Protein kinase a maintains cellular tolerance to mu opioid receptor agonists in hypothalamic neurosecretory cells with chronic morphine treatment: Convergence on a common pathway with estrogen in modulating mu opioid receptor/effector coupling

Edward J. Wagner, Oline Ronnekleiv, Martin Kelly

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Abstract

The present study examined protein kinase A (PKA) and protein kinase C (PKC) involvement in the maintenance of cellular tolerance to mu opioid receptor agonists resulting from chronic opiate exposure in neurosecretory cells of the hypothalamic arcuate nucleus (ARC). The possibility that the diminution of mu opioid receptor/effector coupling produced by acute 17β- estradiol or chronic opiate exposures is mediated by a common kinase pathway also was investigated. Intracellular recordings were made in hypothalamic slices prepared from ovariectomized female guinea pigs. The mu opioid receptor agonist D-Ala2, N-Me-Phe4, Gly-ol5-enkephalin (DAMGO) produced dose-dependent hyperpolarizations of ARC neurons. Chronic morphine treatment for 4 days reduced DAMGO potency 2.5-fold with no change in the maximal response. This effect was mimicked by a 20-min bath application of the PKA activator cAMP, Sp-isomer, or the PKC activator phorbol-12,13-dibutyrate. A 30-min bath application of the broad-spectrum protein kinase inhibitor staurosporine completely abolished the reduced DAMGO potency seen in morphine-tolerant neurosecretory cells, including those immunopositive for gonadotropin-releasing hormone. The effect of staurosporine was mimicked by the PKA inhibitor cAMP, Rp-isomer, but not by the PKC inhibitor calphostin C. Finally, a 20-min bath application of 17β-estradiol did not further reduce DAMGO potency in morphine-tolerant ARC neurons. Therefore, increased PKA activity maintains cellular tolerance to mu opioid receptor agonists in ARC neurosecretory cells caused by chronic morphine treatment. Furthermore, acute 17β-estradiol and chronic opiate treatments attenuate mu opioid receptor- mediated responses via a common PKA pathway.

Original languageEnglish (US)
Pages (from-to)1266-1273
Number of pages8
JournalJournal of Pharmacology and Experimental Therapeutics
Volume285
Issue number3
StatePublished - Jun 1998

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mu Opioid Receptor
Opiate Alkaloids
Cyclic AMP-Dependent Protein Kinases
Arcuate Nucleus of Hypothalamus
Protein Kinases
Morphine
Enkephalins
Estrogens
Protein Kinase Inhibitors
Baths
Protein Kinase C
Estradiol
Staurosporine
Phorbol 12,13-Dibutyrate
Therapeutics
Neurons
Protein C Inhibitor
Gonadotropin-Releasing Hormone
Guinea Pigs
Phosphotransferases

ASJC Scopus subject areas

  • Pharmacology

Cite this

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title = "Protein kinase a maintains cellular tolerance to mu opioid receptor agonists in hypothalamic neurosecretory cells with chronic morphine treatment: Convergence on a common pathway with estrogen in modulating mu opioid receptor/effector coupling",
abstract = "The present study examined protein kinase A (PKA) and protein kinase C (PKC) involvement in the maintenance of cellular tolerance to mu opioid receptor agonists resulting from chronic opiate exposure in neurosecretory cells of the hypothalamic arcuate nucleus (ARC). The possibility that the diminution of mu opioid receptor/effector coupling produced by acute 17β- estradiol or chronic opiate exposures is mediated by a common kinase pathway also was investigated. Intracellular recordings were made in hypothalamic slices prepared from ovariectomized female guinea pigs. The mu opioid receptor agonist D-Ala2, N-Me-Phe4, Gly-ol5-enkephalin (DAMGO) produced dose-dependent hyperpolarizations of ARC neurons. Chronic morphine treatment for 4 days reduced DAMGO potency 2.5-fold with no change in the maximal response. This effect was mimicked by a 20-min bath application of the PKA activator cAMP, Sp-isomer, or the PKC activator phorbol-12,13-dibutyrate. A 30-min bath application of the broad-spectrum protein kinase inhibitor staurosporine completely abolished the reduced DAMGO potency seen in morphine-tolerant neurosecretory cells, including those immunopositive for gonadotropin-releasing hormone. The effect of staurosporine was mimicked by the PKA inhibitor cAMP, Rp-isomer, but not by the PKC inhibitor calphostin C. Finally, a 20-min bath application of 17β-estradiol did not further reduce DAMGO potency in morphine-tolerant ARC neurons. Therefore, increased PKA activity maintains cellular tolerance to mu opioid receptor agonists in ARC neurosecretory cells caused by chronic morphine treatment. Furthermore, acute 17β-estradiol and chronic opiate treatments attenuate mu opioid receptor- mediated responses via a common PKA pathway.",
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T2 - Convergence on a common pathway with estrogen in modulating mu opioid receptor/effector coupling

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AU - Ronnekleiv, Oline

AU - Kelly, Martin

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