Repeated Mu-Opioid Exposure Induces a Novel Form of the Hyperalgesic Priming Model for Transition to Chronic Pain.
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.
Departments of Medicine and Oral Surgery and Division of Neuroscience, University of California at San Francisco, San Francisco, California 94143.
Dioneia
http://orcid.org/0000-0001-8379-2901
D
Araldi
Departments of Medicine and Oral Surgery and Division of Neuroscience, University of California at San Francisco, San Francisco, California 94143.
Luiz F
LF
Ferrari
Departments of Medicine and Oral Surgery and Division of Neuroscience, University of California at San Francisco, San Francisco, California 94143 Jon.Levine@ucsf.edu.
Jon D
http://orcid.org/0000-0003-0681-5545
JD
Levine
D000701:Analgesics, Opioid / Q000494:pharmacology; D000818:Animals; D059350:Chronic Pain / Q000378:metabolism*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D015232:Dinoprostone / Q000378:metabolism; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)- / Q000494:pharmacology; D005260:Female; D006023:Glycoproteins / Q000378:metabolism; D006930:Hyperalgesia / Q000378:metabolism*; D037102:Lectins / Q000378:metabolism; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D017450:Receptors, Opioid, mu / Q000819:agonists / Q000378:metabolism*; D053675:Versicans
D000701:Analgesics, Opioid; D006023:Glycoproteins; D037102:Lectins; D017450:Receptors, Opioid, mu; C508324:Vcan protein, rat; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D053675:Versicans; D017868:Cyclic AMP-Dependent Protein Kinases; D015232:Dinoprostone
chronic pain; hyperalgesia; hyperalgesic priming; mu-opioid receptor; β/γ subunit