TY - JOUR T1 - Signaling Cascades for Delta-opioid Receptor-mediated Inhibition of GABA Synaptic Transmission and Behavioral Antinociception JF - Molecular Pharmacology JO - Mol Pharmacol DO - 10.1124/mol.111.076307 SP - mol.111.076307 AU - Zhi Zhang AU - Zhizhong Z Pan Y1 - 2011/01/01 UR - http://molpharm.aspetjournals.org/content/early/2011/12/05/mol.111.076307.abstract N2 - Membrane trafficking of the delta-opioid receptor (DOR) from intracellular compartments to plasma membrane in central neurons, induced by various pathological conditions such as chronic opioid exposure, represents unique receptor plasticity involved in the mechanisms of chronic opioid effects in opioid addiction and opioid treatment of chronic pain. However, the signaling pathways coupled to the newly emerged functional DOR in central neurons are largely unknown at present. In this study, we investigated the signaling cascades of chronic morphine-induced DOR for its cellular and behavioral effects in neurons of the rat brainstem nucleus raphe magnus (NRM), a key supraspinal site for opioid analgesia. We found that, among the three phospholipase A2 (PLA2)-regulated arachidonic acid (AA) metabolic pathways of lipoxygenase, cyclooxygenase and epoxygenase, 12-lipoxygenase of the lipoxygenase pathway primarily mediated DOR inhibition of GABA synaptic transmission, as inhibitors of 12-lipoxygenase as well as lipoxygenases and PLA2 largely blocked the DOR- or AA-induced GABA inhibition in NRM neurons in brainstem slices in vitro. Blockade of the epoxygenase pathway was ineffective whereas blocking either 5-lipoxygenase of the lipoxygenase pathway or the cyclooxygenase pathway enhanced the DOR-mediated GABA inhibition. Behaviorally in rats in vivo, NRM infusion of 12-lipoxygenase inhibitors significantly reduced DOR-induced antinociceptive effect while inhibitors of 5-lipoxygenase and cyclooxygenase augmented the DOR antinociception. These findings suggest the PLA2-CAA-C12-lipoxygenase pathway as a primary signaling cascade for DOR-mediated analgesia through inhibition of GABA neurotransmission and indicate potential therapeutic benefits of combining 5-lipoxygenase and cyclooxygenase inhibitors for maximal pain inhibition. ER -