Involvement of spinal lipoxygenase metabolites in hyperalgesia and opioid tolerance

Abstract

This study investigated role of spinal lipoxygenase metabolites in induction of hyperalgesia and development of opioid analgesic tolerance. In the rat, nociception was measured using formalin and tail-flick tests. Intrathecal administration of leukotriene receptor agonist (LTB 4) augmented the second phase of the formalin response and marginally increased sensitivity to acute thermal stimulation in the tail-flick test, responses suppressed by 6-(6-(3 R-hydroxy-1 E,5 Z-undecadien-1-yl)-2-pyridinyl)-1,5 S-hexanediol (U75302), a leukotriene BLT receptor antagonist. Treatment with 15-hydroxyperoxyeicosatetranoic acid (HPETE) increased phase II formalin activity, but had no effect on tail-flick responses. 12-HPETE failed to produce an effect in either nociceptive test. In the second part of this study, chronic spinal morphine for 5 days produced progressive decline in morphine antinociception and loss in analgesic potency. These effects were attenuated by co-administration of morphine with selective and nonselective lipoxygenase inhibitors. These results suggest involvement of lipoxygenase metabolites in both pain modulation and induction of opioid tolerance at the spinal level.