Induction of tolerance to intrathecal butorphanol in rats.
BACKGROUND
Butorphanol, an opioid agonist/antagonist, has been administered spinally and epidurally in humans for moderate to severe pain. However, unlike intrathecal (i.t.) morphine, virtually no information is available regarding butorphanol's ability to induce analgesic tolerance at the spinal cord level upon chronic i.t. administration.


METHODS
Continuous infusion of i.t. butorphanol was given via an osmotic minipump. Rats were randomly assigned to four groups (n = 7 each) to receive i.t. infusion (1 microliter/h) consisting of saline, or butorphanol (13, 26, or 52 nmol/h) for 96 h. Tail-flick (TF) latencies were measured during the period of i.t. infusion.


RESULTS
A dose-dependent antinociceptive effect, as measured by TF latency, was demonstrated in the groups receiving i.t. butorphanol as compared to the saline group. The overall antinociceptive effects calculated from the areas under the curve (AUC's) were 372 +/- 3.0, 394 +/- 7.5, and 433 +/- 20 for the 13, 26, and 52 nmol/h butorphanol-infused groups, respectively; the AUC's of the 26 and 52 nmol/h groups were significantly different from the AUC of 356 +/- 3.4 for the saline-infused group (p < 0.01, one way ANOVA; p < 0.05, post hoc Dunnett's test). The TF latencies of the 26 and 52 nmol/h groups were 3.77 +/- 0.05 and 3.73 +/- 0.03 s at the baseline (before the i.t. infusion), respectively; and gradually increased significantly (p < 0.01, two way repeated measure ANOVA; p < 0.05, post hoc Student-Newman-Keuls or SNK test) to the peak values of 4.31 +/- 0.14 and 4.90 +/- 0.28 s, respectively; then decreased significantly from the peaks (p < 0.05, post hoc SNK test) to the final values of 3.87 +/- 0.06 and 4.10 +/- 0.13 s at the end of the 96-h infusion, respectively. The TF values of the saline and the 13 nmol/h groups did not show statistically significant differences throughout the 96-h infusion period.


CONCLUSIONS
Therefore, continuous infusion of i.t. butorphanol at the rate of 26 and 52 nmol/h induced tolerance to tail-flick analgesia within 96 h.
Tsang
B K
BK
Department of Anesthesiology, University of Mississippi Medical Center, Jackson 39216, USA.
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Wongchanapai
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Coleman
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I K
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Eichorn
J H
JH
D000701:Analgesics, Opioid / Q000494:pharmacology*; D000818:Animals; D002077:Butorphanol / Q000008:administration & dosage / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004361:Drug Tolerance; D007278:Injections, Spinal; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley
D000701:Analgesics, Opioid; D002077:Butorphanol