Vincristine hyperalgesia in the rat: A model of painful vincristine neuropathy in humans

doi:10.1016/0306-4522(96)00020-6

Neuroscience

Volume 73, Issue 1, July 1996, Pages 259-265

https://doi.org/10.1016/0306-4522(96)00020-6 Get rights and content

Abstract

To investigate the mechanism of vincristine-induced pain in humans undergoing chemotherapy we have established a model of vincristine-induced hyperalgesia in rat. Vincristine (100 μg/kg)was administered daily over a period of two weeks. An acute dose-dependent decrease in mechanical nociceptive threshold and an increased response to non-noxious mechanical stimuli (“hyperalgesia”) occurred after the second day of administration. Chronic lowered threshold and increased response to stimuli (determined 24h after each injection) was first noted during the second week of vincristine administration. Responses gradually returned to baseline during the two weeks following discontinuation of treatment. Vincristine also increased sensitivity to heat stimulation. At a dose that produced hyperalgesia (100μg/kg), vincristine did not cause a significant motor deficit. Peripheral administration of a μ-opioid agonist did not reduce vincristine-induced acute hyperalgesia.

Hyperalgesia induced by vincristine in the rat provides a good model for the experimental study of painful peripheral neuropathies in human patients receiving vincristine as a chemotherapeutic agent.

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Previously, we showed internal low intensity focused ultrasound (liFUS) improves nociceptive thresholds in rats with vincristine-induced neuropathy (VIN) for 48-h post-treatment. Here, we perform more rigorous behavioral testing with the internal device and introduce external liFUS treatment. Behavioral testing confirmed VIN (Von Frey fibers, VFF; hot plate, HPT; locomotion, OFT). This was followed by internal or external liFUS treatment (2.5 W or 8 W, for 3 min, respectively) to the left L5 dorsal root ganglia (DRG). A thermocouple placed at the DRG documented temperature changes during treatment, to confirm the modulatory nature of our treatment. Behavioral testing was performed pre-liFUS, and for five consecutive days post-liFUS. Groups included: (1) VIN/liFUS, (2) saline/liFUS, (3) VIN/sham liFUS, and (4) saline/sham liFUS. Significant improvements in mechanical (VFF) and thermal (HPT) nociceptive thresholds were seen in the VIN/liFUS group following both internal and external treatment. Hematoxylin and Eosin, and Fluorojade staining showed no histological damage to the DRG. Internal liFUS treatment produced a mean temperature rise of 3.21 ± 0.30 °C, whereas external liFUS resulted in a mean temperature rise of 1.78 °C ± 0.21 °C. We demonstrate that, in a VIN rat model, external liFUS treatment of the L5 DRG significantly reduces nociceptive sensitivity thresholds without causing tissue damage.
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2018, Biomedicine and Pharmacotherapy
Chemotherapy induced peripheral neuropathy (CIPN) is a painful side-effect of commonly used chemotherapeutic agents that profoundly impair the quality of life of patients as the current pharmacotherapeutic strategies are inefficient in providing adequate pain relief. Complementary and alternative medicine (CAM) therapies are preferred by patients with neuropathic pain as they experience insufficient control of pain with conventional medications. This study describes the antinociceptive effect of Tithonia tubaeformis (Jacq.) Cass. in a vincristine mouse model of established CIPN.
Tithonia tubaeformis hydromethanolic extract was tested for preliminary qualitative phytochemical analysis and acute oral toxicity test in mice. The antinociceptive effect was investigated using the abdominal constriction (writhing) and tail immersion tests (25–200 mg/kg). The anti-neuropathic effect was determined in the vincristine mouse model, established by daily administration of vincristine (0.1 mg/kg/day, i.p) for consecutive 14 days. Acute treatment with Tithonia tubaeformis (100 and 200 mg/kg) and the positive control, gabapentin (75 mg/kg) was carried out on the 15th day of the last vincrsitine dose and the animals were tested for allodynia and thermal hyperalgesia at 30–120 min post extract/drug administration.
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2017, European Journal of Pharmacology
Cisplatin is an effective chemotherapeutic agent indicated in cancer chemotherapy. However, its clinical use is associated with peripheral neuropathy that invariably impairs patient quality of life. Gabapentin (GBP) is an effective analgesic for neuropathic pain conditions but its clinical efficacy in cisplatin-induced neuropathic pain (CINP) is limited, in addition to generating unwanted side-effects. In this study, a gabapentin-salicylaldehyde derivative [gabapentsal (GPS)] was synthesized and evaluated to explore any potential benefit in comparison with GBP in a rat model of CIPN. Administration of cisplatin (3.0 mg/kg/week, i.p.) for five consecutive weeks generated reproducible mechanical-allodynia (decreased paw withdrawal threshold to von Frey filament application; PWT, g) and thermal hypoalgesia (increased nociceptive reaction latency in the hot plate paradigm; s). Treatment with GBP or its derivative on the 37th day of the experimental protocol, dose dependently attenuated cisplatin-induced nocifensive behaviors. Accordingly, doses of GBP (50–100 mg/kg, i.p.) and GPS (25–100 mg/kg, i.p.) suppressed the expression of CINP by normalizing the PWT and hot plate response latency 1 h and 3 h post administration. In the rotarod paradigm, GBP at all doses markedly impaired motor performance, whilst GPS was devoid of motor incoordination except at the highest dose, when a mild impairment occurred. Salicylaldehyde alone had no effect on CINP or rotarod performance and neither was there any synergism when coadministered with GBP. These findings suggest that both GBP and GPS have beneficial effects in the neuropathic pain model though GPS may be potentially more useful in the management of CINP.

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Vincristine hyperalgesia in the rat: A model of painful vincristine neuropathy in humans

Abstract

Pain

J. Am. pharmac. Ass.

Toxicology

Pain

Life Sci.

Am. J. Med.

Brain Res.

Neuroscience

Expl Neurol.

Pain

Pain

Pain

Brain Res.

Int. J. Pharmac.

Management of pain in the cancer patient

Anesth. Analg.

Stability of vinca alkaloid anticancer drugs in three commonly used infusion fluids

J. Parent. Sci. Tech.

Peripheral neuropathy associated with malignant neoplasms in dogs

Vet. Path.

Vincristine neuropathy

Brain

Chemosensitivity and sensitization of nociceptive afferents that innervate the hairy skin of monkey

J. Neurophysiol.

Peripheral neuropathy in cancer patients: clinical types, etiology, and presentation

Oncology (Huntington)

Peripheral neuropathy in cancer patients: incidence, features, and pathophysiology

Oncology (Huntington)

Uses of vincristine and vinblastine in dogs and cats

J. Am. vet. Med. Ass.

Axonal transport disturbances in vincristine-induced peripheral neuropathy

Ann. Neurol.