Contribution of adenylyl cyclase modulation of pre- and postsynaptic GABA neurotransmission to morphine antinociception and tolerance

Erin N Bobeck; QiLiang Chen; Michael M Morgan; Susan L Ingram

doi:10.1038/npp.2014.62

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Contribution of adenylyl cyclase modulation of pre- and postsynaptic GABA neurotransmission to morphine antinociception and tolerance

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Contribution of adenylyl cyclase modulation of pre- and postsynaptic GABA neurotransmission to morphine antinociception and tolerance

Erin N Bobeck, QiLiang Chen, Michael M Morgan and Susan L Ingram

Neuropsychopharmacology (New York, N.Y.), Vol.39(9), pp.2142-2152

08/2014

DOI: https://doi.org/10.1038/npp.2014.62

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https://hdl.handle.net/2376/106002

PMCID: PMC4104331

PMID: 24622471

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Abstract

Enzyme Activators - pharmacology

Synaptic Transmission - physiology

gamma-Aminobutyric Acid - metabolism

Nociception - physiology

Analgesics, Opioid - pharmacology

Male

Miniature Postsynaptic Potentials - drug effects

Adenylyl Cyclase Inhibitors

Presynaptic Terminals - enzymology

Nociception - drug effects

Synaptic Transmission - drug effects

GABA-A Receptor Antagonists - pharmacology

Miniature Postsynaptic Potentials - physiology

Adenine - analogs & derivatives

Morphine - pharmacology

Presynaptic Terminals - drug effects

Colforsin - pharmacology

Drug Tolerance

Enzyme Inhibitors - pharmacology

Inhibitory Postsynaptic Potentials - physiology

Adenine - pharmacology

Adenylyl Cyclases - metabolism

Bicuculline - pharmacology

Rats, Sprague-Dawley

Animals

Receptors, GABA-A - metabolism

Inhibitory Postsynaptic Potentials - drug effects

Opioid inhibition of presynaptic GABA release in the ventrolateral periaqueductal gray (vlPAG) activates the descending antinociception pathway. Tolerance to repeated opioid administration is associated with upregulation of adenylyl cyclase activity. The objective of these studies was to test the hypothesis that adenylyl cyclase contributes to opioid tolerance by modulating GABA neurotransmission. Repeated microinjections of morphine or the adenylyl cyclase activator NKH477 into the vlPAG decreased morphine antinociception as would be expected with the development of tolerance. Conversely, microinjection of the adenylyl cyclase inhibitor SQ22536 reversed both the development and expression of morphine tolerance. These behavioral results indicate that morphine tolerance is dependent on adenylyl cyclase activation. Electrophysiological experiments revealed that acute activation of adenylyl cyclase with forskolin increased the frequency of presynaptic GABA release. However, recordings from rats treated with repeated morphine administration did not exhibit increased basal miniature inhibitory postsynaptic current (mIPSC) frequency but showed a decrease in mean amplitude of mIPSCs indicating that repeated morphine administration modulates postsynaptic GABAA receptors without affecting the probability of presynaptic GABA release. SQ22536 reversed this change in mIPSC amplitude and inhibited mIPSC frequency selectively in morphine tolerant rats. Repeated morphine or NKH477 administration also decreased antinociception induced by microinjection of the GABAA receptor antagonist bicuculline, further demonstrating changes in GABA neurotransmission with morphine tolerance. These results show that the upregulation of adenylyl cyclase caused by repeated vlPAG morphine administration produces antinociceptive tolerance by modulating both pre- and postsynaptic GABA neurotransmission.

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Title: Contribution of adenylyl cyclase modulation of pre- and postsynaptic GABA neurotransmission to morphine antinociception and tolerance
Creators: Erin N Bobeck - Department of Psychology, Washington State University, Vancouver, WA, USA
QiLiang Chen - Department of Neurological Surgery, Oregon Health & Science University, Portland, OR, USA
Michael M Morgan - Department of Psychology, Washington State University, Vancouver, WA, USA
Susan L Ingram - Department of Neurological Surgery, Oregon Health & Science University, Portland, OR, USA
Publication Details: Neuropsychopharmacology (New York, N.Y.), Vol.39(9), pp.2142-2152
Academic Unit: Psychology, Department of
Publisher: England
Grant note: DA027625 / NIDA NIH HHS R01 DA015498 / NIDA NIH HHS R01 DA027625 / NIDA NIH HHS DA015498 / NIDA NIH HHS
Identifiers: 99900546853801842
Language: English
Resource Type: Journal article