Augmented responses to morphine and cocaine in mice with a 12-lipoxygenase gene disruption

Rationale. Recent studies have shown that pharmacological inhibition of the 12-lipoxygenase pathway selectively blocks opioid inhibition of GABAergic synaptic currents. A similar mechanism has been shown for the regulation of glutamate release in the ventral tegmental area (VTA) during acute withdrawal from morphine, although the functional significance of these effects in vivo are not known. Objectives. We have utilized mice with a disruption of the 'leukocyte-type' 12-lipoxygenase gene (12-LO-/- mice) to examine a variety of general behavioral responses as well as several specific responses to morphine and cocaine. Methods. Behavioral responses to morphine include sensitivity to thermal stimuli and withdrawal from chronic morphine treatment. Responses to cocaine were measured through locomotor activity. Results. General behavioral responses in 12-LO-/- mice are not different from their wild-type controls. However, these mutant mice showed enhanced morphine-induced analgesia. However, this effect is eliminated following chronic morphine treatment. In addition, 12-LO-/- mice demonstrated enhanced somatic signs of opiate withdrawal relative to littermate controls. Lastly, cocaine-mediated increases in locomotor activity was augmented acutely but not chronically in 12-LO-/- mice. Conclusions. Together, these results suggest a role for metabolites of arachidonic acid metabolism in morphine- and cocaine-induced behavioral responses and may reflect a utilization of this pathway following acute but not chronic drug administration.