Spinal administration of lipoxygenase inhibitors suppresses behavioural and neurochemical manifestations of naloxone-precipitated opioid withdrawal.
1. 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. 2. 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. 3. Intrathecal administration of NDGA (10, 20 microg), a nonselective LOX inhibitor, AA-861 (1.5, 3 microg), a 5-LOX selective inhibitor, or baicalein (1.4, 2.8 microg), 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. 4. 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.
Trang
Tuan
T
Department of Pharmacology and Toxicology, Faculty of Health Sciences, Queen's University, 523 Botterell Hall, Kingston, Ont., Canada K7L 3N6.
Sutak
Maaja
M
Quirion
Remi
R
Jhamandas
Khem
K
D000818:Animals; D016227:Benzoquinones / Q000494:pharmacology; D015740:Calcitonin Gene-Related Peptide / Q000032:analysis*; D004305:Dose-Response Relationship, Drug; D044950:Flavanones; D005419:Flavonoids / Q000494:pharmacology; D007150:Immunohistochemistry; D007278:Injections, Spinal; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology*; D008297:Male; D009637:Masoprocol / Q000494:pharmacology; D009020:Morphine / Q000494:pharmacology; D009021:Morphine Dependence / Q000503:physiopathology / Q000517:prevention & control*; D009270:Naloxone / Q000494:pharmacology; D016760:Proto-Oncogene Proteins c-fos / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D013116:Spinal Cord / Q000737:chemistry / Q000187:drug effects*; D013375:Substance Withdrawal Syndrome / Q000503:physiopathology / Q000517:prevention & control*
D016227:Benzoquinones; D044950:Flavanones; D005419:Flavonoids; D016859:Lipoxygenase Inhibitors; D016760:Proto-Oncogene Proteins c-fos; D009270:Naloxone; C006680:baicalein; D009020:Morphine; D009637:Masoprocol; C036837:2,3,5-trimethyl-6-(12-hydroxy-5,10-dodecadiynyl)-1,4-benzoquinone; D015740:Calcitonin Gene-Related Peptide