Repeated Mu-Opioid Exposure Induces a Novel Form of the Hyperalgesic Priming Model for Transition to Chronic Pain

Dioneia Araldi; Luiz F Ferrari; Jon D Levine

doi:10.1523/JNEUROSCI.1673-15.2015

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Repeated Mu-Opioid Exposure Induces a Novel Form of the Hyperalgesic Priming Model for Transition to Chronic Pain

Journal article

Peer reviewed

Repeated Mu-Opioid Exposure Induces a Novel Form of the Hyperalgesic Priming Model for Transition to Chronic Pain

Dioneia Araldi, Luiz F Ferrari and Jon D Levine

The Journal of neuroscience, Vol.35(36), pp.12502-12517

09/09/2015

DOI: 10.1523/JNEUROSCI.1673-15.2015

PMID: 26354917

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Abstract

The primary afferent nociceptor was used as a model system to study mechanisms of pain induced by chronic opioid administration. Repeated intradermal injection of the selective mu-opioid receptor (MOR) agonist DAMGO induced mechanical hyperalgesia and marked prolongation of prostaglandin E2 (PGE2) hyperalgesia, a key feature of hyperalgesic priming. However, in contrast to prior studies of priming induced by receptor-mediated (i.e., TNFα, NGF, or IL-6 receptor) or direct activation of protein kinase Cε (PKCε), the pronociceptive effects of PGE2 in DAMGO-treated rats demonstrated the following: (1) rapid induction (4 h compared with 3 d); (2) protein kinase A (PKA), rather than PKCε, dependence; (3) prolongation of hyperalgesia induced by an activator of PKA, 8-bromo cAMP; (4) failure to be reversed by a protein translation inhibitor; (5) priming in females as well as in males; and (6) lack of dependence on the isolectin B4-positive nociceptor. These studies demonstrate a novel form of hyperalgesic priming induced by repeated administration of an agonist at the Gi-protein-coupled MOR to the peripheral terminal of the nociceptor. Significance statement: The current study demonstrates the molecular mechanisms involved in the sensitization of nociceptors produced by repeated activation of mu-opioid receptors and contributes to our understanding of the painful condition observed in patients submitted to chronic use of opioids.

Analgesics, Opioid - pharmacology

Animals

Chronic Pain - metabolism

Cyclic AMP-Dependent Protein Kinases - metabolism

Dinoprostone - metabolism

Enkephalin, Ala-MePhe-Gly- - pharmacology

Female

Glycoproteins - metabolism

Hyperalgesia - metabolism

Lectins - metabolism

Male

Rats

Rats, Sprague-Dawley

Receptors, Opioid, mu - agonists

Receptors, Opioid, mu - metabolism

Details

Title: Subtitle: Repeated Mu-Opioid Exposure Induces a Novel Form of the Hyperalgesic Priming Model for Transition to Chronic Pain
Creators: Dioneia Araldi - University of California, San Francisco
Luiz F Ferrari - University of California, San Francisco
Jon D Levine - University of California, San Francisco
Resource Type: Journal article
Publication Details: The Journal of neuroscience, Vol.35(36), pp.12502-12517
DOI: 10.1523/JNEUROSCI.1673-15.2015
PMID: 26354917
ISSN: 0270-6474
eISSN: 1529-2401
Grant note: R01 NS084545 / NINDS NIH HHS NS084545 / NINDS NIH HHS
Language: English
Date published: 09/09/2015
Academic Unit: Neuroscience and Pharmacology
Record Identifier: 9985178664302771

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