Onset Of Allodynia Research Articles

Persistent Hyperalgesia in the Cisplatin-Treated Mouse as Defined by Threshold Measures, the Conditioned Place Preference Paradigm, and Changes in Dorsal Root Ganglia Activated Transcription Factor 3

Painful neuropathy is a dose-limiting side effect in cancer chemotherapy. To characterize this phenomenon, we examined pain behavior and analgesic actions in a mouse model of cisplatin polyneuropathy. Male C57BL/6 mice received intraperitoneal cisplatin or saline (2.3 mg/kg/d) every other day 6 times over 2 weeks for a total dose of 13.8 mg/kg. Thermal escape latencies, mechanical allodynia using von Frey hairs, and observation of behavior/morbidity and body weights were assessed. After onset of allodynia, we examined the actions of intraperitoneal gabapentin (100 mg/kg), etanercept (20 and 40 mg/kg), ketorolac (15 mg/kg), and morphine (1, 3, and 10 mg/kg). Additionally, using the conditioned place preference (CPP) paradigm, we examined the effects of gabapentin and ketorolac on the presumed pain state initiated by cisplatin. Additionally, we examined the spinal cord and dorsal root ganglia (DRG) of cisplatin-treated mice. Cisplatin, but not saline treatment, produced persistent hindpaw tactile allodynia, which persisted 46 days with no effect on thermal escape. Gabapentin and morphine, but neither etanercept nor ketorolac, produced a complete but transient (2-hour) reversal of the allodynia. Etanercept (40 mg/kg) pretreatment resulted in a delay in onset of mechanical allodynia. Using CPP, gabapentin, but not ketorolac, in cisplatin animals resulted in a significant preference for the drug-associated treatment compartment. There was no place preference in non-cisplatin-treated (nonallodynic) mice after gabapentin injection. Immunohistochemistry in cisplatin-treated mice showed no change in glial fibrillary acidic protein (astrocyte) or Iba1 (ionized calcium binding adaptor molecule 1) (microglia) activation states, but a significant increase in activated transcription factor 3 was observed in the DRG. Cisplatintreated mice display allodynia and an activation of DRG activated transcription factor 3, which is paralleled by its effects on behavior in the CPP system, wherein gabapentin, but not ketorolac, in the presence of the cisplatin polyneuropathy, is positively rewarding, confirming that this neuropathy is an aversive (painful) state that is ameliorated by gabapentin.

Extracellular signal-regulated kinase activation in spinal astrocytes and microglia contributes to cancer-induced bone pain in rats

Cancer pain, especially cancer-induced bone pain, affects the quality of life of cancer patients, and current treatments for this pain are limited. The present study demonstrates that spinal extracellular signal-regulated kinase (ERK) activation in glial cells plays a crucial role in cancer-induced bone pain. From day 4 to day 21 after the intra-tibia inoculation with Walker 256 mammary gland carcinoma cells, significant mechanical allodynia was observed as indicated by the decrease of mechanical withdrawal thresholds in the von Frey hair test. Intra-tibia inoculation with carcinoma cells induced a vast and persistent (>21 D) activation of ERK in the bilateral L2–L3 and L4–L5 spinal dorsal horn. The increased pERK1/2-immunoreactivity was observed in both Iba-1-expressing microglia and GFAP-expressing astrocytes but not in NeuN-expressing neurons. A single intrathecal injection of the selective MEK (ERK kinase) inhibitors PD98059 (10μg) on day 12 and U0126 (1.25 and 3μg) on day 14, attenuated the bilateral mechanical allodynia in the von Frey hair test. Altogether, our results suggest that ERK activation in spinal microglia and astrocytes is correlated with the onset of allodynia and is important for allodynia maintenance in the cancer pain model. This study indicated that inhibition of the ERK pathway may provide a new therapy for cancer-induced bone pain.

Abstract 933: Peripheral neuropathy induced by chronic administration of Cisplatin, taxol and bortezomib in several murine models

Abstract Cisplatin (CDDP), Taxol (TAX) and Bortezomib (BZ) are chemotherapeutic drugs commonly employed in clinical practice for the treatment of solid and haematological tumors. Their clinical use is limited by the development of a peripheral neuropathy characterized by sensory alterations, pain and, in part, by motor and autonomic dysfunctions. Several rat models had been performed to study and describe the mechanisms of the peripheral neurotoxicity induced by these drugs. However, since only few cancer cell lines are able to induce the development of cancer in the rat, we focused our attention on mice models to allow the combined study of the antineoplastic activity and of the neurotoxic effects of the anticancer compounds. Moreover, different mice strains should be useful for different kind of studies. Here we investigated the interactions between the mice genotype and their drug response to determine the susceptibility to the development of chemotherapy-induced peripheral neuropathy. To this aim, we investigated the neurophysiological and neuropathological alterations induced by the chronic treatment with different chemotherapy drugs in female Balb/c, CD1 and c57 mice and in male c57 and FVB mice. Mice were injected with Cisplatin (2, 4 mg/Kg, ip, 2qw), or Taxol (50, 70, 80 mg/Kg, iv, 1qw) or Bortezomib (0.4, 0.8 mg/Kg, iv, 2qw) for a period of 4-6 weeks. At the end of the treatment the nerve conduction velocities (NCVs) were determined in the caudal and in the digital nerves and the dorsal root ganglia (DRG) and sciatic nerves collected for the neuropathological analysis; behavioural tests were performed to study if these drugs are able to induce allodynia or hyperalgesia. In all mice models we observed that TAX and CDDP induced a significant alteration in body weight at the end of the treatment. All the drugs induced a significant reduction in the caudal and digital NCV in Balb/c and CD1 mice. TAX and BZ caused the axonal degeneration of the sciatic nerves while CDDP and BZ morphological alterations in the DRG. In c57 female mice, only BZ induced a significant reduction in caudal NCV while in c57 male mice only CDDP caused neurophysiological impairments. By contrast, male FVB mice showed any neurophysiological alterations. All these models, except FVB mice, have shown the onset of allodynia and hyperalgesia at the end of the treatment. In conclusion we can affirm that, even if at different extent, Balb/c, CD1 and c57 mice were able to develop the different chemotherapy-induced peripheral neuropathies. Moreover, also the gender seemed to be involved in the severity of the neuropathy. By contrast, FVB mice were less susceptible to the neurotoxic damage. This study would give a useful guideline for the choice of mouse strains in the combined studies of the antineoplastic activity and of the neurotoxic effects of chemotherapy drugs. Partially supported by a grant from “Fondazione Banca del Monte di Lombardia”. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 933. doi:1538-7445.AM2012-933

Anti-TNF-α Antibody Reduces Pain-Behavioral Changes Induced by Epidural Application of Nucleus Pulposus in a Rat Model Depending on the Timing of Administration

An experimental animal study. To study if antitumor necrosis factor-alpha (TNF-alpha) antibody, which is administered at different times, reduces the pain behavior induced by application of nucleus pulposus (NP) to the nerve root. Treatment with TNF-alpha inhibitor reduces the pain-related behavior induced by epidural application of NP in rats. Left L5 partial laminectomy was performed and NP was applied to the L5 nerve root in 24 rats. The rats were divided into 4 groups. In 3 groups, anti-rat TNF-alpha antibody was intravenously administered immediately after, or 6 or 20 days after NP application. The fourth group was not treated with anti-rat TNF-alpha antibody (untreated rats). The withdrawal threshold of the plantar surface was determined 1 day before up through 28 days after NP application. The withdrawal threshold of rats that had been treated with anti-rat TNF-alpha antibody immediately after or 6 days after, but not 20 days after, NP application, was significantly higher than that of the untreated rats. Anti-TNF-alpha antibody reduced allodynia only when it was administered soon after the onset of allodynia. Late administration of anti-TNF-alpha antibody did not have an antiallodynic effect.

Peripheral Nerve Pathology Following Sciatic Cryoneurolysis: Relationship to Neuropathic Behaviors in the Rat

Sciatic cryoneurolysis (SCN) is an experimental rat mononeuropathy model that produces neuropathic behavioral sequelae distinct from other neuropathy models. Following SCN, there is limited autotomy peaking in severity and incidence at 7-14 days and delayed but sustained allodynia appearing at about 21 days, with no evidence of thermal hyperalgesia. This study quantified peripheral nerve pathology at weekly intervals following SCN to determine the relationship of nerve degeneration and regeneration to the resulting abnormal behaviors. Fiber histograms based on axon diameter and grid morphometry were used to quantify the pathologic state of nerve fibers, activated phagocytic cells, vessels, and edema at the lesion site. Approximately 90% of the axons demonstrated Wallerianlike degeneration by 3 days post-SCN. At 14 days, small diameter axons significantly increased in number from earlier times following SCN (P < 0.05) but were not significantly different from normal values. At 21 days, the number of small diameter axons was significantly increased over both 14 days (P < 0.05) and normal values (P < 0.05). At 28 days, intermediate diameter axons significantly increased in number with respect to all earlier time periods (P < 0.05). These increases in regenerating fibers overlapped with the development of peak autotomy at 7-14 days and the onset of allodynia after 21 days. Autotomy scores at 7 days positively correlated with grid morphometry data of regenerating axons (p = 0.7) and activated macrophages and Schwann cells (p = 0.8) and inversely correlated with edema (p= -0.8) using Spearman's rank correlation analysis. These data suggest a macrophage and Schwann cell involvement in the sensitization of first- and second-order neurons to afferent input which leads to neuropathic behaviors. These results are discussed in the context of a hypothesis for the generation of differential neuropathic behaviors associated with the pathological events of degeneration and regeneration following the chronic constriction injury model of neuropathic pain and SNC.