Regulation of δ opioid receptor-mediated signaling and antinociception in peripheral sensory neurons by arachidonic acid-dependent 12/15-lipoxygenase metabolites

Laura C. Sullivan, Teresa A. Chavera, Xiaoli Gao, Miryam M. Pando, Kelly A Berg

Research output: Contribution to journalArticle

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Abstract

The function of δ opioid receptors (DOR) expressed by peripheral painsensing neurons (nociceptors) is regulated by both cyclooxygenaseand lipoxygenase (LOX)-dependent arachidonic acid (AA) metabolites. Whereas cyclooxygenase metabolites enhance responsiveness, LOX metabolites elicit a refractory, nonsignaling state of the DOR receptor system for antinociceptive signaling. In this study, using high-performance liquid chromatography-tandemmass spectrometry analyses, we have found that the 12-/15-LOX metabolites, 12-hydroxyeicosatetraenoic acid (HETE) and 15-HETE, were elevated after treatment of adult rat primary sensory neuron cultures with AA. Exogenously applied 12-HETE and 15-HETE, but not 5-HETE, completely prevented DOR and κ opioid receptor (KOR) agonist-mediated inhibition of prostaglandin E2 (PGE2)-stimulated cAMP accumulation, but not inhibition, by the 5-HT1 receptor agonist 5-carboxamidotryptamine in cultured peripheral sensory neurons and in Chinese hamster ovary (CHO) cells heterologously expressing DOR or KOR. Similarly, intraplantar injection of 12- or 15-HETE, either alone or in combination, prevented DOR agonistmediated inhibition of PGE2-evoked thermal allodynia. Further, both AA- and carrageenan-mediated induction of the nonresponsive state of theDORsystem was blocked by an intraplantar coinjection of the 12-/15-LOX inhibitors baicalein and luteolin. In contrast to the regulation of cAMP signaling, pretreatment with 12- and 15-HETE had no effect on either DOR or KOR agonist-mediated activation of extracellular signal-regulated kinase in peripheral sensory neurons or CHO cells. These results suggest that the analgesic efficacy of peripherally restricted opioids for treatment of inflammatory pain may be enhanced by adjunct inhibition of LOX activity.

Original languageEnglish (US)
Pages (from-to)200-209
Number of pages10
JournalJournal of Pharmacology and Experimental Therapeutics
Volume362
Issue number1
DOIs
StatePublished - Jul 1 2017

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Hydroxyeicosatetraenoic Acids
Opioid Receptors
Sensory Receptor Cells
Arachidonic Acid
Lipoxygenase Inhibitors
Lipoxygenase
Cricetulus
Dinoprostone
Ovary
Serotonin 5-HT1 Receptors
Arachidonate Lipoxygenases
Serotonin 5-HT1 Receptor Agonists
Luteolin
Nociceptors
Carrageenan
Hyperalgesia
Extracellular Signal-Regulated MAP Kinases
Prostaglandin-Endoperoxide Synthases
Opioid Analgesics
Analgesics

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

Cite this

Regulation of δ opioid receptor-mediated signaling and antinociception in peripheral sensory neurons by arachidonic acid-dependent 12/15-lipoxygenase metabolites. / Sullivan, Laura C.; Chavera, Teresa A.; Gao, Xiaoli; Pando, Miryam M.; Berg, Kelly A.

In: Journal of Pharmacology and Experimental Therapeutics, Vol. 362, No. 1, 01.07.2017, p. 200-209.

Research output: Contribution to journalArticle

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abstract = "The function of δ opioid receptors (DOR) expressed by peripheral painsensing neurons (nociceptors) is regulated by both cyclooxygenaseand lipoxygenase (LOX)-dependent arachidonic acid (AA) metabolites. Whereas cyclooxygenase metabolites enhance responsiveness, LOX metabolites elicit a refractory, nonsignaling state of the DOR receptor system for antinociceptive signaling. In this study, using high-performance liquid chromatography-tandemmass spectrometry analyses, we have found that the 12-/15-LOX metabolites, 12-hydroxyeicosatetraenoic acid (HETE) and 15-HETE, were elevated after treatment of adult rat primary sensory neuron cultures with AA. Exogenously applied 12-HETE and 15-HETE, but not 5-HETE, completely prevented DOR and κ opioid receptor (KOR) agonist-mediated inhibition of prostaglandin E2 (PGE2)-stimulated cAMP accumulation, but not inhibition, by the 5-HT1 receptor agonist 5-carboxamidotryptamine in cultured peripheral sensory neurons and in Chinese hamster ovary (CHO) cells heterologously expressing DOR or KOR. Similarly, intraplantar injection of 12- or 15-HETE, either alone or in combination, prevented DOR agonistmediated inhibition of PGE2-evoked thermal allodynia. Further, both AA- and carrageenan-mediated induction of the nonresponsive state of theDORsystem was blocked by an intraplantar coinjection of the 12-/15-LOX inhibitors baicalein and luteolin. In contrast to the regulation of cAMP signaling, pretreatment with 12- and 15-HETE had no effect on either DOR or KOR agonist-mediated activation of extracellular signal-regulated kinase in peripheral sensory neurons or CHO cells. These results suggest that the analgesic efficacy of peripherally restricted opioids for treatment of inflammatory pain may be enhanced by adjunct inhibition of LOX activity.",
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