A painful peripheral neuropathy in the rat produced by the chemotherapeutic drug, paclitaxel

Abstract

Paclitaxel, an effective anti-neoplastic agent in the treatment of solid tumors, produces a dose-limiting painful peripheral neuropathy in a clinically significant number of cancer patients. Prior work has demonstrated paclitaxel-induced neurodegeneration and sensory loss in laboratory rodents. We describe here an experimental paclitaxel-induced painful peripheral neuropathy. Adult male rats were given four intraperitoneal injections on alternate days of vehicle or 0.5, 1.0, or 2.0 mg/kg of paclitaxel (Taxol). Behavioral tests for pain using mechanical and thermal stimuli applied to the tail and hind paws, and tests for motor performance, were taken before, during and after dosing for 22-35 days. All three doses of paclitaxel caused heat-hyperalgesia, mechano-allodynia, mechano-hyperalgesia, and cold-allodynia, but had no effect on motor performance. Neuropathic pain began within days and lasted for several weeks. We did not detect any dose-response relationship. Tests at the distal, mid, and proximal tail failed to show evidence of a length-dependent neuropathy. Vehicle control injections had no effect on any measure. No significant systemic toxicities were noted in the paclitaxel-treated animals. Light-microscopic inspection of the sciatic nerve (mid-thigh level), L4-L5 dorsal root ganglia, and dorsal and ventral roots, and the gray and white matter of the L4-L5 spinal cord, showed no structural abnormalities. Electron microscopic examination of the sciatic nerve (mid-thigh level) and the L4-L5 dorsal root ganglia and dorsal horns demonstrated no degeneration of myelinated and unmyelinated axons in the sciatic nerve and roots, but revealed endoneurial edema. This model may be useful in understanding a significant source of pain in cancer patients, and in finding ways to avoid the neurotoxicity that limits paclitaxel therapy.

Role of satellite cell-derived l-serine in the dorsal root ganglion in paclitaxel-induced painful peripheral neuropathy

“…In this study, paclitaxel treatment caused mechanical allodynia/hyperalgesia and a reduction of SNCV, as previously described (Polomano et al, 2001;Persohn et al, 2005).…”

“…Rats were given intraperitoneal (ip) injections of paclitaxel (2 mg/kg) or vehicle (1.0 mL of Cremophor EL/dehydrated ethanol diluted in 0.9% NaCl) on 4 alternate days (days 1 [D1], 3 [D3], 5 [D5], and 7 [D7]), according to the method described by Polomano et al (Polomano et al, 2001). Body weight was recorded before and after the initiation of paclitaxel or vehicle treatment.…”

“…We used a preclinical rat model of paclitaxel-induced painful peripheral neuropathy developed by Polomano et al (Polomano et al, 2001). This model produces 7 mechanical allodynia/hyperalgesia and cold allodynia in rats similar to that observed in human patients.…”

Ultrastructural Changes in the Retina during the Process of Paclitaxel-Induced Retinotoxicity Correction using Antioxidant Drug

“…В експери-менті 80 рандомбредним білим щурам масою 150-200 г внутрішньоочеревинно вводили паклітак-сел (Actavis, Румунія) у дозі 2 мг/кг маси тіла через одну добу 4 рази, сумарна доза -8 мг/кг за мето-дом R.S. Polomano et al [1], після чого тварин ран-домізували на І (48 тварин) і ІІ (32 тварин) дослідні групи. У І дослідній групі тваринам вводили внутрі-шньоочеревинно 2-етил-6-метил-3-гідроксипіриди-на сукцинат (Армадін, виробництво ТОВ Науково-виробнича фірма "Мікрохім", Україна) у дозі 10 мг/кг в 0,5 мл води для ін'єкцій.…”

Targeting Neuroprotection as an Alternative Approach to Preventing and Treating Neuropathic Pain

“…[37][38][39][40] Indeed, low doses of paclitaxel caused allodynia and hyperalgesia in rats without inducing degeneration of myelinated and unmyelinated axons in the sciatic nerve and roots. 41,42 Degeneration was rather confined to receptor terminals of the sensory fiber in the skin and was associated with prominent activation of cutaneous Langerhans cells. 43 The earliest defect observed in both C-fibers and myelinated axons was the appearance of swollen and vacuolated mitochondria.…”