Vol. 281, Issue 3, 1381-1391, 1997

Effects of Intrathecal or Intracerebroventricular Administration of Nonsteroidal Anti-inflammatory Drugs on a C-Fiber Reflex in Rats¹

Diego Bustamante, Carlos Paeile, Jean-Claude Willer and Daniel Le Bars

Department of Pharmacology, Faculty of Medicine, University of Chile, Santiago, Chile (D.B., C.P.), Laboratoire de Neurophysiologie, Hôpital Pitié-Salpétriêre, Paris, France (J.-C.W.), and INSERM U161, Paris, France (D.L.B.)

A C-fiber reflex elicited by electrical stimulation within the territory of the sural nerve was recorded from the ipsilateral biceps femoris muscle in anesthetized rats. The temporal evolution of the response was studied using a constant stimulus intensity (3 times threshold), and recruitment curves were built by varying the stimulus intensity from 0 to 7 times threshold. The intrathecal (i.t.) but not i.c.v. administration of aspirin, indomethacin, ketoprofen and lysine clonixinate resulted in dose-dependent depressions of the C-fiber reflex. In contrast, saline was ineffective. Regardless of the route of administration, the drugs never produced disturbances in heart rate and/or acid-base equilibrium. When a constant level of stimulation was used, 500 µg of aspirin i.t. induced a blockade of the reflex immediately after the injection, followed by a partial recovery. Indomethacin produced a stable depression, which reached 80 to 90% with an i.t. dose of 500 µg. Ketoprofen and lysine clonixinate produced a more stable effect; the highest doses (500 µg) produced a steady-state depression of approximately 50% for approximately 30 min. When the recruitment curves were built with a range of nociceptive stimulus intensities, all of the drugs except for indomethacin produced a dose-dependent decrease in the slopes and the areas under the recruitment curves without major modifications in the thresholds; indomethacin also induced a significant dose-related increase in the threshold. The orders of potency for both stimulation paradigms with the i.t. route were the same, namely aspirin > indomethacin > lysine clonixinate  ketoprofen. It is concluded that nonsteroidal anti-inflammatory drugs elicit significant antinociceptive effects at a spinal level, which do not depend on the existence of a hyperalgesic or inflammatory state. Such effects were not seen after injections within the lateral ventricle.