Antagonism of antinociception produced by intrathecal clonidine by ketorolac in the rat: The role of the opioid system

The management of severe pain may require "balanced analgesia," involving t he use of analgesics with different modes of action. Clonidine, an alpha(2) -adrenoreceptor agonist produces analgesia by itself as well as when given with morphine and local anesthetics. Ketorolac is indicated for the managem ent of moderately severe acute pain and causes analgesia equivalent to morp hine. This study was designed to investigate whether the addition of ketoro lac promotes antinociception produced by intrathecal administration of clon idine in male Sprague-Dawley rats. Intrathecal injection of clonidine (1-30 mu g) induced a dose-dependent increase in antinociception as measured by the tail flick (TF) and hot plate tests. Ketorolac alone (150-600 mu g) inc reased the antinociception by 50%-60% only in the TF test. Ketorolac (10 mu g) decreased clonidine (10 mu g)-induced antinociception from 69.1% +/- 7. 8% to 23.5% +/- 1.6% (P < 0.05) in the TF test and 35.7% +/- 4.7% to 4.5% /- 0.1% (P < 0.05) maximum possible effect in the hot plate test. Ketorolac also antagonized the effect of 30 mu g of clonidine. The opioid receptor a ntagonist naloxone antagonized the antinociceptive effect of clonidine and ketorolac, indicating the involvement of the opioid system in the antinocic eption produced by clonidine or ketorolac. However, neither clonidine nor k etorolac (10(-8) to 10(-3) M) inhibited the binding of specific ligands to mu-, delta-, and kappa-opioid receptors, indicating a lack of direct intera ction of clonidine and ketorolac with opioid receptors. These results sugge st that intrathecal injection of ketorolac antagonizes the antinociception produced by clonidine.