketorolac in cisplatin (allodynic) and vehicle control (nonallodynic) animals. We used a 3-compartment (A, B, C) box (each compartment measuring 90 × 90 × 165 cm) with the B compartment (center) separated from each of the adjacent compartments by a divider with an entryway. The A and C compartments had different-patterned walls and texturally distinct floors. The obscuration by the animal of the light path of 3 red LED lights in chambers A and C was used to measure the time spent in each chamber. The testing paradigm was as follows. On days 1 and 2, animals were allowed to explore freely for 30 minutes and the time spent in each chamber was determined. On days 3 and 4, in the morning, the animal was placed for 30 minutes in one closed chamber, immediately after receiving vehicle. In the afternoon (4 hours later), the mouse was placed for 30 minutes in the other chamber after receiving the test drug. On day 5, the animal was placed in the start chamber (B) and allowed free access for 30 minutes to either chamber. The time spent in the 2 chambers was recorded. Chamber pairings were counterbalanced. To define drug effect, the mean of the time spent in the drug-associated chamber during adaptation (days 1 and 2) was subtracted from the time spent in that chamber on the test day (day 5).
On day 30, The lumbar spinal cords (L4-6) and DRG were harvested as described previously.16 Spinal cord sections (30 μm) were incubated with anti-GFAP (glial fibrillary acidic protein) antibody (1:10,000; Chemicon, Temecula, CA) or anti-Iba1 (ionized calcium binding adaptor molecule 1) antibody (1:1000; Wako, Richmond, VA). Binding sites were visualized with secondary antibodies conjugated with fluoro-Alexa-488 and Alexa-594 (1:1000; Molecular Probes, Eugene, OR). For DRG (10 μm), nonspecific binding was blocked by incubation in 2% normal goat serum in phosphate-buffered saline with 0.3% Triton X-100 followed by incubation with primary ATF3 antibody (generated in rabbit, 1:1000; Santa Cruz Biotechnology, Santa Cruz, CA) overnight at 4°C under gentle agitation. Binding sites were visualized with antirabbit immunoglobulin G antibodies conjugated with Alexa-488 (1:500; Invitrogen). Nuclei were counterstained using Topro3 (1:500; Invitrogen). All images were captured by a Leica TCS SP5 confocal imaging system and quantified using Image-Pro Plus v.5.1 software. Microglia (Iba1), astrocyte (GFAP), and ATF3 staining was quantified by measuring the total integrated intensity of pixels divided by the total number of pixels in a standardized area. Staining intensity was examined in laminae I–II of the superficial dorsal horn using a standardized box with 4 to 6 mice per experimental condition. Only pixels above a preset background threshold were included. An increase in the integrated intensity/pixels for Iba1 and GFAP staining was interpreted to signify microglia and astrocyte reactivity, respectively. Iba1 and GFAP data are presented as the total threshold intensity area. ATF3 data are presented as percentage change from the corresponding control group. Statistics were performed on raw data values.
Results are expressed as mean ± SE. Statistical analysis was performed using GraphPad Prism (version 5.0; GraphPad Software, San Diego, CA). For comparison of mechanical and thermal hyperalgesia, 2-way analysis of variance was used to determine general differences, depending on the treatment group and time. This was followed by Bonferroni multiple comparisons test. For CPP tests, data were analyzed before conditioning (mean) and after conditioning using 1-way analysis of variance followed by a Newman-Keuls multiple comparison test. Group differences were analyzed using paired t tests. Difference scores were calculated for each mouse using the following formula: test time in chamber − preconditioning mean time spent in chamber. For comparison of microglia, astrocyte, and ATF3 changes, a t test was used. A P value <0.05 was considered significant.
Cisplatin Treatment Produces Significant and Persistent Mechanical Allodynia
None of the cisplatin-injected mice showed any motor dysfunction or complications. No animal required early euthanasia.
Mechanical withdrawal threshold was significantly reduced after cisplatin treatment from day 3 and through day 30 as compared with the baseline (P < 0.0001; Fig. 1A). There were no changes in thermal escape latency when measured on day 29 (P > 0.05; Fig. 1B). The cisplatin-injected mice showed a modestly retarded weight gain compared with vehicle-treated mice during the initial dosing, but there was no statistical difference in the posttreatment phase with normal weight gain after cisplatin treatment (P > 0.05; Fig. 1C). All animals with demonstrated allodynia showed normal symmetric ambulation with no loss of placing or stepping responses. Cisplatin, but not vehicle, produced significant and persistent mechanical allodynia.
Analgesic Pharmacology of Cisplatin-Evoked Tactile Allodynia
In mice with established allodynia (approximately 15 to 19 days after initiation of cisplatin treatment), gabapentin (100 mg/kg, IP) and morphine (10 mg/kg, but not 1 or 3 mg/kg, IP) treatment resulted in a reversal of the allodynia for periods of 30 through 240 minutes (P < 0.0001; Fig. 2A) and of 30 through 180 minutes (P < 0.0001; Fig. 2C) after drug injection, compared with vehicle, respectively. In contrast, neither ketorolac (15 mg/kg, IP) nor etanercept (20 or 40 mg/kg, IP) altered the highly significant allodynia as compared with vehicle treatment (P < 0.0001; Figs. 2B and 3A). In separate groups, pretreatment (e.g., before the first cisplatin injection) with etanercept (40 mg/kg, IP) delayed the onset of allodynia through day 12 (P < 0.0001; Fig. 3B).
Conditioned Place Preference
Preconditioning times spent in the saline- or gabapentin- or ketorolac-paired chambers did not differ across all treatment groups (P > 0.05, data not shown). In initial studies, we used the paradigm of a 3-day adaptation, 1-day drug pairing, and 1-day test paradigm. With the 1-day treatment schedule, gabapentin administration (100 mg/kg, IP) induced place preference in cisplatin-treated mice as compared with saline vehicle mice (P < 0.05, data not shown), but there was no significant difference from baseline scores in the gabapentin and saline groups (P > 0.05, data not shown). We then used a 2-day drug treatment schedule. In the 2-day drug treatment paradigm, gabapentin administration (100 mg/kg, IP) induced a significant place preference in cisplatin-treated mice (P < 0.05 versus preconditioning, versus saline, and versus ketorolac). The difference from baseline scores confirmed that 2-day gabapentin treatment showed stronger positive reinforcement than the 1-day treatment in the cisplatin mice treated with gabapentin (P < 0.05 versus saline; Fig. 4A). In contrast, sham (noncisplatin) mice that were treated with gabapentin showed no difference in time spent on test day in the gabapentin- and saline-paired chambers (P > 0.05 versus saline; Fig. 4B). This indicates that gabapentin with a 2-day drug-pairing paradigm will initiate a significant place preference in the presence of allodynia, but in the absence of allodynia, it has no ability to initiate a CPP (i.e., in the normal animal, it is not positive reinforcing).
The threshold intensity area of both microglia (Iba1) and astrocyte (GFAP) in the spinal cords of cisplatin mice showed a modest numerical increase in cisplatin-treated mice. However, this difference was not statistically significant as compared with the control group (P > 0.05; Fig. 5, A–F). In vehicle-treated mice, there were few ATF3(+) cells. In contrast, cisplatin-treated mice showed significant activation of neuronal ATF3 as compared with the control group (P < 0.05; Fig. 6, A–C).
This study demonstrates that cisplatin initiates robust allodynia that is attenuated by gabapentin and morphine, but not by ketorolac or etanercept. Importantly, this antiallodynic effect of gabapentin paralleled the observation that in the cisplatin-treated animal, gabapentin had a positive reinforcing effect leading to a CPP.
In humans, cisplatin in doses of 8.1 to 12.2 mg/kg or 300 to 450 mg/m2 body area over intervals of 3 to 4 weeks led to robust tactile allodynia and ongoing dysesthesia.6,17–20 We found that total doses of 13.8 mg/kg, equivalent to 41.4 mg/m2 in mice delivered in divided doses, led to allodynia after 3 to 5 days. In the present work, animals received IP lactated Ringer’s solution, which reduced the toxic effects of the therapy on peripheral organ systems.21 Although higher dosing has been reported,6,7 the present paradigm resulted in pain correlates that were accompanied by only modest weight loss, no evident morbidity, or any effects on the placing and stepping reflexes, confirming that the behavioral changes reported herein were not the result of changes in motor function or from loss of response to light touch.
Cisplatin Pain Phenotype
The pain behavior exhibited by cisplatin mice in our study is comparable to that which has been previously reported.6,7 Although several groups have reported thermal hyperalgesia,6,22 we failed to see effects on thermal thresholds, in agreement with other investigators.23–25 An important component of this model is persistent tactile allodynia. In these cisplatin mice, such allodynia extended to at least 46 days.6,7 This persistency is in agreement with the dysesthesia reported in the human chemotherapy patient.17,19
Mechanisms Underlying Allodynia
As a therapeutic drug, cisplatin exerts its activity by inhibiting transcription through binding to DNA.26 Previous work has shown that DRG neurons accumulate Pt-DNA adducts over time after cisplatin exposure.27 This family of agents does not produce axon loss in mice.28 In the present work, glial activation typical of nerve injury was not observed. Interestingly, in the cisplatin-treated mice displaying allodynia, there was an increase in ATF3, a marker of nerve injury. Previous work has shown that ATF3 can be increased after intense peripheral stimulation.10 The significant changes may reflect on the nominal effects on afferent integrity and perhaps a direct effect on the DRG. Other possibilities include the potential effects on mitochondria.29
Herein we show that allodynia was readily reversed by gabapentin and morphine, but not by ketorolac or etanercept. There has been no study that has described the effect of ketorolac, etanercept, and gabapentin in a cisplatin-induced neuropathic model. There are several reports regarding gabapentin in paclitaxel- and vincristine-induced neuropathic models.30,31 Gabapentin acts by binding to the α2δ subunit of the calcium channel. This drug has efficacy in allodynia, which occurs after nerve injury32 or chronic inflammation.16,33 Ketorolac and etanercept have been shown to have effects in models of inflammatory hyperalgesia.16,34,35 The absence of these effects in the cisplatin model distinguishes this allodynia from models of local inflammation. Pretreatment with etanercept was effective in delaying onset of mechanical allodynia suggesting that during the early phase of allodynia, TNF has a mediating role. The absence of posttreatment effects with etanercept was unexpected. Previous work in neuropathic pain has shown this drug to be relatively effective in several models of established mono- and polyneuropathy such as sciatic nerve constriction injury and diabetic neuropathy.36–38 The role of TNF in this model is thus not clear, but it does not have a sustaining role in established cisplatin-initiated allodynia. This transition to a TNF-insensitive later phase thus sets the chemotherapy model apart from other models of neuropathy.
Conditioned Place Preference
An important component of the present work was the examination of the effects of drugs on the cisplatin-induced state using the CPP model. Although chemotherapeutics, such as cisplatin, can produce changes in mechanical and thermal threshold measures, there is controversy about the meaning of such end points in the preclinical evaluation of drug efficacy in persistent pain states. Of interest has been the implementation of the CPP model to define the effects of analgesic drugs in these persistent pain models.11,12 In this paradigm, there is the assertion that (i) the animal is in a state of discomfort (pain), (ii) a specific drug targets that pain state, and (iii) the drug has no intrinsic reinforcing properties. In this model, the animal is exposed to a drug at doses that are believed to be analgesic, or to a vehicle, each in a distinct environment. Later in a test period, the animal is given the choice of being in either a drug or vehicle chamber. If the animal is in discomfort and if the drug alters that discomforting state, it is presumed that the pain relief becomes a positive rewarding element and the animal will choose the environment in which it received that drug therapy. In the present work, we attempted to define the effects of gabapentin and ketorolac in establishing a place preference. Gabapentin has efficacy in a variety of nerve injury models associated with allodynia39 and has demonstrated efficacy in cisplatin neuropathy as defined by robust effects on the von Frey thresholds. As indicated, with 2, but not a single drug pairing, the effects of gabapentin, at a dose that was observed to reverse tactile allodynia, established a robust place preference. In contrast, ketorolac had no effect. The need for a 2-day versus 1-day drug-pairing paradigm is a property consistent with the learning nature of the drug-related response. An essential control in this paradigm was that treatment of the normal animal (e.g., not displaying allodynia) with gabapentin failed to result in a place preference, indicating that gabapentin in the absence of a proposed state of facilitated pain processing had no reinforcing actions. The effects thus depended on the pain state of the cisplatin-treated mouse. These studies were not performed with systemic morphine because it can initiate a place preference in the absence of any abnormal sensory condition (e.g., unlike gabapentin or ketorolac, it has intrinsic rewarding properties).
Our studies validate the presence of a hyperalgesic state in cisplatin-treated mice and reveal a correlation between the pharmacology of that hyperalgesic state with persistent allodynia as defined by the CPP model. The upregulation of ATF3 in the DRG in the absence of prominent spinal glial activation suggests a change in afferent processing resembling injury to the peripheral nerve.
Name: Hue Jung Park, MD, PhD.
Contribution: This author helped design the study, conduct the study, analyze the data, and write the manuscript.
Attestation: Hue Jung Park has seen the original study data, reviewed the analysis of the data, approved the final manuscript, and is the author responsible for archiving the study files.
Name: Jennifer A. Stokes, MS.
Contribution: This author helped design the study, conduct the study, and analyze the data.
Attestation: Jennifer A. Stokes has seen the original study data, reviewed the analysis of the data, and approved the final manuscript.
Name: Elaine Pirie, BS.
Contribution: This author helped conduct the study.
Attestation: Elaine Pirie has seen the original study data, reviewed the analysis of the data, and approved the final manuscript.
Name: James Skahen.
Contribution: This author helped conduct the study.
Attestation: James Skahen has seen the original study data, reviewed the analysis of the data, and approved the final manuscript.
Name: Yuri Shtaerman.
Contribution: This author helped conduct the study.
Attestation: Yuri Shtaerman has seen the original study data, reviewed the analysis of the data, and approved the final manuscript.
Name: Tony L. Yaksh, PhD.
Contribution: This author helped design the study, analyze the data, and write the manuscript.
Attestation: Tony L. Yaksh has seen the original study data, reviewed the analysis of the data, and approved the final manuscript.
This manuscript was handled by: Jianren Mao, MD, PhD.
We thank Bethany Fitzsimmons, William Ho, and Nancy Lin who helped in early work to develop the cisplatin model. We appreciate reading and correcting of the manuscript by Christine Radewicz.
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