Terminal arbor degeneration – a novel lesion produced by the antineoplastic agent paclitaxel

• Published in: The European journal of neuroscience Vol. 33; no. 9; pp. 1667 - 1676
• Main Authors: Bennett, Gary J., Liu, Guo K., Xiao, Wen H., Jin, Hai W., Siau, Chiang
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01.05.2011
• Subjects: Animals; Antineoplastic Agents, Phytogenic - pharmacology; Axons; Basal lamina; Behavior, Animal - physiology; chemotherapy neuropathy; Degeneration; Drugs; Electron microscopy; Epidermis - innervation; Fibers; intraepidermal nerve fiber; Male; Nerve Degeneration - chemically induced; Nerve Degeneration - pathology; Nerve Fibers - drug effects; Nerve Fibers - pathology; Nerve Fibers - ultrastructure; Nervous system; Neuralgia - chemically induced; Neuralgia - pathology; Neurodegeneration; neuropathic pain; Neuropathy; Paclitaxel; Paclitaxel - pharmacology; Pain Measurement; Peripheral nerves; Peripheral Nerves - drug effects; Peripheral Nerves - pathology; Peripheral Nerves - ultrastructure; Peripheral neuropathy; Presynapse; rat; Rats; Rats, Sprague-Dawley; Sampling; Sensory neurons; sensory neuropathy; Skin; taxol
• ISSN: 0953-816X; 1460-9568
• DOI: 10.1111/j.1460-9568.2011.07652.x

The antineoplastic agent paclitaxel causes a dose‐limiting distal, symmetrical, sensory peripheral neuropathy that is often accompanied by a neuropathic pain syndrome. In a low‐dose model of paclitaxel‐evoked painful peripheral neuropathy in the rat, we have shown that the drug causes degeneration of intraepidermal nerve fibers (IENFs), i.e. the fibers which give rise to the sensory afferent’s terminal receptor arbor. However, we did not find any evidence for axonal degeneration in samples taken at the mid‐nerve level. Here we aimed to determine whether the absence of degenerating peripheral nerve axons was due to sampling a level that was too proximal. We used electron microscopy to study the distal‐most branches of the nerves innervating the hind paw glabrous skin of normal and paclitaxel‐treated rats. We confirmed that we sampled at a time when IENF degeneration was prominent. Because degeneration might be easier to detect with higher paclitaxel doses, we examined a four‐fold cumulative dose range (8–32 mg/kg). We found no evidence of degeneration in the superficial subepidermal axon bundles (sSAB) that are located just a few microns below the epidermal basal lamina. Specifically, for all three dose groups there was no change in the number of sSAB per millimeter of epidermal border, no change in the number of axons per sSAB and no change in the diameter of sSAB axons. We conclude that paclitaxel produces a novel type of lesion that is restricted to the afferent axon’s terminal arbor; we name this lesion ‘terminal arbor degeneration’.