Spinal administration of lipoxygenase inhibitors suppresses behavioural and neurochemical manifestations of naloxone‐precipitated opioid withdrawal

This study investigated the role of spinal lipoxygenase (LOX) products in the induction and expression of opioid physical dependence using behavioural assessment of withdrawal and immunostaining for CGRP and Fos protein expression in the spinal cord. Administration of escalating doses (5–50 mg kg −1 ; i.p.) of morphine for 5 days markedly elevated CGRP‐like immunoreactivity in the dorsal horn of the rat spinal cord. Naloxone (2 mg kg −1 ; i.p.) challenge precipitated a robust withdrawal syndrome that depleted CGRP‐like immunoreactivity and increased the number of Fos‐like immunoreactive neurons in the dorsal horn. Intrathecal administration of NDGA (10, 20 μ g), a nonselective LOX inhibitor, AA‐861 (1.5, 3 μ g), a 5‐LOX selective inhibitor, or baicalein (1.4, 2.8 μ g), a 12‐LOX selective inhibitor, concurrently with systemic morphine for 5 days or as a single injection immediately preceding naloxone challenge, blocked the depletion of CGRP‐like immunoreactivity, prevented increase in the number of Fos‐like immunoreactive neurons in the dorsal horn, and significantly attenuated the morphine withdrawal syndrome. The results of this study suggest that activity of LOX products, at the spinal level, contributes to the expression of opioid physical dependence, and that this activity may be expressed through increased sensory neuropeptide release.British Journal of Pharmacology (2003) 140 , 295–304. doi: 10.1038/sj.bjp.0705440