Pharmacological modulation of leukotriene D4 attenuates the development of opioid dependence in a mouse model of naloxone-induced opioid withdrawal syndrome

The present study was designed to investigate the effect of montelukast sodium, a leukotriene D4 receptor antagonist, and 1,2,3,4,tetrahydroisoquinoline, a leukotriene D4 synthetic pathway inhibitor, on the development of morphine dependence in a mouse model of naloxone-induced opioid withdrawal syndrome. Morphine (5 mg/kg, i.p.) was administered twice daily for a period of 5 days following which a single injection of naloxone (8 mg/kg, i.p.) precipitated the opioid withdrawal syndrome in mice. Behavioral observations were made for a period of 30 min immediately after naloxone treatment. The withdrawal syndrome was quantitatively assessed in terms of withdrawal severity score and the frequency of jumping, rearing, fore paw licking and circling. Montelukast sodium as well as 1,2,3,4,tetrahydroisoquinoline, markedly and dose dependently (p < 0.01) attenuated the morphine-naloxone-induced opioid withdrawal syndrome in mice. However, administration of montelukast sodium or 1,2,3,4,tetrahydroisoquinoline did not alter the activity of the central nervous system, assessed in terms of locomotor activity count thus ruling out any per se sedative action of montelukast sodium. Further, pretreatment with montelukast sodium or 1,2,3,4,tetrahydroisoquinoline did not alter the acute analgesic effect of morphine. Thus, leukotriene D4 may be involved in the development of opioid dependence and the precipitation of its withdrawal syndrome and thus may serve as a viable pharmacological target to tackle the problem of opioid addiction.