Shared mechanisms for opioid tolerance and a transition to chronic pain.
Clinical pain conditions may remain responsive to opiate analgesics for extended periods, but such persistent acute pain can undergo a transition to an opiate-resistant chronic pain state that becomes a much more serious clinical problem. To test the hypothesis that cellular mechanisms of chronic pain in the primary afferent also contribute to the development of opiate resistance, we used a recently developed model of the transition of from acute to chronic pain, hyperalgesic priming. Repeated intradermal administration of the potent and highly selective mu-opioid agonist, [d-Ala(2),N-MePhe(4),gly-ol]-enkephalin (DAMGO), to produce tolerance for its inhibition of prostaglandin E(2) hyperalgesia, simultaneously produced hyperalgesic priming. Conversely, injection of an inflammogen, carrageenan, used to produce priming produced DAMGO tolerance. Both effects were prevented by inhibition of protein kinase Cepsilon (PKCepsilon). Carrageenan also induced opioid dependence, manifest as mu-opioid receptor antagonist (d-Phe-Cys-Tyr-d-Trp-Orn-Thr-Pen-Thr-NH(2))-induced hyperalgesia that, like priming, was PKCepsilon and G(i) dependent. These findings suggest that the transition from acute to chronic pain, and development of mu-opioid receptor tolerance and dependence may be linked by common cellular mechanisms in the primary afferent.
Joseph
Elizabeth K
EK
Departments of Medicine and Oral Surgery, Division of Neuroscience, University of California, San Francisco, San Francisco, California 94143-0440, USA.
Reichling
David B
DB
Levine
Jon D
JD
D000208:Acute Disease; D000701:Analgesics, Opioid / Q000494:pharmacology; D000818:Animals; D002351:Carrageenan / Q000494:pharmacology; D002908:Chronic Disease; D004361:Drug Tolerance; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)- / Q000494:pharmacology; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000502:physiology; D019205:GTP-Binding Protein alpha Subunits, Gs / Q000502:physiology; D006930:Hyperalgesia / Q000209:etiology / Q000276:immunology / Q000503:physiopathology; D007249:Inflammation / Q000150:complications; D008297:Male; D009619:Nociceptors / Q000378:metabolism; D009293:Opioid-Related Disorders / Q000276:immunology / Q000503:physiopathology*; D010146:Pain / Q000209:etiology / Q000276:immunology / Q000503:physiopathology*; D051744:Protein Kinase C-epsilon / Q000037:antagonists & inhibitors / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017450:Receptors, Opioid, mu / Q000819:agonists / Q000037:antagonists & inhibitors; D015398:Signal Transduction; D013375:Substance Withdrawal Syndrome / Q000503:physiopathology
D000701:Analgesics, Opioid; D017450:Receptors, Opioid, mu; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D002351:Carrageenan; D051744:Protein Kinase C-epsilon; D019206:GTP-Binding Protein alpha Subunits, Gi-Go; D019205:GTP-Binding Protein alpha Subunits, Gs