Abstract
Membrane trafficking of the δ-opioid receptor (DOR) from intracellular compartments to plasma membrane in central neurons, induced by various pathological conditions such as long-term opioid exposure, represents unique receptor plasticity involved in the mechanisms of long-term 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 long-term 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, because 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 whereas inhibitors of 5-lipoxygenase and cyclooxygenase augmented the DOR antinociception. These findings suggest the PLA2-AA-12-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.
Footnotes
This work was supported by the National Institutes of Health National Institute on Drug Abuse [Grants DA023069, DA027541].
Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org.
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ABBREVIATIONS:
- MOR
- μ-opioid receptor
- DOR
- δ-opioid receptor
- GPCR
- G protein-coupled receptor
- AA
- arachidonic acid
- PLA2
- phospholipase A2
- COX
- cyclooxygenase
- LOX
- lipoxygenase
- P450
- cytochrome P450
- NRM
- nucleus raphe magnus
- IPSC
- inhibitory postsynaptic current
- NDGA
- nordihydroguaiaretic acid
- AA-861
- 2-(12-hydroxydodeca-5,10-diynyl)-3,5,6-trimethyl-p-benzoquinone
- PD146176
- 11-dihydro[1]benzothiopyrano[4,3-b]indole
- mIPSC
- miniature inhibitory postsynaptic current
- HPETE
- hydroperoxyeicosatetraenoic acid
- HETE
- hydroxyeicosatetraenoic acids
- PKA
- protein kinase A
- DAMGO
- [d-Ala2,N-Me-Phe4,Gly5-ol]-enkephalin.
- Received October 10, 2011.
- Accepted December 5, 2011.
- Copyright © 2012 The American Society for Pharmacology and Experimental Therapeutics
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