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Evaluation of the Toxicity of Subarachnoid Clonidine, Guanfacine, and a Substance P-Antagonist on Rat Spinal Cord and Nerve Roots

Light and Electron Microscopic Observations after Chronic Intrathecal Administration

Received from the Department of Anaesthesiology and the Laboratory of Neuropathology, Institute of Pathology, Uppsala University, Uppsala; and ASTRA Research and Development Laboratories, Södertälje, Sweden.

Abstract

Clonidine has been reported to produce analgesia in man after epidural and intrathecal administration. In the present investigation the ₂-adrenoceptor agonists clonidine and guanfacine were tested to evaluate their potential spinal neurotoxic effects. Rats were injected daily for 14 consecutive days via catheters implanted in the intrathecal space. Clonidine was administered at a dose of 1.63 µg or 16.3 µg, and guanfacine at 16.3 or 75 µg. After perfusion with a buffered 3% glutaraldehyde solution, the spinal cords and nerve roots were taken for neuropathological analysis using light and electron microscopy. Compared to animals injected with 0.9% saline, clonidine and guanfacine gave rise to no detectable neurotoxic changes in the doses employed. An additional group of rats had intrathecal injections of a substance P-antagonist (D-Arg¹, D-Trp^7,9, Leu¹¹)-substance P (spantide) with known neurotoxic effect as a test of the histotechnical methods used. Degenerative lesions, with a preference for the ventral horns, were consistently present in the grey matter of the cord in these animals. We conclude that the absence of detectable changes in rats given clonidine and guanfacine is probably a real expression of the low degree of toxicity for these compounds on rat spinal cord and nerve roots and not an artifact of the sensitivity of the histotechniques applied. The doses of clonidine administered were considerably greater than those reported to produce clinical greater than those reported to produce clinical analgesia.

Key Words: SYMPATHETIC NERVOUS SYSTEM, -ADRENOCEPTOR AGONISTS—clonidine, guanfacine.

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Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins with the assistance of Stanford University Libraries' HighWire Press®. Copyright 2006 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999